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Archive for the ‘Blindness’ Category


Familial transthyretin amyloid polyneuropathy

Curator: Larry H. Bernstein, MD, FCAP

LPBI

 

First-Ever Evidence that Patisiran Reduces Pathogenic, Misfolded TTR Monomers and Oligomers in FAP Patients

We reported data from our ongoing Phase 2 open-label extension (OLE) study of patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic polyneuropathy (FAP). Alnylam scientists and collaborators from The Scripps Research Institute and Misfolding Diagnostics, Inc. were able to measure the effects of patisiran on pathogenic, misfolded TTR monomers and oligomers in FAP patients. Results showed a rapid and sustained reduction in serum non-native conformations of TTR (NNTTR) of approximately 90%. Since NNTTR is pathogenic in ATTR amyloidosis and the level of NNTTR reduction correlated with total TTR knockdown, these results provide direct mechanistic evidence supporting the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. Furthermore, complete 12-month data from all 27 patients that enrolled in the patisiran Phase 2 OLE study showed sustained mean maximum reductions in total serum TTR of 91% for over 18 months and a mean 3.1-point decrease in mNIS+7 at 12 months, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics. Importantly, patisiran administration continues to be generally well tolerated out to 21 months of treatment.

Read our press release

View the non-native TTR poster (480 KB PDF)

View the complete 12-month patisiran Phase 2 OLE data presentation (620 KB PDF)

We are encouraged by these new data that provide continued support for our hypothesis that patisiran has the potential to halt neuropathy progression in patients with FAP. If these results are replicated in a randomized, double-blind, placebo-controlled study, we believe that patisiran could emerge as an important treatment option for patients suffering from this debilitating, progressive and life-threatening disease.

 

Hereditary ATTR Amyloidosis with Polyneuropathy (hATTR-PN)

ATTR amyloidosis is a progressive, life-threatening disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in multiple organs, but primarily in the peripheral nerves and heart. ATTR amyloidosis can lead to significant morbidity, disability, and mortality. The TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein – one of the vehicles used to transport vitamin A around the body.  Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils that typically contain both mutant and wild-type TTR that deposit in tissues such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.

Click to Enlarge

 

ATTR represents a major unmet medical need with significant morbidity and mortality. There are over 100 reported TTR mutations; the particular TTR mutation and the site of amyloid deposition determine the clinical manifestations of the disease whether it is predominantly symptoms of neuropathy or cardiomyopathy.

Specifically, hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease leading to death within 5 to 15 years. It is due to a mutation in the transthyretin (TTR) gene, which causes misfolded TTR proteins to accumulate as amyloid fibrils predominantly in peripheral nerves and other organs. hATTR-PN can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death.

It is estimated that hATTR-PN, also known as FAP, affects approximately 10,000 people worldwide.  Patients have a life expectancy of 5 to 15 years from symptom onset, and the only treatment options for early stage disease are liver transplantation and TTR stabilizers such as tafamidis (approved in Europe) and diflunisal.  Unfortunately liver transplantation has limitations, including limited organ availability as well as substantial morbidity and mortality. Furthermore, transplantation eliminates the production of mutant TTR but does not affect wild-type TTR, which can further deposit after transplantation, leading to cardiomyopathy and worsening of neuropathy. There is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

Our ATTR program is the lead effort in our Genetic Medicine Strategic Therapeutic Area (STAr) product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of rare diseases with high unmet medical need.  We are developing patisiran (ALN-TTR02), an intravenously administered RNAi therapeutic, to treat the hATTR-PN form of the disease.

Patisiran for the Treatment hATTR-PN

APOLLO Phase 3 Trial

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran and revusiran, for the treatment of ATTR amyloidosis in Japan and the broader Asian-Pacific region. In early 2014, this relationship was extended as a significantly broader alliance to advance RNAi therapeutics as genetic medicines. Under this new agreement, Alnylam will lead development and commercialization of patisiran in North America and Europe while Genzyme will develop and commercialize the product in the rest of world.

 

Hereditary ATTR Amyloidosis with Cardiomyopathy (hATTR-CM)

ATTR amyloidosis is a progressive, life-threatening disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in multiple organs, but primarily in the peripheral nerves and heart. ATTR amyloidosis can lead to significant morbidity, disability, and mortality. The TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein – one of the vehicles used to transport vitamin A around the body.  Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils that typically contain both mutant and wild-type TTR that deposit in tissues such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.

Click to Enlarge                            http://www.alnylam.com/web/assets/tetramer.jpg

ATTR represents a major unmet medical need with significant morbidity and mortality. There are over 100 reported TTR mutations; the particular TTR mutation and the site of amyloid deposition determine the clinical manifestations of the disease, whether it is predominantly symptoms of neuropathy or cardiomyopathy.

Specifically, hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM), also known as familial amyloidotic cardiomyopathy (FAC), is an inherited, progressive disease leading to death within 2 to 5 years. It is due to a mutation in the transthyretin (TTR) gene, which causes misfolded TTR proteins to accumulate as amyloid fibrils primarily in the heart. Hereditary ATTR amyloidosis with cardiomyopathy can result in heart failure and death.

While the exact numbers are not known, it is estimated hATTR-CM, also known as FAC affects at least 40,000 people worldwide.  hATTR-CM is fatal within 2 to 5 years of diagnosis and treatment is currently limited to supportive care.  Wild-type ATTR amyloidosis (wtATTR amyloidosis), also known as senile systemic amyloidosis, is a nonhereditary, progressive disease leading to death within 2 to 5 years. It is caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid fibrils in the heart. Wild-type ATTR amyloidosis can cause cardiomyopathy and result in heart failure and death. There are no approved therapies for the treatment of hATTR-CM or SSA; hence there is a significant unmet need for novel therapeutics to treat these patients.

Our ATTR program is the lead effort in our Genetic Medicine Strategic Therapeutic Area (STAr) product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of rare diseases with high unmet medical need.  We are developing revusiran (ALN-TTRsc), a subcutaneously administered RNAi therapeutic for the treatment of hATTR-CM.

Revusiran for the Treatment of hATTR-CM

ENDEAVOUR Phase 3 Trial

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran and revusiran, for the treatment of ATTR amyloidosis in Japan and the broader Asian-Pacific region. In early 2014, this relationship was extended as a broader alliance to advance RNAi therapeutics as genetic medicines. Under this new agreement, Alnylam and Genzyme have agreed to co-develop and co-commercialize revusiran in North America and Europe, with Genzyme developing and commercializing the product in the rest of world. This broadened relationship on revusiran is aimed at expanding and accelerating the product’s global value.

Pre-Clinical Data and Advancement of ALN-TTRsc02 for Transthyretin-Mediated Amyloidosis

We presented pre-clinical data with ALN-TTRsc02, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis).  In pre-clinical studies, including those in non-human primates (NHPs), ALN-TTRsc02 achieved potent and highly durable knockdown of serum TTR of up to 99% with multi-month durability achieved after just a single dose, supportive of a potentially once quarterly dose regimen. Results from studies comparing TTR knockdown activity of ALN-TTRsc02 to that of revusiran showed that ALN-TTRsc02 has a markedly superior TTR knockdown profile.  Further, in initial rat toxicology studies, ALN-TTRsc02 was found to be generally well tolerated with no significant adverse events at doses as high as 100 mg/kg.

Read our press release

View the presentation

http://www.alnylam.com/product-pipeline/hereditary-attr-amyloidosis-with-cardiomyopathy/

 

Emerging Therapies for Transthyretin Cardiac Amyloidosis Could Herald a New Era for the Treatment of HFPEF

Oct 14, 2015   |  Adam Castano, MDDavid Narotsky, MDMathew S. Maurer, MD, FACC

http://www.acc.org/latest-in-cardiology/articles/2015/10/13/08/35/emerging-therapies-for-transthyretin-cardiac-amyloidosis#sthash.9xzc0rIe.dpuf

Heart failure with a preserved ejection fraction (HFPEF) is a clinical syndrome that has no pharmacologic therapies approved for this use to date. In light of failed medicines, cardiologists have refocused treatment strategies based on the theory that HFPEF is a heterogeneous clinical syndrome with different etiologies. Classification of HFPEF according to etiologic subtype may, therefore, identify cohorts with treatable pathophysiologic mechanisms and may ultimately pave the way forward for developing meaningful HFPEF therapies.1

A wealth of data now indicates that amyloid infiltration is an important mechanism underlying HFPEF. Inherited mutations in transthyretin cardiac amyloidosis (ATTRm) or the aging process in wild-type disease (ATTRwt) cause destabilization of the transthyretin (TTR) protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure (Figure 1). In an autopsy study of HFPEF patients, almost 20% without antemortem suspicion of amyloid had left ventricular (LV) TTR amyloid deposition.2 Even more resounding evidence for the contribution of TTR amyloid to HFPEF was a study in which 120 hospitalized HFPEF patients with LV wall thickness ≥12 mm underwent technetium-99m 3,3-diphosphono-1,2-propranodicarboxylic acid (99mTc-DPD) cardiac imaging,3,4 a bone isotope known to have high sensitivity and specificity for diagnosing TTR cardiac amyloidosis.5,6 Moderate-to-severe myocardial uptake indicative of TTR cardiac amyloid deposition was detected in 13.3% of HFPEF patients who did not have TTR gene mutations. Therefore, TTR cardiac amyloid deposition, especially in older adults, is not rare, can be easily identified, and may contribute to the underlying pathophysiology of HFPEF.

Figure 1

As no U.S. Food and Drug Administration-approved drugs are currently available for the treatment of HFPEF or TTR cardiac amyloidosis, the development of medications that attenuate or prevent TTR-mediated organ toxicity has emerged as an important therapeutic goal. Over the past decade, a host of therapies and therapeutic drug classes have emerged in clinical trials (Table 1), and these may herald a new direction for treating HFPEF secondary to TTR amyloid.

Table 1

TTR Silencers (siRNA and Antisense Oligonucleotides)

siRNA

Ribonucleic acid interference (RNAi) has surfaced as an endogenous cellular mechanism for controlling gene expression. Small interfering RNAs (siRNAs) delivered into cells can disrupt the production of target proteins.7,8 A formulation of lipid nanoparticle and triantennary N-acetylgalactosamine (GalNAc) conjugate that delivers siRNAs to hepatocytes is currently in clinical trials.9 Prior research demonstrated these GalNAc-siRNA conjugates result in robust and durable knockdown of a variety of hepatocyte targets across multiple species and appear to be well suited for suppression of TTR gene expression and subsequent TTR protein production.

The TTR siRNA conjugated to GalNAc, ALN-TTRSc, is now under active investigation as a subcutaneous injection in phase 3 clinical trials in patients with TTR cardiac amyloidosis.10 Prior phase 2 results demonstrated that ALN-TTRSc was generally well tolerated in patients with significant TTR disease burden and that it reduced both wild-type and mutant TTR gene expression by a mean of 87%. Harnessing RNAi technology appears to hold great promise for treating patients with TTR cardiac amyloidosis. The ability of ALN-TTRSc to lower both wild-type and mutant proteins may provide a major advantage over liver transplantation, which affects the production of only mutant protein and is further limited by donor shortage, cost, and need for immunosuppression.

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are under clinical investigation for their ability to inhibit hepatic expression of amyloidogenic TTR protein. Currently, the ASO compound, ISIS-TTRRx, is under investigation in a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with familial amyloid polyneuropathy (FAP).11 The primary objective is to evaluate its efficacy as measured by change in neuropathy from baseline relative to placebo. Secondary measures will evaluate quality of life (QOL), modified body mass index (mBMI) by albumin, and pharmacodynamic effects on retinol binding protein. Exploratory objectives in a subset of patients with LV wall thickness ≥13 mm without a history of persistent hypertension will examine echocardiographic parameters, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and polyneuropathy disability score relative to placebo. These data will facilitate analysis of the effect of antisense oligonucleotide-mediated TTR suppression on the TTR cardiac phenotype with a phase 3 trial anticipated to begin enrollment in 2016.

TTR Stabilizers (Diflunisal, Tafamidis)

Diflunisal

Several TTR-stabilizing agents are in various stages of clinical trials. Diflunisal, a traditionally used and generically available nonsteroidal anti-inflammatory drug (NSAID), binds and stabilizes familial TTR variants against acid-mediated fibril formation in vitro and is now in human clinical trials.12,13 The use of diflunisal in patients with TTR cardiac amyloidosis is controversial given complication of chronic inhibition of cyclooxygenase (COX) enzymes, including gastrointestinal bleeding, renal dysfunction, fluid retention, and hypertension that may precipitate or exacerbate heart failure in vulnerable individuals.14-17 In TTR cardiac amyloidosis, an open-label cohort study suggested that low-dose diflunisal with careful monitoring along with a prophylactic proton pump inhibitor could be safely administered to compensated patients.18 An association was observed, however, between chronic diflunisal use and adverse changes in renal function suggesting that advanced kidney disease may be prohibitive in diflunisal therapy.In FAP patients with peripheral or autonomic neuropathy randomized to diflunisal or placebo, diflunisal slowed progression of neurologic impairment and preserved QOL over two years of follow-up.19 Echocardiography demonstrated cardiac involvement in approximately 50% of patients.20 Longer-term safety and efficacy data over an average 38 ± 31 months in 40 Japanese patients with hereditary ATTR amyloidosis who were not candidates for liver transplantation showed that diflunisal was mostly well tolerated.12 The authors cautioned the need for attentive monitoring of renal function and blood cell counts. Larger multicenter collaborations are needed to determine diflunisal’s true efficacy in HFPEF patients with TTR cardiac amyloidosis.

Tafamidis

Tafamidis is under active investigation as a novel compound that binds to the thyroxine-binding sites of the TTR tetramer, inhibiting its dissociation into monomers and blocking the rate-limiting step in the TTR amyloidogenesis cascade.21 The TTR compound was shown in an 18-month double-blind, placebo-controlled trial to slow progression of neurologic symptoms in patients with early-stage ATTRm due to the V30M mutation.22 When focusing on cardiomyopathy in a phase 2, open-label trial, tafamidis also appeared to effectively stabilize TTR tetramers in non-V30M variants, wild-type and V122I, as well as biochemical and echocardiographic parameters.23,24 Preliminary data suggests that clinically stabilized patients had shorter disease duration, lower cardiac biomarkers, less myocardial thickening, and higher EF than those who were not stabilized, suggesting early institution of therapy may be beneficial. A phase 3 trial has completed enrollment and will evaluate the efficacy, safety, and tolerability of tafamidis 20 or 80 mg orally vs. placebo.25 This will contribute to long-term safety and efficacy data needed to determine the therapeutic effects of tafamidis among ATTRm variants.

Amyloid Degraders (Doxycycline/TUDCA and Anti-SAP Antibodies)

Doxycycline/TUDCA

While silencer and stabilizer drugs are aimed at lowering amyloidogenic precursor protein production, they cannot remove already deposited fibrils in an infiltrated heart. Removal of already deposited fibrils by amyloid degraders would be an important therapeutic strategy, particularly in older adults with heavily infiltrated hearts reflected by thick walls, HFPEF, systolic heart failure, and restrictive cardiomyopathy. Combined doxycycline and tauroursodeoxycholic acid (TUDCA) disrupt TTR amyloid fibrils and appeared to have an acceptable safety profile in a small phase 2 open-label study among 20 TTR patients. No serious adverse reactions or clinical progression of cardiac or neuropathic involvement was observed over one year.26 An active phase 2, single-center, open-label, 12-month study will assess primary outcome measures including mBMI, neurologic impairment score, and NT-proBNP.27 Another phase 2 study is examining the tolerability and efficacy of doxycycline/TUDCA over an 18-month period in patients with TTR amyloid cardiomyopathy.28 Additionally, a study in patients with TTR amyloidosis is ongoing to determine the effect of doxycycline alone on neurologic function, cardiac biomarkers, echocardiographic parameters, modified body mass index, and autonomic neuropathy.29

Anti-SAP Antibodies

In order to safely clear established amyloid deposits, the role of the normal, nonfibrillar plasma glycoprotein present in all human amyloid deposits, serum amyloid P component (SAP), needs to be more clearly understood.30 In mice with amyloid AA type deposits, administration of antihuman SAP antibody triggered a potent giant cell reaction that removed massive visceral amyloid deposits without adverse effects.31 In humans with TTR cardiac amyloidosis, anti-SAP antibody treatments could be feasible because the bis-D proline compound, CPHPC, is capable of clearing circulating human SAP, which allow anti-SAP antibodies to reach residual deposited SAP. In a small, open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis, none of whom had clinical evidence of cardiac amyloidosis, were treated with CPHPC followed by human monoclonal IgG1 anti-SAP antibody.32 No serious adverse events were reported and amyloid deposits were cleared from the liver, kidney, and lymph node. Anti-SAP antibodies hold promise as a potential amyloid therapy because of their potential to target all forms of amyloid deposits across multiple tissue types.

Mutant or wild-type TTR cardiac amyloidoses are increasingly recognized as a cause of HFPEF. Clinicians need to be aware of this important HFPEF etiology because the diverse array of emerging disease-modifying agents for TTR cardiac amyloidosis in human clinical trials has the potential to herald a new era for the treatment of HFPEF.

References

  1. Maurer MS, Mancini D. HFpEF: is splitting into distinct phenotypes by comorbidities the pathway forward? J Am Coll Cardiol 2014;64:550-2.
  2. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113-22.
  3. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015.
  4. Castano A, Bokhari S, Maurer MS. Unveiling wild-type transthyretin cardiac amyloidosis as a significant and potentially modifiable cause of heart failure with preserved ejection fraction. Eur Heart J 2015 Jul 28. [Epub ahead of print]
  5. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120:1203-12.
  6. Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6:195-201.
  7. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998;391:806-11.
  8. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001;411:494-8.
  9. Kanasty R, Dorkin JR, Vegas A, Anderson D. Delivery materials for siRNA therapeutics. Nature Mater 2013;12:967-77.
  10. U.S. National Institutes of Health. Phase 2 Study to Evaluate ALN-TTRSC in Patients With Transthyretin (TTR) Cardiac Amyloidosis (ClinicalTrials.gov website). 2014. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01981837. Accessed 8/19/2015.
  11. U.S. National Institutes of Health. Efficacy and Safety of ISIS-TTRRx in Familial Amyloid Polyneuropathy (Clinical Trials.gov Website. 2013. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01737398. Accessed 8/19/2015.
  12. Sekijima Y, Dendle MA, Kelly JW. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 2006;13:236-49.
  13. Tojo K, Sekijima Y, Kelly JW, Ikeda S. Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neurosci Res 2006;56:441-9.
  14. Epstein M. Non-steroidal anti-inflammatory drugs and the continuum of renal dysfunction. J Hypertens Suppl 2002;20:S17-23.
  15. Wallace JL. Pathogenesis of NSAID-induced gastroduodenal mucosal injury. Best Pract Res Clin Gastroenterol 2001;15:691-703.
  16. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.
  17. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160:777-84.
  18. Castano A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail 2012;18:315-9.
  19. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013;310:2658-67.
  20. Quarta CCF, Solomon RH Suhr SD, et al. The prevalence of cardiac amyloidosis in familial amyloidotic polyneuropathy with predominant neuropathy: The Diflunisal Trial. International Symposium on Amyloidosis 2014:88-9.
  21. Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A 2002;99 Suppl 4:16427-32.
  22. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79:785-92.
  23. Merlini G, Plante-Bordeneuve V, Judge DP, et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res 2013;6:1011-20.
  24. Maurer MS, Grogan DR, Judge DP, et al. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ Heart Fail 2015;8:519-26.
  25. U.S. National Institutes of Health. Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy (ATTR-ACT) (ClinicalTrials.gov website). 2014. Available at: http://www.clinicaltrials.gov/show/NCT01994889. Accessed 8/19/2015.
  26. Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 2012;19 Suppl 1:34-6.
  27. U.S. National Institutes of Health. Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis (ClinicalTrials.gov website). 2011. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01171859. Accessed 8/19/2015.
  28. U.S. National Institutes of Health. Tolerability and Efficacy of a Combination of Doxycycline and TUDCA in Patients With Transthyretin Amyloid Cardiomyopathy (ClinicalTrials.gov website). 2013. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01855360. Accessed 8/19/2015.
  29. U.S. National Institutes of Health. Safety and Effect of Doxycycline in Patients With Amyloidosis (ClinicalTrials.gov website).2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01677286. Accessed 8/19/2015.
  30. Pepys MB, Dash AC. Isolation of amyloid P component (protein AP) from normal serum as a calcium-dependent binding protein. Lancet 1977;1:1029-31.
  31. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 2010;468:93-7.
  32. Richards DB, Cookson LM, Berges AC, et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med 2015;373:1106-14.

 

The Acid-Mediated Denaturation Pathway of Transthyretin Yields a Conformational Intermediate That Can Self-Assemble into Amyloid

Zhihong Lai , Wilfredo Colón , and Jeffery W. Kelly *
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255
Biochemistry199635 (20), pp 6470–6482   http://dx.doi.org:/10.1021/bi952501g
Publication Date (Web): May 21, 1996  Copyright © 1996 American Chemical Society

Transthyretin (TTR) amyloid fibril formation is observed during partial acid denaturation and while refolding acid-denatured TTR, implying that amyloid fibril formation results from the self-assembly of a conformational intermediate. The acid denaturation pathway of TTR has been studied in detail herein employing a variety of biophysical methods to characterize the intermediate(s) capable of amyloid fibril formation. At physiological concentrations, tetrameric TTR remains associated from pH 7 to pH 5 and is incapable of amyloid fibril formation. Tetrameric TTR dissociates to a monomer in a process that is dependent on both pH and protein concentration below pH 5. The extent of amyloid fibril formation correlates with the concentration of the TTR monomer having an altered, but defined, tertiary structure over the pH range of 5.0−3.9. The inherent Trp fluorescence-monitored denaturation curve of TTR exhibits a plateau over the pH range where amyloid fibril formation is observed (albeit at a higher concentration), implying that a steady-state concentration of the amyloidogenic intermediate with an altered tertiary structure is being detected. Interestingly, 1-anilino-8-naphthalenesulfonate fluorescence is at a minimum at the pH associated with maximal amyloid fibril formation (pH 4.4), implying that the amyloidogenic intermediate does not have a high extent of hydrophobic surface area exposed, consistent with a defined tertiary structure. Transthyretin has two Trp residues in its primary structure, Trp-41 and Trp-79, which are conveniently located far apart in the tertiary structure of TTR. Replacement of each Trp with Phe affords two single Trp containing variants which were used to probe local pH-dependent tertiary structural changes proximal to these chromophores. The pH-dependent fluorescence behavior of the Trp-79-Phe mutant strongly suggests that Trp-41 is located near the site of the tertiary structural rearrangement that occurs in the formation of the monomeric amyloidogenic intermediate, likely involving the C-strand−loop−D-strand region. Upon further acidification of TTR (below pH 4.4), the structurally defined monomeric amyloidogenic intermediate begins to adopt alternative conformations that are not amyloidogenic, ultimately forming an A-state conformation below pH 3 which is also not amyloidogenic. In summary, analytical equilibrium ultracentrifugation, SDS−PAGE, far- and near-UV CD, fluorescence, and light scattering studies suggest that the amyloidogenic intermediate is a monomeric predominantly β-sheet structure having a well-defined tertiary structure.

 

Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics

Per Hammarström*, R. Luke Wiseman*, Evan T. Powers, Jeffery W. Kelly   + Author Affiliations

Science  31 Jan 2003; 299(5607):713-716   http://dx.doi.org:/10.1126/science.1079589

Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 → methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.

 

Rational design of potent human transthyretin amyloid disease inhibitors

Thomas Klabunde1,2, H. Michael Petrassi3, Vibha B. Oza3, Prakash Raman3, Jeffery W. Kelly3 & James C. Sacchettini1

Nature Structural & Molecular Biology 2000; 7: 312 – 321.                http://dx.doi.org:/10.1038/74082

The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein–drug complexes have been determined to allow detailed analyses of the protein–drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4,6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.

 

First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy

Adams, Davida; Suhr, Ole B.b; Hund, Ernstc; Obici, Laurad; Tournev, Ivailoe,f; Campistol, Josep M.g; Slama, Michel S.h; Hazenberg, Bouke P.i; Coelho, Teresaj; from the European Network for TTR-FAP (ATTReuNET)

Current Opin Neurol: Feb 2016; 29 – Issue – p S14–S26      http://dx.doi.org:/10.1097/WCO.0000000000000289

Purpose of review: Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe.

Recent findings: The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes.

Summary: This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient’s treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP.

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Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly debilitating and irreversible neurological disorder presenting symptoms of progressive sensorimotor and autonomic neuropathy [1▪,2▪,3]. TTR-FAP is caused by misfolding of the transthyretin (TTR) protein leading to protein aggregation and the formation of amyloid fibrils and, ultimately, to amyloidosis (commonly in the peripheral and autonomic nervous system and the heart) [4,5]. TTR-FAP usually proves fatal within 7–12 years from the onset of symptoms, most often due to cardiac dysfunction, infection, or cachexia [6,7▪▪].

The prevalence and disease presentation of TTR-FAP vary widely within Europe. In endemic regions (northern Portugal, Sweden, Cyprus, and Majorca), patients tend to present with a distinct genotype in large concentrations, predominantly a Val30Met substitution in the TTR gene [8–10]. In other areas of Europe, the genetic footprint of TTR-FAP is more varied, with less typical phenotypic expression [6,11]. For these sporadic or scattered cases, a lack of awareness among physicians of variable clinical features and limited access to diagnostic tools (i.e., pathological studies and genetic screening) can contribute to high rates of misdiagnosis and poorer patient outcomes [1▪,11]. In general, early and late-onset variants of TTR-FAP, found within endemic and nonendemic regions, present several additional diagnostic challenges [11,12,13▪,14].

Delay in the time to diagnosis is a major obstacle to the optimal management of TTR-FAP. With the exception of those with a clearly diagnosed familial history of FAP, patients still invariably wait several years between the emergence of first clinical signs and accurate diagnosis [6,11,14]. The timely initiation of appropriate treatment is particularly pertinent, given the rapidity and irreversibility with which TTR-FAP can progress if left unchecked, as well as the limited effectiveness of available treatments during the later stages of the disease [14]. This review aims to consolidate the existing literature and present an update of the best practices in the management of TTR-FAP in Europe. A summary of the methods used to achieve a TTR-FAP diagnosis is presented, as well as a review of available treatments and recommendations for treatment according to disease status.

Patients with TTR-FAP can present with a range of symptoms [11], and care should be taken to acquire a thorough clinical history of the patient as well as a family history of genetic disease. Delay in diagnosis is most pronounced in areas where TTR-FAP is not endemic or when there is no positive family history [1▪]. TTR-FAP and TTR-familial amyloid cardiomyopathy (TTR-FAC) are the two prototypic clinical disease manifestations of a broader disease spectrum caused by an underlying hereditary ATTR amyloidosis [19]. In TTR-FAP, the disease manifestation of neuropathy is most prominent and definitive for diagnosis, whereas cardiomyopathy often suggests TTR-FAC. However, this distinction is often superficial because cardiomyopathy, autonomic neuropathy, vitreous opacities, kidney disease, and meningeal involvement all may be present with varying severity for each patient with TTR-FAP.

Among early onset TTR-FAP with usually positive family history, symptoms of polyneuropathy present early in the disease process and usually predominate throughout the progression of the disease, making neurological testing an important diagnostic aid [14]. Careful clinical examination (e.g., electromyography with nerve conduction studies and sympathetic skin response, quantitative sensation test, quantitative autonomic test) can be used to detect, characterize, and scale the severity of neuropathic abnormalities involving small and large nerve fibres [10]. Although a patient cannot be diagnosed definitively with TTR-FAP on the basis of clinical presentation alone, symptoms suggesting the early signs of peripheral neuropathy, autonomic dysfunction, and cardiac conduction disorders or infiltrative cardiomyopathy are all indicators that further TTR-FAP diagnostic investigation is warranted. Late-onset TTR-FAP often presents as sporadic cases with distinct clinical features (e.g., milder autonomic dysfunction) and can be more difficult to diagnose than early-onset TTR-FAP (Table 2) [1▪,11,12,13▪,14,20].

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Genetic testing is carried out to allow detection of specific amyloidogenic TTR mutations (Table 1), using varied techniques depending on the expertise and facilities available in each country (Table S2, http://links.lww.com/CONR/A39). A targeted approach to detect a specific mutation can be used for cases belonging to families with previous diagnosis. In index cases of either endemic and nonendemic regions that do not have a family history of disease, are difficult to confirm, and have atypical symptoms, TTR gene sequencing is required for the detection of both predicted and new amyloidogenic mutations [26,27].

Following diagnosis, the neuropathy stage and systemic extension of the disease should be determined in order to guide the next course of treatment (Table 4) [3,30,31]. The three stages of TTR-FAP severity are graded according to a patient’s walking disability and degree of assistance required [30]. Systemic assessment, especially of the heart, eyes, and kidney, is also essential to ensure all aspects of potential impact of the disease can be detected [10].

Table 4

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The goals of cardiac investigations are to detect serious conduction disorders with the risk of sudden death and infiltrative cardiomyopathy. Electrocardiograms (ECG), Holter-ECG, and intracardiac electrophysiology study are helpful to detect conduction disorders. Echocardiograms, cardiac magnetic resonance imaging, scintigraphy with bone tracers, and biomarkers (e.g., brain natriuretic peptide, troponin) can all help to diagnose infiltrative cardiomyopathy[10]. An early detection of cardiac abnormalities has obvious benefits to the patient, given that the prophylactic implantation of pacemakers was found to prevent 25% of major cardiac events in TTR-FAP patients followed up over an average of 4 years [32▪▪]. Assessment of cardiac denervation with 123-iodine meta-iodobenzylguanidine is a powerful prognostic marker in patients diagnosed with FAP [33].

…..

Tafamidis

Tafamidis is a first-in-class therapy that slows the progression of TTR amyloidogenesis by stabilizing the mutant TTR tetramer, thereby preventing its dissociation into monomers and amyloidogenic and toxic intermediates [55,56]. Tafamidis is currently indicated in Europe for the treatment of TTR amyloidosis in adult patients with stage I symptomatic polyneuropathy to delay peripheral neurological impairment [57].

In an 18-month, double-blind, placebo-controlled study of patients with early-onset Val30Met TTR-FAP, tafamidis was associated with a 52% lower reduction in neurological deterioration (P = 0.027), a preservation of nerve function, and TTR stabilization versus placebo [58▪▪]. However, only numerical differences were found for the coprimary endpoints of neuropathy impairment [neuropathy impairment score in the lower limb (NIS-LL) responder rates of 45.3% tafamidis vs 29.5% placebo; P = 0.068] and quality of life scores [58▪▪]. A 12-month, open-label extension study showed that the reduced rates of neurological deterioration associated with tafamidis were sustained over 30 months, with earlier initiation of tafamidis linking to better patient outcomes (P = 0.0435) [59▪]. The disease-slowing effects of tafamidis may be dependent on the early initiation of treatment. In an open-label study with Val30Met TTR-FAP patients with late-onset and advanced disease (NIS-LL score >10, mean age 56.4 years), NIS-LL and disability scores showed disease progression despite 12 months of treatment with tafamidis, marked by a worsening of neuropathy stage in 20% and the onset of orthostatic hypotension in 22% of patients at follow-up [60▪].

Tafamidis is not only effective in patients exhibiting the Val30Met mutation; it also has proven efficacy, in terms of TTR stabilization, in non-Val30Met patients over 12 months [61]. Although tafamidis has demonstrated safe use in patients with TTR-FAP, care should be exercised when prescribing to those with existing digestive problems (e.g., diarrhoea, faecal incontinence) [60▪].

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Diflunisal

Diflunisal is a nonsteroidal anti-inflammatory drug (NSAID) that, similar to tafamidis, slows the rate of amyloidogenesis by preventing the dissociation, misfolding, and misassembly of the mutated TTR tetramer [62,63]. Off-label use has been reported for patients with stage I and II disease, although diflunisal is not currently licensed for the treatment of TTR-FAP.

Evidence for the clinical effectiveness of diflunisal in TTR-FAP derives from a placebo-controlled, double-blind, 24-month study in 130 patients with clinically detectable peripheral or autonomic neuropathy[64▪]. The deterioration in NIS scores was significantly more pronounced in patients receiving placebo compared with those taking diflunisal (P = 0.001), and physical quality of life measures showed significant improvement among diflunisal-treated patients (P = 0.001). Notable during this study was the high rate of attrition in the placebo group, with 50% more placebo-treated patients dropping out of this 2-year study as a result of disease progression, advanced stage of the disease, and varied mutations.

One retrospective analysis of off-label use of diflunisal in patients with TTR-FAP reported treatment discontinuation in 57% of patients because of adverse events that were largely gastrointestinal [65]. Conclusions on the safety of diflunisal in TTR-FAP will depend on further investigations on the impact of known cardiovascular and renal side-effects associated with the NSAID drug class [66,67].

 

 

 

 

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Roche’s Avastin is 1/30th of the the price of Novartis’ Lucentis:  off-label treat wet age-related macular degeneration (AMD) – FDA has not approved it for that use

Reporter: Aviva Lev-Ari, PhD, RN

 

Off-label use of Avastin in India hospitalizes 15, sales halted in two states

 

The main rationale for using Avastin instead of Lucentis in patients with wet AMD is to save money. Both Avastin and Lucentis’ mechanism of action involves inhibition of vascular endothelial growth factor (VEGF). VEGF inhibitors reduce the growth of new blood vessels, including in the eyes, thereby decreasing growth of abnormal blood vessels in the central retina of patients with AMD.

The FDA has not approved Avastin for AMD treatment, nor does Roche recommend its off-label use.

Last September, France irked the pharma industry when its pharmaceuticals regulator put a law into effect allowing Avastin to be used to treat AMD. Avastin is considerably cheaper (1/30th of the cost) than Novartis’ Lucentis and other drugs indicated for treatment of AMD.

However, Avastin has not been tested for ophthalmic applications. In response to the situation in India, Roche noted using Avastin off-label risks contamination, as reported by Reuters.

As for Novartis, in November 2015, the Swiss company clarified its position on the Avastin versus Lucentis issue. According to a release from Novartis:

  • Lucentis and Avastin are different molecules with distinct molecular and pharmacological profiles and are manufactured to different standards.
  • Only Lucentis was developed for and is approved by regulatory authorities for use in the eye.
  • Avastin is approved and manufactured for intravenous use in cancer patients.

The situation in India was serious enough to warrant surgery for all 15 patients. A week later, six of these patients are still in the hospital. Regulators in India are testing the Avastin used to see if it was a counterfeit version of Avastin.

SOURCE

http://www.biopharmadive.com/news/off-label-use-of-avastin-in-india-hospitalizes-15-sales-halted-in-two-stat/412349/

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Rhodopsin role in ciliary trafficking

Jillian N Pearring
Department of Ophthalmology, Duke University School of Medicine, Durham, United States
No competing interests declared

” data-author-inst=”DukeUniversitySchoolofMedicineUnitedStates”>Jillian N Pearring

William J Spencer
Department of Ophthalmology, Duke University School of Medicine, Durham, United States
No competing interests declared

” data-author-inst=”DukeUniversitySchoolofMedicineUnitedStates”>William J Spencer

Eric C Lieu
Department of Ophthalmology, Duke University School of Medicine, Durham, United States
No competing interests declared

” data-author-inst=”DukeUniversitySchoolofMedicineUnitedStates”>Eric C Lieu, 

Vadim Y Arshavsky
Department of Ophthalmology, Duke University School of Medicine, Durham, United States
For correspondence: vadim.arshavsky@duke.edu
No competing interests declared

” data-author-inst=”DukeUniversitySchoolofMedicineUnitedStates”>Vadim Y Arshavsky
eLife 2015;10.7554/eLife.12058   http://dx.doi.org/10.7554/eLife.12058

Sensory cilia are populated by a select group of signaling proteins that detect environmental stimuli. How these molecules are delivered to the sensory cilium and whether they rely on one another for specific transport remains poorly understood. Here, we investigated whether the visual pigment, rhodopsin, is critical for delivering other signaling proteins to the sensory cilium of photoreceptor cells, the outer segment. Rhodopsin is the most abundant outer segment protein and its proper transport is essential for formation of this organelle, suggesting that such a dependency might exist. Indeed, we demonstrated that guanylate cyclase-1, producing the cGMP second messenger in photoreceptors, requires rhodopsin for intracellular stability and outer segment delivery. We elucidated this dependency by showing that guanylate cyclase-1 is a novel rhodopsin-binding protein. These findings expand rhodopsin’s role in vision from being a visual pigment and major outer segment building block to directing trafficking of another key signaling protein.

 

Photoreceptor cells transform information entering the eye as photons into patterns of neuronal electrical activity. This transformation takes place in the sensory cilium organelle, the outer segment. Outer segments are built from a relatively small set of structural and signaling proteins, including components of the classical GPCR phototransduction cascade. Such a distinct functional and morphological specialization allow outer segments to serve as a nearly unmatched model system for studying general principles of GPCR signaling (Arshavsky et al., 2002) and, in more recent years, a model for ciliary trafficking (Garcia-Gonzalo and Reiter, 2012; Nemet et al., 2015; Pearring et al., 2013; Schou et al., 2015; Wang and Deretic, 2014). Despite our deep understanding of visual signal transduction, little is known how the outer segment is populated by proteins performing this function. Indeed, nearly all mechanistic studies of outer segment protein trafficking were devoted to rhodopsin (Nemet et al., 2015; Wang and Deretic, 2014), which is a GPCR visual pigment comprising the majority of the outer segment membrane protein mass (Palczewski, 2006). The mechanisms responsible for outer segment delivery of other transmembrane proteins remain essentially unknown. Some of them contain short outer segment targeting signals, which can be identified through site-specific mutagenesis (Deretic et al., 1998; Li et al., 1996; Pearring et al., 2014; Salinas et al., 2013; Sung et al., 1994; Tam et al., 2000; Tam et al., 2004). A documented exception is retinal guanylate cyclase 1 (GC-1), whose exhaustive mutagenesis did not yield a distinct outer segment targeting motif (Karan et al., 2011).

GC-1 is a critical component of the phototransduction machinery responsible for synthesizing the second messenger, cGMP (Wen et al., 2014). GC-1 is the only guanylate cyclase isoform expressed in the outer segments of cones and the predominant isoform in rods (Baehr et al., 2007; Yang et al., 1999). GC-1 knockout in mice is characterized by severe degeneration of cones and abnormal light-response recovery kinetics in rods (Yang et al., 1999). Furthermore, a very large number of GC-1 mutations found in human patients cause one of the most severe forms of early onset retinal dystrophy, called Leber’s congenital amaurosis (Boye, 2014; Kitiratschky et al., 2008). Many of these mutations are located outside the catalytic site of GC-1, which raises great interest to understanding the mechanisms of its intracellular processing and trafficking.

In this study, we demonstrate that, rather than relying on its own targeting motif, GC-1 is transported to the outer segment in a complex with rhodopsin. We conducted a comprehensive screen of outer segment protein localization in rod photoreceptors of rhodopsin knockout (Rho-/- ) mice and found that GC-1 was the only protein severely affected by this knockout. We next showed that this unique property of GC-1 is explained by its interaction with rhodopsin, which likely initiates in the biosynthetic membranes and supports both intracellular stability and outer segment delivery of this enzyme. These findings explain how GC-1 reaches its specific intracellular destination and also expand the role of rhodopsin in supporting normal vision by showing that it guides trafficking of another key phototransduction protein.

 

GC-1 is the outer segment-resident protein severely down-regulated in rhodopsin knockout rods

GC-1 stability and trafficking require the transmembrane core of rhodopsin but not its outer 119 segment targeting domain

GC-1 is a rhodopsin-interacting protein

 

The findings reported in this study expand our understanding of how the photoreceptor’s sensory cilium is populated by its specific membrane proteins. We have found that rhodopsin serves as an interacting partner and a vehicle for ciliary delivery of a key phototransduction protein, GC-1. This previously unknown function adds to the well-established roles of rhodopsin as a GPCR visual pigment and a major building block of photoreceptor membranes. We further showed that GC-1 is unique in its reliance on rhodopsin, as the other nine proteins tested in this study were expressed in significant amounts and faithfully localized to rod outer segments in the absence of rhodopsin.

Our data consolidate a number of previously published observations, including a major puzzle related to GC-1: the lack of a distinct ciliary targeting motif encoded in its sequence. The shortest recombinant fragment of GC-1 which localized specifically to the outer segment was found to be very large and contain both transmembrane and cytoplasmic domains (Karan et al., 2011). Our study shows that GC-1 delivery requires rhodopsin and, therefore, can rely on specific targeting information encoded in the rhodopsin molecule. Interestingly, we also found that this information can be replaced by an alternative ciliary targeting sequence from a GPCR not endogenous to photoreceptors. This suggests that the functions of binding/stabilization of GC-1 and ciliary targeting are performed by different parts of the rhodopsin molecule. Our findings also shed new light on the report that both rhodopsin and GC-1 utilize intraflagellar transport (IFT) for their ciliary trafficking and co-precipitate with IFT proteins (Bhowmick et al., 2009). The authors hypothesized that GC-1 plays a primary role in assembling cargo for the IFT particle bound for ciliary delivery. Our data suggest that it is rhodopsin that drives this complex, at least in photoreceptor cells where these proteins are specifically expressed. Unlike GC-1’s reliance on rhodopsin for its intracellular stability or outer segment trafficking, rhodopsin does not require GC-1 as its expression level and localization remain normal in rods of GC-1 knockout mice ((Baehr et al., 2007) and this study). The outer segment trafficking of cone opsins is not affected by the lack of GC-1 either (Baehr et al., 2007; Karan et al., 2008), although GC-1 knockout cones undergo rapid degeneration, likely because they do not express GC-2 – an enzyme with redundant function. The primary role of rhodopsin in guiding GC-1 to the outer segment is further consistent with rhodopsin directly interacting with IFT20, a mobile component of the IFT complex responsible for recruiting IFT cargo at the Golgi network (Crouse et al., 2014; Keady et al., 2011).

It was also reported that GC-1 trafficking requires participation of chaperone proteins, most importantly DnaJB6 (Bhowmick et al., 2009). Our data suggest that GC-1 interaction with DnaJB6 is transient, most likely in route to the outer segment, since we were not able to co-precipitate DnaJB6 with GC-1 from whole retina lysates (Figure 5). In contrast, the majority of GC-1 co-precipitates with rhodopsin from these same lysates, suggesting that these proteins remain in a complex after being delivered to the outer segment. Although our data do not exclude that the mature GC-1-rhodopsin complex may contain additional protein component(s), our attempts to identify such components by mass spectrometry have not yielded potential candidates.

Interestingly, GC-1 was previously shown to stably express in cell culture where it localizes to either ciliary or intracellular membranes (Bhowmick et al., 2009; Peshenko et al., 2015). This strikes at the difference between the composition of cellular components supporting membrane protein stabilization and transport in cell culture models versus functional photoreceptors. The goal of future experiments is to determine whether these protein localization patterns would be affected by co-expressing GC-1 with rhodopsin, thereby gaining further insight into the underlying intracellular trafficking mechanisms.

Finally, GC-1 trafficking was reported to depend on the small protein, RD3, thought to stabilize both guanylate cyclase isoforms, GC-1 and GC-2, in biosynthetic membranes (Azadi et al., 2010; Zulliger et al., 2015). In the case of GC-1, this stabilization would be complementary to that by rhodopsin and potentially could take place at different stages of GC-1 maturation and trafficking in photoreceptors. Another proposed function of RD3 is to inhibit the activity of guanylate cyclase isoforms outside the outer segment in order to prevent undesirable cGMP synthesis in other cellular compartments (Peshenko et al., 2011a).

In summary, this study explains how GC-1 reaches its intracellular destination without containing a dedicated targeting motif, expands our understanding of the role of rhodopsin in photoreceptor biology and extends the diversity of signaling proteins found in GPCR complexes to a member of the guanylate cyclase family. Provided that the cilium is a critical site of GPCR signaling in numerous cell types (Schou et al., 2015), it would be interesting to learn whether other ciliary GPCRs share rhodopsin’s ability to stabilize and deliver fellow members of their signaling pathways

 

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Disease Disablers


Disease Disablers

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Gene Hackers 

A powerful new technology enables us to manipulate our DNA more easily than ever before.

BY

Annals of Science NOVEMBER 16, 2015 ISSUE

http://www.newyorker.com/magazine/2015/11/16/the-gene-hackers

 

CRISPR’s unprecedented ability to edit genetic code will make possible a new generation of medical treatments.

 

At thirty-four, Feng Zhang is the youngest member of the core faculty at the Broad Institute of Harvard and M.I.T. He is also among the most accomplished. In 1999, while still a high-school student, in Des Moines, Zhang found a structural protein capable of preventing retroviruses like H.I.V. from infecting human cells. The project earned him third place in the Intel Science Talent Search, and he applied the fifty thousand dollars in prize money toward tuition at Harvard, where he studied chemistry and physics. By the time he received his doctorate, from Stanford, in 2009, he had shifted gears, helping to create optogenetics, a powerful new discipline that enables scientists to use light to study the behavior of individual neurons.

Zhang decided to become a biological engineer, forging tools to repair the broken genes that are responsible for many of humanity’s most intractable afflictions. The following year, he returned to Harvard, as a member of the Society of Fellows, and became the first scientist to use a modular set of proteins, called TALEs, to control the genes of a mammal. “Imagine being able to manipulate a specific region of DNA . . . almost as easily as correcting a typo,” one molecular biologist wrote, referring to TALEs, which stands for transcription activator-like effectors. He concluded that although such an advance “will probably never happen,” the new technology was as close as scientists might get.
Having already helped assemble two critical constituents of the genetic toolbox used in thousands of labs throughout the world, Zhang was invited, at the age of twenty-nine, to create his own research team at the Broad. One day soon after his arrival, he attended a meeting during which one of his colleagues mentioned that he had encountered a curious region of DNA in some bacteria he had been studying. He referred to it as a CRISPR sequence.

“I had never heard that word,” Zhang told me recently as we sat in his office, which looks out across the Charles River and Beacon Hill. Zhang has a perfectly round face, its shape accentuated by rectangular wire-rimmed glasses and a bowl cut. “So I went to Google just to see what was there,” he said. Zhang read every paper he could; five years later, he still seemed surprised by what he found. CRISPR, he learned, was a strange cluster of DNA sequences that could recognize invading viruses, deploy a special enzyme to chop them into pieces, and use the viral shards that remained to form a rudimentary immune system. The sequences, identical strings of nucleotides that could be read the same way backward and forward, looked like Morse code, a series of dashes punctuated by an occasional dot. The system had an awkward name—clustered regularly interspaced short palindromic repeats—but a memorable acronym.

CRISPR has two components. The first is essentially a cellular scalpel that cuts DNA. The other consists of RNA, the molecule most often used to transmit biological information throughout the genome. It serves as a guide, leading the scalpel on a search past thousands of genes until it finds and fixes itself to the precise string of nucleotides it needs to cut. It has been clear at least since Louis Pasteur did some of his earliest experiments into the germ theory of disease, in the nineteenth century, that the immune systems of humans and other vertebrates are capable of adapting to new threats. But few scientists had considered the possibility that single bacterial cells could defend themselves in the same way. The day after Zhang heard about CRISPR, he flew to Florida for a genetics conference. Rather than attend the meetings, however, he stayed in his hotel room and kept Googling. “I just sat there reading every paper on CRISPR I could find,” he said. “The more I read, the harder it was to contain my excitement.”

It didn’t take Zhang or other scientists long to realize that, if nature could turn these molecules into the genetic equivalent of a global positioning system, so could we. Researchers soon learned how to create synthetic versions of the RNA guides and program them to deliver their cargo to virtually any cell. Once the enzyme locks onto the matching DNA sequence, it can cut and paste nucleotides with the precision we have come to expect from the search-and-replace function of a word processor. “This was a finding of mind-boggling importance,” Zhang told me. “And it set off a cascade of experiments that have transformed genetic research.”

With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system.
The potential impact of CRISPR on the biosphere is equally profound. Last year, by deleting all three copies of a single wheat gene, a team led by the Chinese geneticist Gao Caixia created a strain that is fully resistant to powdery mildew, one of the world’s most pervasive blights. In September, Japanese scientists used the technique to prolong the life of tomatoes by turning off genes that control how quickly they ripen. Agricultural researchers hope that such an approach to enhancing crops will prove far less controversial than using genetically modified organisms, a process that requires technicians to introduce foreign DNA into the genes of many of the foods we eat.

The technology has also made it possible to study complicated illnesses in an entirely new way. A few well-known disorders, such as Huntington’s disease and sickle-cell anemia, are caused by defects in a single gene. But most devastating illnesses, among them diabetes, autism, Alzheimer’s, and cancer, are almost always the result of a constantly shifting dynamic that can include hundreds of genes. The best way to understand those connections has been to test them in animal models, a process of trial and error that can take years. CRISPR promises to make that process easier, more accurate, and exponentially faster.

Inevitably, the technology will also permit scientists to correct genetic flaws in human embryos. Any such change, though, would infiltrate the entire genome and eventually be passed down to children, grandchildren, great-grandchildren, and every subsequent generation. That raises the possibility, more realistically than ever before, that scientists will be able to rewrite the fundamental code of life, with consequences for future generations that we may never be able to anticipate. Vague fears of a dystopian world, full of manufactured humans, long ago became a standard part of any debate about scientific progress. Yet not since J. Robert Oppenheimer realized that the atomic bomb he built to protect the world might actually destroy it have the scientists responsible for a discovery been so leery of using it.

For much of the past century, biology has been consumed with three essential questions: What does each gene do? How do we find the genetic mutations that make us sick? And how can we overcome them? With CRISPR, the answers have become attainable, and we are closing in on a sort of grand unified theory of genetics. “I am not sure what a Golden Age looks like,” Winston Yan, a member of Zhang’s research team, told me one day when I was with him in the lab, “but I think we are in one.”
At least since 1953, when James Watson and Francis Crick characterized the helical structure of DNA, the central project of biology has been the effort to understand how the shifting arrangement of four compounds—adenine, guanine, cytosine, and thymine—determines the ways in which humans differ from each other and from everything else alive. CRISPR is not the first system to help scientists pursue that goal, but it is the first that anyone with basic skills and a few hundred dollars’ worth of equipment can use.

“CRISPR is the Model T of genetics,” Hank Greely told me when I visited him recently, at Stanford Law School, where he is a professor and the director of the Center for Law and the Biosciences. “The Model T wasn’t the first car, but it changed the way we drive, work, and live. CRISPR has made a difficult process cheap and reliable. It’s incredibly precise. But an important part of the history of molecular biology is the history of editing genes.”

Scientists took the first serious step toward controlling our genes in the early nineteen-seventies, when they learned to cut chains of DNA by using proteins called restriction enzymes. Suddenly, genes from organisms that would never have been able to mate in nature could be combined in the laboratory. But those initial tools were more hatchet than scalpel, and, because they could recognize only short stretches within the vast universe of the human genome, the editing was rarely precise. (Imagine searching through all of Shakespeare for Hamlet’s soliloquy on suicide, relying solely on the phrase “to be.” You’d find the passage, but only after landing on several hundred unrelated citations.)
When the first draft of the Human Genome Project was published, in 2001, the results were expected to transform our understanding of life. In fundamental ways, they have; the map has helped researchers locate thousands of genes associated with particular illnesses, including hundreds that cause specific types of cancer. To understand the role that those genes play in the evolution of a disease, however, and repair them, scientists need to turn genes on and off systematically and in many combinations. Until recently, though, altering even a single gene took months or years of work.

That began to change with the growing use of zinc fingers, a set of molecular tools that, like CRISPR clusters, were discovered by accident. In 1985, scientists studying the genetic code of the African clawed frog noticed a finger-shaped protein wrapped around its DNA. They soon figured out how to combine that tenacious grip with an enzyme that could cut the DNA like a knife. Two decades later, geneticists began using TALEs, which are made up of proteins secreted by bacteria. But both engineering methods are expensive and cumbersome. Even Zhang, who published the first report on using TALEs to alter the genes of mammals, realized that the system was little more than an interim measure. “It is difficult to use,” he told me. “I had to assign a graduate student just to make the proteins and test them before I could begin to use them in an experiment. The procedure was not easy.”

Zhang’s obsession with science began in middle school, when his mother prodded him to attend a Saturday-morning class in molecular biology. “I was thirteen and had no idea what molecular biology was,” he said one evening as we walked across the M.I.T. campus on the way to the fiftieth-anniversary celebration of the Department of Brain and Cognitive Sciences, where Zhang is also a faculty member. “It really opened my imagination.” His parents, both engineers, moved the family to Iowa when he was eleven. They stayed largely because they thought he would get a better education in the United States than in China.

In 1997, when Zhang was fifteen, he was offered an internship in a biosafety facility at the Des Moines Human Gene Therapy Research Institute—but he was told that federal law prohibited him from working in a secure lab until he was sixteen. “So I had to wait,” he said. On his birthday, Zhang went to the lab and met the scientists. “I was assigned to a man who had a Ph.D. in chemistry but trained as a molecular biologist,” he continued. “He had a lot of passion for science, and he had a very big impact on me and my research.” On his first day, Zhang spent five hours in the lab, and nearly as much time every day after school until he graduated.
Zhang is unusually reserved, and he speaks in low, almost sleepy tones. I asked him if he considered himself to be mellow, a characteristic rarely associated with prize-winning molecular biologists. “You came to the lab meeting, right?” he replied. Earlier that morning, I had caught the tail end of a weekly meeting that Zhang holds for his group. I watched as he gently but relentlessly demolished a presentation given by one of the people on his team. When I mentioned it to one of the scientists who was at the meeting, he responded, “That was nothing. You should have been there from the start.”

At his Saturday-morning classes, Zhang learned how to extract DNA from cells and determine the length of each sequence. But that isn’t what he remembers best. “They showed us ‘Jurassic Park,’ ” he said, his voice moving up a register. “And it was amazing to me. The teacher explained the different scientific concepts in the movie, and they all seemed completely feasible.”

We had reached the cocktail party, a tepid affair crowded with men in khakis and women wearing sensible shoes. Zhang left after barely twenty minutes and headed back to the lab. He retains his position on the cognitive-sciences faculty, because he hopes that his research will help neuroscientists study the brain in greater detail. He told me that when he was young he had a friend who suffered from serious depression, and he had been surprised to find that there was almost no treatment available. It spurred a lasting interest in psychiatry. “People think you are weak if you are depressed,” he said. “It is still a common prejudice. But many people suffer from problems we cannot begin to address. The brain is still the place in the universe with the most unanswered questions.”

The Broad Institute was founded, in 2003, by the entrepreneur Eli Broad and his wife, Edythe, to foster research into the molecular components of life and their connections to disease. One afternoon in Zhang’s laboratory, Winston Yan offered to walk me through the mechanics of using CRISPR to edit a gene. “We need to be able to break DNA in a very precise place in the genome,” he said as I watched him at work. He swivelled in his chair and pointed to a row of vials that contained DNA samples to be analyzed and edited. Yan, a thin, bespectacled man, wore black laboratory gloves and a white Apple Watch; he clapped his hands and shrugged, as if to suggest that the work was simple.

Ordering the genetic parts required to tailor DNA isn’t as easy as buying a pair of shoes from Zappos, but it seems to be headed in that direction. Yan turned on the computer at his lab station and navigated to an order form for a company called Integrated DNA Technologies, which synthesizes biological parts. “It takes orders online, so if I want a particular sequence I can have it here in a day or two,” he said. That is not unusual. Researchers can now order online almost any biological component, including DNA, RNA, and the chemicals necessary to use them. One can buy the parts required to assemble a working version of the polio virus (it’s been done) or genes that, when put together properly, can make feces smell like wintergreen. In Cambridge, I.D.T. often makes same-day deliveries. Another organization, Addgene, was established, more than a decade ago, as a nonprofit repository that houses tens of thousands of ready-made sequences, including nearly every guide used to edit genes with CRISPR. When researchers at the Broad, and at many other institutions, create a new guide, they typically donate a copy to Addgene.
The RNA that CRISPR relies upon to guide the molecular scalpel to its target is made of twenty base pairs. Humans have twenty thousand genes, and twenty base pairs occupy roughly the same percentage of space in a single gene as would one person standing in a circle that contained the entire population of the United States. CRISPR is better at locating specific genes than any other system, but it isn’t perfect, and sometimes it cuts the wrong target. Yan would order a ready-made probe from Addgene. When it arrives, he pairs it with a cutting enzyme and sends it to the designated gene.

Yan joined Zhang’s lab just before what he described as “the CRISPR craze” began. But, he added, the technology has already transformed the field. “For many years, there was a reductionist approach to genetics,” he said. “A kind of wishful thinking: ‘We will find the gene that causes cancer or the gene that makes you prone to heart disease.’ It is almost never that simple.”

The next morning, I walked over to the Broad’s new Stanley Building and rode the elevator to the top floor, where I emptied my pockets, put on a mask and gown, and slipped booties over my shoes. Then I passed through an air chamber that was sealed with special gaskets and had a fan blowing continuously to keep out foreign microbes. I entered the vivarium, a long, clean floor that looked like a combination of research unit and hospital ward. The vivarium, which opened last year, provides thousands of mice with some of the world’s most carefully monitored accommodations.

Despite our growing knowledge of the way that cancer develops in human cells, mutations can’t be studied effectively in a petri dish, and, since the late nineteen-eighties, genetically modified mice have served as the standard proxy. What cures (or kills) a mouse won’t necessarily have the same effect on a human, but the mouse genome is surprisingly similar to our own, and the animals are cheap and easy to maintain. Like humans, and many other mammals, mice develop complex diseases that affect the immune system and the brain. They get cancer, atherosclerosis, hypertension, and diabetes, among other chronic illnesses. Mice also reproduce every three weeks, which allows researchers to follow several generations at once. Typically, technicians would remove a stem cell from the mouse, then edit it in a lab to produce a particular gene or to prevent the gene from working properly. After putting the stem cell back into the developing embryo of the mouse, and waiting for it to multiply, they can study the gene’s effect on the animal’s development. The process works well, but it generally allows for the study of only one characteristic in one gene at a time.
The vivarium at the Broad houses an entirely different kind of mouse, one that carries the protein Cas9 (which stands for CRISPR-associated nuclease) in every cell. Cas9, the part of the CRISPR system that acts like a genetic scalpel, is an enzyme. When scientists originally began editing DNA with CRISPR, they had to inject both the Cas9 enzyme and the probe required to guide it. A year ago, Randall Platt, another member of Zhang’s team, realized that it would be possible to cut the CRISPR system in two. He implanted the surgical enzyme into a mouse embryo, which made it a part of the animal’s permanent genome. Every time a cell divided, the Cas9 enzyme would go with it. In other words, he and his colleagues created a mouse that was easy to edit. Last year, they published a study explaining their methodology, and since then Platt has shared the technique with more than a thousand laboratories around the world.

The “Cas9 mouse” has become the first essential tool in the emerging CRISPR arsenal. With the enzyme that acts as molecular scissors already present in every cell, scientists no longer have to fit it onto an RNA guide. They can dispatch many probes at once and simply make mutations in the genes they want to study.

To demonstrate a potential application for cancer research, the team used the Cas9 mouse to model lung adenocarcinoma, the most common form of lung cancer. Previously, scientists working with animal models had to modify one gene at a time or cross-breed animals to produce a colony with the needed genetic modifications. Both processes were challenging and time-consuming. “Now we can activate CRISPR directly in the cells we’re interested in studying, and modify the genome in whatever way we want,” Platt said, as he showed me around the vivarium. We entered a small exam room with a commanding view of Cambridge. I watched as a technician placed a Cas9 mouse in a harness inside a biological safety cabinet. Then, peering through a Leica microscope, she used a fine capillary needle to inject a single cell into the mouse’s tail.

“And now we have our model,” Platt said, explaining that the mouse had just received an injection that carried three probes, each of which was programmed to carry a mutation that scientists believe is associated with lung cancer. “The cells will carry as many mutations as we want to study. That really is a revolutionary development.”
“In the past, this would have taken the field a decade, and would have required a consortium,” Platt said. “With CRISPR, it took me four months to do it by myself.” In September, Zhang published a report, in the journal Cell, describing yet another CRISPR protein, called Cpf1, that is smaller and easier to program than Cas9.

The lab employs a similar approach to studying autism. Recent experiments suggest that certain psychiatric conditions can be caused by just a few malfunctioning neurons out of the trillions in every brain. Studying the way neurons function within the brain is difficult. But by re-creating, in the lab, genetic mutations that others have linked to autism and schizophrenia Zhang’s team has been able to investigate faulty neurons that may play a role in those conditions.

As the price of sequencing plunges, cancer clinics throughout the United States have begun to study their patients’ tumors in greater detail. Tumors are almost never uniform; one may have five mutations or fifty, which means, essentially, that every cancer is a specific, personal disease. Until CRISPR became available, the wide genetic variations in cancer cells often made it hard to develop effective treatments.

“What I love most about the CRISPR process is that you can take any cancer-cell line, knock out every gene, and identify every one of the cell’s Achilles’ heels,” Eric Lander, the fifty-eight-year-old director of the Broad, told me recently. Lander, who was among the leaders of the Human Genome Project, said that he had never encountered a more promising research tool. “You can also use CRISPR to systematically study the ways that a cancer cell can escape from a treatment,” he said. “That should make it possible to build a comprehensive road map for cancer.”

Lander went on to say that each vulnerability of a tumor might be attacked by a single drug. But cancer cells elude drugs in many ways, and, to succeed, a therapy may need to block them all. That strategy has proved effective for infectious diseases like AIDS. “Remember the pessimism about H.I.V.,” he said, referring to the early years of the AIDS epidemic, when a diagnosis was essentially a death sentence. Eventually, virologists developed a series of drugs that interfere with the virus’s ability to replicate. The therapy became truly successful, however, only when those drugs, working together, could block the virus completely.

The same approach has proved successful in treating tuberculosis. Lander is convinced that it will also work for many cancers: “With triple-drug therapy,” for H.I.V., “we reached an inflection point: we were losing badly, and one day suddenly we were winning.”

He stood up and walked across the office toward his desk, then pointed at the wall and described his vision for the future of cancer treatment. “There will be an enormous chart,” he said. “Well, it will be electronic, and it will contain the therapeutic road map of every trick that cancer cells have—how they form, all the ways you can defeat them, and all the ways they can escape and defeat a treatment. And when we have that we win. Because every cancer cell starts naïve. It doesn’t know what we have waiting in the freezer for it. Infectious diseases are a different story; they share their knowledge as they spread. They learn from us as they move from person to person. But every person’s cancer starts naïve. And this is why we will beat it.”
Developing any technology as complex and widely used as CRISPR invariably involves contributions from many scientists. Patent fights over claims of discovery and licensing rights are common. Zhang, the Broad Institute, and M.I.T. are now embroiled in such a dispute with Jennifer Doudna and the University of California; she is a professor of chemistry and of molecular biology at Berkeley. By 2012, Doudna, along with Emmanuelle Charpentier, a medical microbiologist who studies pathogens at the Helmholtz Centre for Infection Research, in Germany, and their lab teams, demonstrated, for the first time, that CRISPR could edit purified DNA. Their paper was published that June. In January of 2013, though, Zhang and George Church, a professor of genetics at both Harvard Medical School and M.I.T., published the first studies demonstrating that CRISPR could be used to edit human cells. Today, patents are generally awarded to the first people to file—in this case, Doudna and Charpentier. But Zhang and the Broad argued that the earlier success with CRISPR had no bearing on whether the technique would work in the complex organisms that matter most to scientists looking for ways to treat and prevent diseases.

Zhang was awarded the patent, but the University of California has requested an official reassessment, and a ruling has not yet been issued. Both he and Doudna described the suit to me as “a distraction” that they wished would go away. Both pledged to release all intellectual property to researchers without charge (and they have). But both are also involved in new companies that intend to develop CRISPR technology as therapies, as do many pharmaceutical firms and other profit-seeking enterprises.
CRISPR research is becoming big business: venture-capital firms are competing with one another to invest millions, and any patent holder would have the right to impose licensing fees. Whoever wins stands to make a fortune. Other achievements are also at stake, possibly including a Nobel Prize. (Doudna’s supporters have described her as America’s next female Nobel Prize winner, and at times the publicity war seems a bit like the battles waged by movie studios during Academy Award season.) Last year, the National Science Foundation presented Zhang with its most prestigious award, saying that his fundamental research “moves us in the direction” of eliminating schizophrenia, autism, and other brain disorders. A few months later, Doudna and Charpentier received three million dollars each for the Breakthrough Prize, awarded each year for scientific achievement. The prize was established, in 2012, by several Silicon Valley billionaires who are seeking to make science a more attractive career path. The two women also appeared on Time’s annual list of the world’s hundred most influential people.
In fact, neither group was involved in the earliest identification of CRISPR or in the first studies to demonstrate how it works. In December, 1987, biologists at the Research Institute of Microbial Diseases, in Osaka, Japan, published the DNA sequence of a gene taken from the common intestinal bacterium E. coli. Those were early days in the genomic era, and thousands of labs around the world had embarked on similar attempts to map the genes of species ranging from fruit flies to humans. In an effort to better understand how this particular gene functioned, the Japanese scientists also sequenced some of the DNA that surrounded it. When they examined the data, they were surprised to see cellular structures that none of them recognized: they had no idea what to make of the strange phenomenon, but they took note of it, writing in the final sentence of their report, published in the Journal of Bacteriology, that the “biological significance of these sequences is not known.”

The mystery remained until 2005, when Francisco Mojica, a microbiologist at the University of Alicante, who had long sought to understand CRISPR, decided to compare its DNA with the DNA of tens of thousands of similar organisms. What he saw amazed him: every unknown sequence turned out to be a fragment of DNA from an invading virus.

The pace of research quickened. In 2007, Rodolphe Barrangou and Philippe Horvath, microbiologists then working for Danisco, the Danish food company, had noticed that some of its yogurt cultures were routinely destroyed by viruses and others were not. They decided to find out why. The scientists infected the microbe Streptococcus thermophilus, which is widely used to make yogurt, with two viruses. Most of the bacteria died, but those which survived had one property in common: they all contained CRISPR molecules to defend them.

“No single person discovers things anymore,” George Church told me when we met in his office at Harvard Medical School. “The whole patent battle is silly. There has been much research. And if anybody should be making a fuss about this I should be making a fuss. But I am not doing that, because I don’t think it matters. They are all nice people. They are all doing important work. It’s a tempest in a teapot.”

From the moment that manipulating genes became possible, many people, including some of those involved in the experiments, were horrified by the idea of scientists in lab coats rearranging the basic elements of life. In 1974, David Baltimore, the pioneering molecular biologist, who was then at M.I.T., and Paul Berg, of Stanford, both of whom went on to win a Nobel Prize for their research into the fundamentals of viral genetics, called for a moratorium on gene-editing research until scientists could develop safety principles for handling organisms that contained recombinant DNA. That meeting, which took place in 1975, at a conference center in Asilomar, California, has come to be regarded as biotechnology’s Constitutional Convention.
Roughly a hundred and fifty participants, most of them scientists, gathered to discuss ways to limit the risks of accidentally releasing genetically modified organisms. At the time, the possibility of creating “designer babies”—a prospect that, no matter how unlikely, is attached to almost everything written or said about CRISPR—was too remote to consider. Nevertheless, the technology seemed frightening. In Cambridge, home to both M.I.T. and Harvard, the city council nearly banned such research altogether. The work went on, but decoding sequences of DNA wasn’t easy. “In 1974, thirty base pairs”—thirty rungs on the helical ladder of the six billion nucleotides that make up our DNA—“was a good year’s work,” George Church told me. Now the same work would take seconds.

At least for the foreseeable future, CRISPR’s greatest impact will lie in its ability to help scientists rapidly rewrite the genomes of animal and plant species. In laboratories, agricultural companies have already begun to use CRISPR to edit soybeans, rice, and potatoes in an effort to make them more nutritious and more resistant to drought. Scientists might even be able to edit allergens out of foods like peanuts.

Normally, it takes years for genetic changes to spread through a population. That is because, during sexual reproduction, each of the two versions of any gene has only a fifty per cent chance of being inherited. But a “gene drive”—which is named for its ability to propel genes through populations over many generations—manages to override the traditional rules of genetics. A mutation made by CRISPR on one chromosome can copy itself in every generation, so that nearly all descendants would inherit the change. A mutation engineered into a mosquito that would block the parasite responsible for malaria, for instance, could be driven through a large population of mosquitoes within a year or two. If the mutation reduced the number of eggs produced by that mosquito, the population could be wiped out, along with any malaria parasites it carried.

Kevin Esvelt, an evolutionary biologist at Harvard, was the first to demonstrate how gene drives and CRISPR could combine to alter the traits of wild populations. Recently, he has begun to study the possibility of using the technology to eliminate Lyme disease by rewriting the genes of mice in the wild. Lyme disease is caused by a bacterium and transmitted by ticks, and more than eighty-five per cent of the time they become infected after biting a mouse. Once exposed, however, some mice naturally acquire resistance or immunity. “My idea is to take the existing genes that confer resistance to Lyme and make sure that all mice have the most effective version,’’ Esvelt said. To do that, scientists could encode the most protective genes next to the CRISPR system and force them to be passed on together. Esvelt stressed that such an approach would become possible only after much more research and a lengthy series of public discussions on the risks and benefits of the process.

 

The promise of CRISPR research becomes more evident almost every month. Recently, Church reported that he had edited sixty-two genes simultaneously in a pig cell. The technique, if it proves accurate and easy to repeat, could help alleviate the constant shortage of organ donors in the U.S. For years, scientists have tried to find a way to use pig organs for transplants, but a pig’s DNA is filled with retroviruses that have been shown in labs to infect human cells. Church and his colleagues discovered that those viruses share a common genetic sequence. He deployed CRISPR to their exact locations and snipped them out of the genome. In the most successful of the experiments, the CRISPR system deleted all sixty-two of the retroviruses embedded in the pig’s DNA. Church then mixed those edited cells with human cells in the laboratory, and none became infected.

While CRISPR will clearly make it possible to alter our DNA, serious risks remain. Jennifer Doudna has been among the most vocal of those calling for caution on what she sees as the inevitable march toward editing human genes. “It’s going to happen,” she told me the first time we met, in her office at Berkeley. “As a research tool, CRISPR could hardly be more valuable—but we are far from the day when it should be used in a clinical setting.” Doudna was a principal author of a letter published in Science this spring calling for a temporary research moratorium. She and others have organized a conference to discuss the ethics of editing DNA, a sort of Asilomar redux. The conference, to be attended by more than two hundred scientists—from the U.S., England, and China, among other countries—will take place during the first week of December at the National Academy of Sciences, in Washington.

Until April, the ethical debate over the uses of CRISPR technology in humans was largely theoretical. Then a group at Sun Yat-sen University, in southern China, attempted to repair, in eighty-six human embryos, the gene responsible for betathalassemia, a rare but often fatal blood disorder. If those disease genes, and genes that cause conditions like cystic fibrosis, could be modified successfully in a fertilized egg, the alteration could not only protect a single individual but eventually eliminate the malady from that person’s hereditary lineage. Given enough time, the changes would affect all of humanity. The response to the experiment was largely one of fear and outrage. The Times carried the story under the headline “CHINESE SCIENTISTS EDIT GENES OF HUMAN EMBRYOS, RAISING CONCERNS.”

Critics called the experiment irresponsible and suggested that the scientists had violated an established code of conduct. “This paper demonstrates the enormous safety risks that any such attempt would entail, and underlines the urgency of working to forestall other such efforts,” Marcy Darnovsky, of the Center for Genetics and Society, told National Public Radio when the report was published. “The social dangers of creating genetically modified human beings cannot be overstated.”
There seems to be little disagreement about that. But the Chinese researchers were not trying to create genetically modified humans. They were testing the process, and every CRISPR researcher I spoke to considered the experiment to have been well planned and carried out with extraordinary care. The scientists also agreed that the results were illuminating. “That was an ethical paper, and a highly responsible project,’’ Lander told me. “What did they do? They took triploid zygotes’’—a relatively common genetic aberration—“from I.V.F. clinics. They deliberately chose those because they knew no human could ever develop from them. And what did the paper say? ‘Boy, we see problems everywhere.’ That was good science, and it was cautionary.”

Fewer than half the embryos were edited successfully, and, of those, most retained none of the new DNA that was inserted into the genes. The experiment, which was published in the Beijing-based journal Protein & Cell, demonstrated clearly that the day when scientists could safely edit humans is far off. The CRISPR system also made unintended cuts and substitutions, the potential effects of which are unknown. In other cases, it made the right changes in some cells of the embryo but not in all of them, which could cause other problems. “These authors did a very good job, pointing out the challenges,” Dieter Egli, a stem-cell researcher at Columbia University, said when the study was published. “They say themselves that this type of technology is not ready for any kind of application.”

Doudna agreed that the Chinese experiment yielded valuable results. She is fifty-one, and has been at Berkeley since 2002, when she and her husband, the biochemist Jamie Cate, were offered joint appointments to the departments of chemistry and molecular and cell biology. Their offices are next to each other, with the same commanding view of San Francisco Bay and the Golden Gate Bridge. Doudna’s work, unlike that of the scientists at the Broad, has been focussed on molecules, not mammalian genetics. For years, she has been leading investigations into the shape, structure, and capabilities of RNA, and in 2011 Charpentier asked for her help in exploring the mechanism of CRISPR. Doudna is tall, with graying blond hair and piercing blue eyes. She grew up in Hawaii, where her parents were academics; when it was time for college, she decided to leave the island and study in California, at Pomona. She earned her doctorate at Harvard and then moved on to Yale. “I have always been a bit of a restless soul,” she said. “I may spend too much time wondering what comes next.”

Doudna is a highly regarded biochemist, but she told me that not long ago she considered attending medical school or perhaps going into business. She said that she wanted to have an effect on the world and had begun to fear that the impact of her laboratory research might be limited. The promise of her work on CRISPR, however, has persuaded her to remain in the lab. She told me that she was constantly amazed by its potential, but when I asked if she had ever wondered whether the powerful new tool might do more harm than good she looked uncomfortable. “I lie in bed almost every night and ask myself that question,” she said. “When I’m ninety, will I look back and be glad about what we have accomplished with this technology? Or will I wish I’d never discovered how it works?”

 

Her eyes narrowed, and she lowered her voice almost to a whisper. “I have never said this in public, but it will show you where my psyche is,” she said. “I had a dream recently, and in my dream”—she mentioned the name of a leading scientific researcher—“had come to see me and said, ‘I have somebody very powerful with me who I want you to meet, and I want you to explain to him how this technology functions.’ So I said, Sure, who is it? It was Adolf Hitler. I was really horrified, but I went into a room and there was Hitler. He had a pig face and I could only see him from behind and he was taking notes and he said, ‘I want to understand the uses and implications of this amazing technology.’ I woke up in a cold sweat. And that dream has haunted me from that day. Because suppose somebody like Hitler had access to this—we can only imagine the kind of horrible uses he could put it to.”

Nobody is going to employ CRISPR technology to design a baby, let alone transform the genetic profile of humanity, anytime soon. Even if scientists become capable of editing human embryos, it would take years for the genetically modified baby to grow old enough to reproduce—and then many generations for the alteration to disseminate throughout the population.

But there are long-term consequences to consider. Modern medicine already shapes our genome, by preserving genes that might otherwise have been edited out of our genome by natural selection. Today, millions of people suffer from myopia, and many of them are legally blind. Were it not for the invention of glasses, which have turned poor eyesight largely into a nuisance rather than an existential threat, the genes responsible for myopia might be less prevalent than they are today. The same could be said about many infectious diseases, and even chronic conditions like diabetes.

Humans also carry genes that protect us from one disease but increase our susceptibility to others, and it’s impossible to predict the impact of changing all or even most of them. The AIDS virus often enters our blood cells through a protein called CCR5. One particular genetic variant of that protein, called the Delta32 mutation, prevents H.I.V. from locking onto the cell. If every person carried that mutation, nobody would get AIDS. So why not introduce that mutation into the human genome? Several research teams are working to develop drugs that do that in people who have already been infected.

Yet it’s important to note that, while such a procedure would prevent H.I.V. infection, it would also elevate our susceptibility to West Nile virus. Today, that trade-off may seem worth the risk, but there’s no way of knowing whether it would be true seven or ten generations from now. For example, sickle cells, which cause anemia, evolved as a protection against malaria; the shape of the cell blocks the spread of the parasite. If CRISPR technology had been available two hundred thousand years ago, it might have seemed sensible to edit sickle cells into the entire human population. But the results would have been devastating.

“This is a little bit like geoengineering,” Zhang told me, referring to attempts to deliberately alter the climate to offset damages associated with global warming. “Once you go down that path, it may not be so reversible.”

George Church disagrees. “It strikes me as a fake argument to say that something is irreversible,” he told me. “There are tons of technologies that are irreversible. But genetics is not one of them. In my lab, we make mutations all the time and then we change them back. Eleven generations from now, if we alter something and it doesn’t work properly we will simply fix it.”

In 1997, Scottish scientists shocked the world by announcing that they had cloned a lamb, which they named Dolly. Scores of journalists (including me) descended on Edinburgh, and wrote that the achievement, while wondrous, also carried the ominous implication that scientists had finally pried open Pandora’s box. Many articles about cloning and the value of human life were published. Evil people and dictators would clone themselves, their children, their pets. A new class of humans would arise.

Eighteen years later, the closest we have come to cloning a person was a failed attempt at a monkey, in 2007. Nobody spends much time worrying about it today. In Cambridge this summer, one of the researchers at the Broad told me that he and Louise Brown, the first success of in-vitro fertilization, were both born in 1978. “Did that set off an uproar?” he asked. It did. Even seven years earlier, James Watson had written, in The Atlantic, that the coming era of designer babies might overwhelm us all. Today, though, with more than five million children on earth born through in-vitro fertilization, that particular furor, too, seems to have passed.

CRISPR technology offers a new outlet for the inchoate fear of tinkering with the fundamentals of life. There are many valid reasons to worry. But it is essential to assess both the risks and the benefits of any new technology. Most people would consider it dangerous to fundamentally alter the human gene pool to treat a disease like AIDS if we could cure it with medicine or a vaccine. But risks always depend on the potential result. If CRISPR helps unravel the mysteries of autism, contributes to a cure for a form of cancer, or makes it easier for farmers to grow more nutritious food while reducing environmental damage, the fears, like the many others before them, will almost certainly disappear.

 

www.youtube.com/embed/EMLHtywaqSY?feature=player_embedded

 

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Diabetic Retinopathy


Diabetic Retinopathy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Lucentis effective for proliferative diabetic retinopathy

NIH-funded clinical trial marks first major advance in therapy in 40 years.

http://www.nih.gov/news-events/news-releases/lucentis-effective-proliferative-diabetic-retinopathy

Illustration of ruptured blood vessels

http://www.nih.gov/sites/default/files/styles/featured_media_breakpoint-large-extra/public/news-events/news-releases/2015/20151116-eye-blood-vessels.jpg

Abnormal blood vessels bleeding into the center of the eye due to proliferative diabetic retinopathy.

https://youtu.be/jPoCIa0_1po

A clinical trial funded by the National Institutes of Health has found that the drug ranibizumab (Lucentis) is highly effective in treating proliferative diabetic retinopathy. The trial, conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) compared Lucentis with a type of laser therapy called panretinal or scatter photocoagulation, which has remained the gold standard for proliferative diabetic retinopathy since the mid-1970s. The findings demonstrate the first major therapy advance in nearly 40 years.

“These latest results from the DRCR Network provide crucial evidence for a safe and effective alternative to laser therapy against proliferative diabetic retinopathy,” said Paul A. Sieving, M.D., Ph.D., director of NIH’s National Eye Institute (NEI), which funded the trial.  The results were published online today in the Journal of the American Medical Association.

Treating abnormal retinal blood vessels with laser therapy became the standard treatment for proliferative diabetic retinopathy after the NEI announced results of the Diabetic Retinopathy Study in 1976. Although laser therapy effectively preserves central vision, it can damage night and side vision; so, researchers have sought therapies that work as well or better than laser but without such side effects.

A complication of diabetes, diabetic retinopathy can damage blood vessels in the light-sensitive retina in the back of the eye. As the disease worsens, blood vessels may swell, become distorted and lose their ability to function properly. Diabetic retinopathy becomes proliferative when lack of blood flow in the retina increases production of a substance called vascular endothelial growth factor, which can stimulate the growth of new, abnormal blood vessels. These new vessels are prone to bleeding into the center of the eye, often requiring a surgical procedure called a vitrectomy to clear the blood. The abnormal blood vessels can also cause scarring and retinal detachment. Lucentis is among several drugs that block the effects of vascular endothelial growth factor.

About 7.7 million U.S. residents have diabetic retinopathy, a leading cause of blindness among working-age Americans. Among these, about 1.5 percent have PDR.

The DRCR.net enrolled 305 participants (394 eyes) with proliferative diabetic retinopathy in one or both eyes at 55 clinical sites across the country. Eyes were assigned randomly to treatment with Lucentis or laser. For participants who enrolled both eyes in the study, one eye was assigned to the laser group and the other was assigned to the Lucentis group. About half of the eyes assigned to the laser group required more than one round of laser treatment. In the other group, Lucentis (0.5 mg/0.05 ml) was given via injections into the eye once per month for three consecutive months, and then as needed until the disease resolved or stabilized.

Because Lucentis is commonly used to treat diabetic macular edema—the build-up of fluid in the central area of the retina—the study permitted the use of Lucentis for diabetic macular edema in the laser group, if necessary. Slightly more than half (53 percent) of eyes in the laser group received Lucentis injections to treat diabetic macular edema. About 6 percent of eyes in the Lucentis group received laser therapy, mostly to treat retinal detachment or bleeding.

At two years, vision in the Lucentis group improved by about half a line on an eye chart compared with virtually no change in the laser group. There was little change in side vision with injection (average worsening of 23 decibels) but a substantial loss of side vision with laser (average worsening of 422 decibels).   The vitrectomy rate was lower in the Lucentis group (8 of 191 eyes) than in the laser group (30 of 203 eyes).

Rates of serious systemic adverse events, including cardiac arrest and stroke, were similar between the two groups. One patient in the Lucentis group developed endophthalmitis, an infection in the eye. Other side effects were low, with little difference between treatment groups.

“Lucentis should be considered a viable treatment option for people with proliferative diabetic retinopathy, especially for individuals needing anti-vascular endothelial growth factor for diabetic macular edema,” said Jeffrey G. Gross, M.D., of the Carolina Retina Center in Columbia, South Carolina, who chaired the study. Dr. Gross presented results November 13, 2015, at the annual meeting of the American Academy of Ophthalmology in Las Vegas.

In addition to treating proliferative diabetic retinopathy, the report suggests Lucentis may even help prevent diabetic macular edema from occurring. Among people without diabetic macular edema at the start of the study, only 9 percent of Lucentis-treated eyes developed diabetic macular edema during the study, compared with 28 percent in the laser group. The DRCR.net will continue to follow patients in this study for a total of five years.

The DRCR.net is dedicated to facilitating multicenter clinical research of diabetic eye disease. The network formed in 2002 and comprises more than 350 physicians practicing at more than 140 clinical sites across the country. For more information, visit the DRCR.net website at http://drcrnet.jaeb.org/(link is external).

The study was funded by NEI grants EY14231, EY23207, EY18817.

Lucentis was provided by Genentech. Additional research funding for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, also a part of the NIH.

The study is registered as NCT01489189 at ClinicalTrials.gov(link is external).

The NEI provides information about diabetic eye disease at http://www.nei.nih.gov/health/diabetic/.

Information about diabetes is available through the National Diabetes Education Program, www.ndep.nih.gov/.

View an NEI video about the study at https://youtu.be/jPoCIa0_1po(link is external).

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The Significant Burden of Childhood Malnutrition and Stunting


The Significant Burden of Childhood Malnutrition and Stunting

Curator: Larry H. Bernstein, MD, FCAP

Micronutrients

Quite a few  trace elements or micronutrients—vitamins and minerals—are important for health. Three very important micronutrient deficiencies in terms of health consequences for poor people in developing countries are:

Iron

Vitamin A

Iodine

Children and hunger

Children are the most visible victims of undernutrition.  Black et al (2013) estimate that undernutrition in the aggregate—including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding—is a cause of 3·1 million child deaths annually or 45% of all child deaths in 2011 (Black et al. 2013).  Undernutrition magnifies the effect of every disease, including measles and malaria. The estimated proportions of deaths in which undernutrition is an underlying cause are roughly similar for diarrhea (61%), malaria (57%), pneumonia (52%), and measles (45%) (Black 2003, Bryce 2005). Malnutrition can also be caused by diseases, such as the diseases that cause diarrhea, by reducing the body’s ability to convert food into usable nutrients.

Stunting

Wasting and severe wasting ·

Under-five Protein Energy Malnutrition Admitted at the University of In Nigeria Teaching Hospital, Enugu: a 10 year retrospective review

Agozie C Ubesie12*, Ngozi S Ibeziako12, Chika I Ndiokwelu3, Chinyeaka M Uzoka3 andChinelo A Nwafor3

Nutrition Journal 2012, 11:43  doi:10.1186/1475-2891-11-43

http://www.nutritionj.com/content/11/1/43

To determine the prevalence, risk factors, co-morbidities and case fatality rates of Protein Energy Malnutrition (PEM) admissions at the paediatric ward of the University of Nigeria Teaching Hospital Enugu, South-east Nigeria over a 10 year period.

Design

A retrospective study using case Notes, admission and mortality registers retrieved from the Hospital’s Medical Records Department.

Subjects

All children aged 0 to 59 months admitted into the hospital on account of PEM between 1996 and 2005.

Results

A total of 212 children with PEM were admitted during the period under review comprising of 127 (59.9%) males and 85(40.1%) females. The most common age groups with PEM were 6 to 12 months (55.7%) and 13 to 24 months (36.8%). Marasmus (34.9%) was the most common form of PEM noted in this review. Diarrhea and malaria were the most common associated co-morbidities. Majority (64.9%) of the patients were from the lower socio-economic class. The overall case fatality rate was 40.1% which was slightly higher among males (50.9%). Mortality in those with marasmic-kwashiokor and in the unclassified group was 53.3% and 54.5% respectively.

Conclusion

Most of the admissions and case fatality were noted in those aged 6 to 24 months which coincides with the weaning period. Marasmic-kwashiokor is associated with higher case fatality rate than other forms of PEM. We suggest strengthening of the infant feeding practices by promoting exclusive breastfeeding for the first six months of life, followed by appropriate weaning with continued breast feeding. Under-five children should be screened for PEM at the community level for early diagnosis and prompt management as a way of reducing the high mortality associated with admitted severe cases.

Globally, PEM continues to be a major health burden in developing countries and the most important risk factor for illnesses and death especially among young children [1]. The World Health Organization estimates that about 60% of all deaths, occurring among children aged less than five years in developing countries, could be attributed to malnutrition [2]. The improvement of nutrition therefore, is the main prerequisite for the reduction of high infant and under five mortality rates, the assurance of physical growth, social and mental development of children as well as academic achievement [3]. Sub-saharan Africa bears the brunt of PEM in the world. On the average, the PEM associated mortality in sub-Saharan Africa is between 25 and 35% [4,5]. In Nigeria, 22 to 40% of under-five mortality has been attributed to PEM [6]. PEM is also associated with a number of co-morbidities such as lower respiratory tract infections including tuberculosis, diarrhea diseases, malaria and anaemia [7,8]. These co-morbidities may prolong the duration of hospital stay and death among affected children.

There is a knowledge gap on the incidence and outcome of PEM seen in the Nigerian tertiary health facilities. In this study, the type of PEM among admitted under-five children, the associated morbidities, and duration of hospitalization and outcome at the University of Nigeria Teaching Hospital Enugu over a 10 year period is reviewed.

Relevant information was extracted from each retrieved case file and/or hospital registers and transferred into the proforma. Diagnosis of PEM was based on the Modified Wellcome Classification because it was the method used for clinical diagnosis by the clinicians. This classified PEM into kwashiorkor, underweight kwashiorkor, underweight, marasmus, marasmic kwashiorkor and there was also provision for unclassified PEM. Marasmus and the various forms of kwashiorkor are part of the recently defined Severe Acute Malnutrition (SAM) by the World Health Organization (WHO). The WHO defined SAM by a very low weight for height (below -3z scores of the median WHO growth standards), visible severe wasting or the presence of nutritional oedema [11,12]. Modified Wellcome classification uses weight for age and the presence or absence of oedema to classify PEM. The weights were measured using infant weighing scales (Waymaster) and stadiometers (Health Scale) depending on the age of the child. A total of 212 proforma were completed covering the entire period of the study.

Diagnosis of HIV was made using Enzyme Linked Immunosorbent Assay [ELISA] and Westerblot. In children aged less than 18 months, positive antibody test was combined with clinical features to make presumptive diagnosis of HIV infection. Diagnosis of malaria was confirmed using blood film and bronchopneumonia using chest X-ray. Diarrhea was defined as passage of watery or loose stools or an increase in frequency above normal for a child. Severe anaemia was defined using a packed cell volume of less than 15%. Sepsis was defined as clinical features of systemic inflammatory response (fever, tachycardia, tachypnea, leukocytosis or leukopenia) associated with infection. Diagnosis of tuberculosis was made in the presence of chronic cough that have lasted for more three weeks supported by varied combination of the following: positive family history of tuberculosis, positive mantoux, suggestive chest X-ray and elevated erythrocyte sedimentation rate. Diagnosis of scabies was clinical based on the typical itching papular rash located at the intertrigous areas. Chronic suppurative otitis media and rickets were suspected clinically and confirmed by culture of ear swab and X-ray of the limbs respectively.

Subjects

A total of 7703 children were admitted into the paediatric wards and 212 of them were cases of PEM during the period under review. This represented about 2.8% of the total paediatric admissions. One hundred and twenty seven (59.9%) were males while 85 (40.1) were females giving a male: female ratio of 1: 0.7. The age group studied was 6 to 59 months (under-5). The mean age of the participants was 15.4 ± 9.3 months.

PEM and demography

PEM was most common among the age groups 6 to 12 and 13 to 24 months, and these accounted for 55.7% and 36.8% of the study population respectively. There was however, no statistically significant difference between the age groups and various forms of PEM as shown in Table 1(χ² = 19.38, df =16, p = 0. 249). The most common form of PEM noted in this review was marasmus (34.9%). Except for marasmic-kwashiokor, more males than females had more of all the various types although this was not statistically significant (χ² = 8.382, df =4, p = 0. 079) as shown in Table2. Admissions for PEM were recorded more in 1996, 1999 and 2004 (15.1, 13.7 and 12.3% respectively), but there were no consistent pattern in the yearly admissions of children with PEM during the period under review (Figure 1).

PEM admissions according to the age groups (months)
PEM type 0-12 m (%) 13-24 m (%) 25-36 m (%) 37-60 m (%) 49-60 m (%)
Kwashiokor 16 (13.6) 19 (24.4) 3 (33.3) 1 (33.3) 1 (25)
Underweight 11 (9.3) 6 (7.7) 0 (0) 0 (0) 0 (0)
Marasmic-kwash 6 (5.1) 8 (10.3) 0 (0) 1 (33.3) 0 (0)
Marasmus 48 (40.7) 24 (30.8) 2 (22.2) 0 (0) 0 (0)
Unclassified 37 (31.4) 21 (26.9) 4 (44.4) 1 (33.3) 3 (75)
Total 118 (100) 78 (100) 9 (100) 3(100) 4 (100)

χ² = 19.38, df =16, P = 0. 249.

Table 3
The associated co-morbidities seen among patients
Co-morbidity Frequency
(%)
Diarrhea 48 (72.2)
Malaria 29 (43.9)
Sepsis 25 (37.9)
Severe anaemia 16 (24.2)
Bronchopneumonia. 11 (16.7)
HIV 9 (13.6)
Tuberculosis 8 (12.1)
other 5 (7.5)

The table shows the associated co-morbidities noted in the patients.

Table 4
Prevalence of PEM by breastfeeding pattern
Breastfeeding pattern Prevalence 95% Confidence Intervals
(%)
Exclusive breast feeding for 0–3 months 18.9 11.2 – 26.6
Predominant breastfeeding 0–3 months 48.6 38.8 – 58.4
Predominant breastfeeding 4–6 months 24.3 15.9 – 32.7
Breast milk substitutes 8.1 2.7 – 13.5

The table shows the prevalence of the various pattern of feeding for the children during their early infancy. The 95% confidence interval is also reported.

Ubesie et al.

Ubesie et al. Nutrition Journal 2012 11:43   doi:10.1186/1475-2891-11-43

Prognostic indicators

The duration of hospitalization was available in only 84 subjects and ranged from 0 to 62 days. The mean duration of hospitalization was 16 ± 15 days. Kwashiokor patients had the highest mean hospitalization days of 19.15 days while marasmic and underweight patients had the least days of 14.52 and 14.55 days respectively. There was no statistically significant difference in the mean hospitalization days for the various types of PEM (F = 0.317, df =4, P = 0. 866). A total of 85 (40.1%) children died while on admission, 124 (58.5%) recovered and were discharged home while 3 (1.4%) were discharged against medical advice. Mortality was higher among the males (50.9%) than females (34.1%) although this was not statistically significant (χ² = 0.723, df =2, P = 0. 697). Most of the deaths were recorded in the age groups 0–12 (55.3%) and 13–24 (36.5%) months although this difference was not statistically significant (χ² = 10.98, df =8, p = 0. 203). The marasmic-kwashiokor and unclassified groups had higher mortality rates (53.3% and 54.5% respectively) than the marasmus (37.8%) or kwashiorkor groups (30%). There was a statistically significant difference in the mortality rates of the various types of PEM as shown in Table 5 (χ² = 17.26, df =4, p = 0. 002) The number of complications ranged from none to four. Kwashiokor has the highest mean number of complications (2.06) while unclassified had the least number of 1.26. There was a statistically significant difference in the number of complications and the various PEM (F = 8.92, df =4, P <0.05)

High PEM associated mortality

The overall mortality in our study was 40.1% which although lower than the WHO estimated 60%[2] is still very high. Studies conducted in various parts of Africa have documented unacceptable high mortality rates among children admitted for PEM. In Oshogbo, South West Nigeria, Ibekwe and Ashworth [6] documented an average mortality rate of 22% over a five year period among 803 children admitted for PEM in a Nutritional Rehabilitation Center. Similarly, in a hospital based study in north-eastern Zambia, involving children below the age of five years, Gernaat et al.[4] documented an overall mortality rate of 25.8% among 288 children admitted for various types of severe/complicated malnutrition . Higher mortality rate for marasmic kwashiorkor than marasmus or kwashiorkor was noted in this review. Gernaat et al.[4] noted similar finding in their review among Zambian children admitted and managed for PEM. This reason for this is unclear. However, Ibekwe and Ashworth [6] did note that PEM associated mortality among oedematous patients was significantly higher compared to those with marasmus. It can be argued therefore, that presence of oedema in a malnourished child connotes poor prognosis. The mean duration of hospitalization was 16 days which is similar to 13.1 and 14.3 days reported by Cartmell et al. [13] but differs from the 35 days reported by Ibekwe and Ashworth [6]. Both this review and the study by Cartmell et al. were hospital based while that of Ibekwe and Ashworth was conducted in a Nutrition Rehabilitation Center. The pressure on bed spaces in a hospital setting could have contributed to earlier discharges in hospital settings.

Associated risk factors for PEM

Our review noted that PEM was more common among children from the lower social class (69.4%) and those predominantly breast fed for three months or less (48.6%) compared to exclusively breast fed children (18.9%). The reason for this may not be unconnected to the fact that poor families have low purchasing power for adequate nutritious foods for their families. Illiteracy on the other hand, may influence feeding practices. The low rate of exclusive breast feeding noted in this review despite the Baby Friendly Initiatives is also very worrisome. Poverty and illiteracy as risk factors for PEM have been documented in the literature. . In a case control study conducted in Dhaka, Bangladesh which involved children aged six to 24 months, Nahar et al.[15] compared 507 children with weight-for-age z-score (WAZ) < −3 matched for age, sex and place of residence with 500 children whose weight-for-age z-score (WAZ) were > −2.5 . They documented that severely-underweight children were more likely to have: undernourished poorly educated teenage mothers, history of shorter duration of predominant breastfeeding, and fathers who were poorly educated and unskilled day-labourers [15].

Diarrhea, malaria, sepsis and severe anaemia were the most prevalent associated co-morbidities from our review in that order. In Maputo, the most prevalent co-morbidities associated with PEM by Cartmell et al. were anaemia, bronchopneumonia, malaria and diarrhea. The prevalence of human immune deficiency virus (HIV) from our review was 13.6% and this compares to a prevalence of 12% in the Maputo study. This finding underscored the high rate of HIV infection among children with severe forms of PEM and the need to routinely screen such children for HIV when they present at a health facility.

Conclusions

Younger children aged less than two years accounted for most of the admissions in this review. Marasmic-kwashiokor was associated with higher case fatality rate than other types of PEM. There is need therefore to strengthen the infant feeding practices by promoting exclusive breastfeeding for the first 6 months of life, followed by appropriate weaning with continued breast feeding till second year of life. PEM was associated with high rate of mortality in this hospital setting and preventive strategies need to be emphasized instead.

Below are 10 interesting facts about poverty and malnutrition.

  1. Malnutrition takes two general forms. Protein-energy malnutrition, which is basically a lack of calories and protein. This form of malnutrition is the most lethal and is the type of malnutrition that is referred to when world hunger is discussed. The second type of malnutrition is micronutrient or vitamin and mineral deficiency.
  2. According to The United Nations Food and Agriculture Organization, it is estimated that nearly 870 million people of the 7.1 billion people in the world – or one in eight – were suffering from chronic undernourishment in 2010-2012.
  3. Poverty and malnutrition have a direct link – poverty is the main and principal cause of malnutrition. The World Bank estimated that in 2008 that there were about 1.35 million poor people in developing countries who live on $1.25 a day or less.
  4. In addition to poverty, the other main causes of malnutrition are harmful economic systems, war and conflict and climate change.
  5. The countries with the highest rates of malnutrition also have the lowest economic indicators.
  6. Children are the most vulnerable victims of malnutrition.  Poor nutrition plays a role in at least half of the 10.9 million child deaths each year.
  7. Mothers who lack access to proper nutrients bear malnourished children. These children face greater challenges in their ability to learn and thrive. They are more susceptible to illness and disease. Their compromised opportunities for healthy development and mental and physical agility usually means the cycle of poverty continues.
  8. In another link between poverty and malnutrition, the WHO reports that one out of three people in developing countries are affected by vitamin and mineral deficiencies.
  9. The world produces enough food to feed everyone. The real problem is that many people in the world do not have sufficient land to grow or income to purchase enough food. Poverty and malnutrition can create a self-sustaining cycle where there is never enough security or stability for recovery of health or economic development.
  10. Some countries address the problem of poverty and malnutrition by administering programs that provide assistance to those who suffer from a lack of nutrients in their diet by offering dietary supplements and fortified foods. This is seen as a cost-effective strategy in combating poverty and malnutrition.

– Nina Verfaillie

http://borgenproject.org/10-facts-poverty-malnutrition/

Chapter 12. Protein-energy malnutrition

http://www.fao.org/docrep/w0073e/w0073e05.htm

Protein-energy malnutrition (PEM) in young children is currently the most important nutritional problem in most countries in Asia, Latin America, the Near East and Africa. Energy deficiency is the major cause. No accurate figures exist on the world prevalence of PEM, but World Health Organization (WHO) estimates suggest that the prevalence of PEM in children under five years of age in developing countries has fallen progressively, from 42.6 percent in 1975 to 34.6 percent in 1995. However, in some regions this fall in percentage has not been as rapid as the rise in population; thus in some regions, such as Africa and South Asia, the number of malnourished children has in fact risen. In fact the number of underweight children worldwide has risen from 195 million in 1975 to an estimated 200 million at the end of 1994, which means that more than one-third of the world’s under-five population is still malnourished.

Failure to grow adequately is the first and most important manifestation of PEM. It often results from consuming too little food, especially energy, and is frequently aggravated by infections. A child who manifests growth failure may be shorter in length or height or lighter in weight than expected for a child of his or her age, or may be thinner than expected for height.

The conceptual framework described in Chapter 1 suggests that there are three necessary conditions to prevent malnutrition or growth failure:

If any one of these is absent, PEM is a likely outcome.

The term protein-energy malnutrition entered the medical literature fairly recently, but the condition has been known for many years. In earlier literature it was called by other names, including protein-calorie malnutrition (PCM) and protein-energy deficiency.

The term PEM is used to describe a broad array of clinical conditions ranging from the mild to the serious. At one end of the spectrum, mild PEM manifests itself mainly as poor physical growth in children; at the other end of the spectrum, kwashiorkor (characterized by the presence of oedema) and nutritional marasmus (characterized by severe wasting) have high case fatality rates.

It has been known for centuries that grossly inadequate food intake during famine and food shortages leads to weight loss and wasting and eventually to death from starvation. However, it was not until the 1930s that Cicely Williams, working in Ghana, described in detail the condition she termed “kwashiorkor” (using the local Ga word meaning “the disease of the displaced child”). In the 1950s kwashiorkor began to get a great deal of attention. It was often described as the most important form of malnutrition, and it was believed to be caused mainly by protein deficiency. The solution seemed to be to make more protein-rich foods available to children at risk. This stress on kwashiorkor and on protein led to a relative neglect of nutritional marasmus and adequate food and energy intakes for children.

The current view is that most PEM is the result of inadequate intake or poor utilization of food and energy, not a deficiency of one nutrient and not usually simply a lack of dietary protein. It has also been increasingly realized that infections contribute importantly to PEM. Nutritional marasmus is now recognized to be often more prevalent than kwashiorkor. It is unknown why a given child may develop one syndrome as opposed to the other, and it is now seen that these two serious clinical forms of PEM constitute only the small tip of the iceberg. In most populations studied in poor countries, the point prevalence rate for kwashiorkor and nutritional marasmus combined is 1 to 5 percent, whereas 30 to 70 percent of children up to five years of age manifest what is now termed mild or moderate PEM, diagnosed mainly on the basis of anthropometric measurements.

Causes and epidemiology

PEM, unlike the other important nutritional deficiency diseases, is a macronutrient deficiency, not a micronutrient deficiency. Although termed PEM, it is now generally accepted to stem in most cases from energy deficiency, often caused by insufficient food intake. Energy deficiency is more important and more common than protein deficiency. It is very often associated with infections and with micronutrient deficiencies. Inadequate care, for example infrequent feeding, may play a part.

The cause of PEM (and of some other deficiency diseases prevalent in developing countries) should not, however, be viewed simply in terms of inadequate intake of nutrients. For satisfactory nutrition, foods and the nutrients they contain must be available to the family in adequate quantity; the correct balance of foods and nutrients must be fed at the right intervals; the individual must have an appetite to consume the food; there must be proper digestion and absorption of the nutrients in the food; the metabolism of the person must be reasonably normal; and there should be no conditions that prevent body cells from utilizing the nutrients or that result in abnormal losses of nutrients. Factors that adversely influence any of these requisites can be causes of malnutrition, particularly PEM. The aetiology, therefore, can be complex. Certain factors that contribute to PEM, particularly in the young child, are related to the host, the agent (the diet) and the environment. The underlying causes could also be categorized as those related to the child’s food security, health (including protection from infections and appropriate treatment of illness) and care, including maternal and family practices such as those related to frequency of feeding, breastfeeding and weaning.
Protein-Energy Malnutrition

http://emedicine.medscape.com/article/1104623-overview

The World Health Organization (WHO)[1] defines malnutrition as “the cellular imbalance between the supply of nutrients and energy and the body’s demand for them to ensure growth, maintenance, and specific functions.” The term protein-energy malnutrition (PEM) applies to a group of related disorders that include marasmus, kwashiorkor (see the images below), and intermediate states of marasmus-kwashiorkor. The term marasmus is derived from the Greek word marasmos, which means withering or wasting. Marasmus involves inadequate intake of protein and calories and is characterized by emaciation. The term kwashiorkor is taken from the Ga language of Ghana and means “the sickness of the weaning.” Williams first used the term in 1933, and it refers to an inadequate protein intake with reasonable caloric (energy) intake. Edema is characteristic of kwashiorkor but is absent in marasmus.

This photograph shows children and a nurse attendant at a Nigerian orphanage in the late 1960s. Notice four of the children with gray-blond hair, a symptom of the protein-deficiency disease kwashiorkor. Image courtesy of Dr. Lyle Conrad and the CDC Public Health Image Library.

This late 1960s photograph shows a seated, listless child who was among many kwashiorkor cases found in Nigerian relief camps during the Nigerian-Biafran war. Kwashiorkor is a disease brought on due to a severe dietary protein deficiency, and this child, whose diet fit such a deficiency profile, presented with symptoms including edema of legs and feet, light-colored, thinning hair, anemia, a pot-belly, and shiny skin. Image courtesy of Dr. Lyle Conrad and the CDC Public Health Image Library.

Studies suggest that marasmus represents an adaptive response to starvation, whereas kwashiorkor represents a maladaptive response to starvation. Children may present with a mixed picture of marasmus and kwashiorkor, and children may present with milder forms of malnutrition. For this reason, Jelliffe suggested the term protein-calorie (energy) malnutrition to include both entities.

Although protein-energy malnutrition affects virtually every organ system, this article primarily focuses on its cutaneous manifestations. Patients with protein-energy malnutrition may also have deficiencies of vitamins, essential fatty acids, and trace elements, all of which may contribute to their dermatosis.

In general, marasmus is an insufficient energy intake to match the body’s requirements. As a result, the body draws on its own stores, resulting in emaciation. In kwashiorkor, adequate carbohydrate consumption and decreased protein intake lead to decreased synthesis of visceral proteins. The resulting hypoalbuminemia contributes to extravascular fluid accumulation. Impaired synthesis of B-lipoprotein produces a fatty liver.

Protein-energy malnutrition also involves an inadequate intake of many essential nutrients. Low serum levels of zinc have been implicated as the cause of skin ulceration in many patients. In a 1979 study of 42 children with marasmus, investigators found that only those children with low serum levels of zinc developed skin ulceration. Serum levels of zinc correlated closely with the presence of edema, stunting of growth, and severe wasting. The classic “mosaic skin” and “flaky paint” dermatosis of kwashiorkor bears considerable resemblance to the skin changes of acrodermatitis enteropathica, the dermatosis of zinc deficiency.

In 2007, Lin et al[2] stated that “a prospective assessment of food and nutrient intake in a population of Malawian children at risk for kwashiorkor” found “no association between the development of kwashiorkor and the consumption of any food or nutrient.”

Marasmus and kwashiorkor can both be associated with impaired glucose clearance that relates to dysfunction of pancreatic beta-cells.[3] In utero, plastic mechanisms appear to operate, adjusting metabolic physiology and adapting postnatal undernutrition and malnutrition to define whether marasmus and kwashiorkor will develop.[4]

United States

Protein-energy malnutrition is the most common form of nutritional deficiency among patients who are hospitalized in the United States. As many as half of all patients admitted to the hospital have malnutrition to some degree. In a recent survey in a large children’s hospital, the prevalence of acute and chronic protein-energy malnutrition was more than one half. This is very much a disease that occurs in 21st century America, and a case in an 8-month-old child in suburban Detroit, Mich, was reported in 2010.[9] Additional cases of kwashiorkor have been noted to occur in the United States. An interesting report of a baby with a clinical picture imitating Stevens-Johnson syndrome but who in fact had kwashiorkor has been noted.[10] Babies solely fed on rice milk can develop kwashiorkor even in the United States.

In a survey focusing on low-income areas of the United States, 22-35% of children aged 2-6 years were below the 15th percentile for weight. Another survey showed that 11% of children in low-income areas had height-for-age measurements below the 5th percentile. Poor growth is seen in 10% of children in rural populations.

In hospitalized elderly persons, up to 55% are undernourished. Up to 85% of institutionalized elderly persons are undernourished. Studies have shown that up to 50% have vitamin and mineral intake that is less than the recommended dietary allowance and up to 30% of elderly persons have below-normal levels of vitamins and minerals.

International

In 2000, the WHO[11] estimated that malnourished children numbered 181.9 million (32%) in developing countries. In addition, an estimated 149.6 million children younger than 5 years are malnourished when measured in terms of weight for age. In south central Asia and eastern Africa, about half the children have growth retardation due to protein-energy malnutrition. This figure is 5 times the prevalence in the western world.

A cross-sectional study of Palestinian adolescents found that 55.66% of boys and 64.81% of girls had inadequate energy intake, with inadequate protein intake in 15.07% of boys and 43.08% of girls. The recommended daily allowance for micronutrients was met by less than 80% of the study subjects.[12]

Mortality/Morbidity

Approximately 50% of the 10 million deaths each year in developing countries occur because of malnutrition in children younger than 5 years. In kwashiorkor, mortality tends to decrease as the age of onset increases.

Race

Dermatologic findings appear more significant and occur more frequently among darker-skinned peoples. This finding is likely explained by the greater prevalence and the increased severity of protein-energy malnutrition in developing countries and not to a difference in racial susceptibility.

The hungry and forgotten

Reprints

chinese child

chinese child

Pilot projects in cooperation with the Ministry of Health have demonstrated the effectiveness of Ying Yang Bao, a simple easy-to-use complementary food supplement, in preventing and controlling childhood malnutrition.UNICEF has been supporting intensive efforts on finding solutions.

Even where children get the calories they need—as most do in rural China—they are not being fed the right things. In one study of 1,800 infants in rural Shaanxi province in China’s north-west, 49% were anaemic and 40% were significantly hampered in developing either cognitive or motor skills. Fewer than one in ten were stunted or wasting, meaning that in most cases the problem was not lack of calories, but lack of nutrients.

China shares this affliction with much of the developing world. But it has the resources to respond. Parents have the means to feed their babies properly. And with a relatively modest investment, the government could do a better job of improving childhood nutrition. The difficulties lie in educating parents—and officials.

“Babies are probably 50% malnourished” in poor rural areas, says Scott Rozelle, co-director of the Rural Education Action Programme (REAP), a research outfit at Stanford University which has done extensive tests on anaemia in rural China. “But almost no mums are malnourished.” Mr Rozelle says that in one of his surveys rural mothers showed a better understanding of how to feed pigs than babies: 71% said pigs need micronutrients, whereas only 20% said babies need them.

Mr Lu’s charity and REAP argue that a nutritional supplement called ying yang bao should be available to rural mothers. A powdery concoction of soyabeans, iron, zinc, calcium and vitamins, it is supposed to be sprinkled on food once a day. Each packet costs less than one yuan (16 cents) to produce and one yuan to distribute, paid by the government.

Trials conducted since 2006 have consistently shown that ying yang bao reduces anaemia and improves growth and development in infants and toddlers. But persuading parents of this (or grandparents, if the parents are off working in cities) has not been easy. About half give up feeding it to their children. “Poor people feel very suspicious”, Mr Lu says. They wonder if free supplements are unsafe, or fake. “Then they worry will we charge later?”

This may be the legacy in rural China of years of seeing government invest little—and often charge a lot—for basic services. Moreover, at the local level the workers who are meant to help mothers may well be family-planning officials responsible for controlling population, a role that hardly inspires trust.

At higher levels of government, too, officials need a lot of persuading that nutrition programmes are not a waste of public money. In 2011 China began instituting a programme similar to America’s federal school-lunch programme for the poor, at a cost of 16 billion yuan ($2.6 billion) a year. But one assessment suggests that perhaps half the schools are providing substandard, uncooked meals, partly because some local governments refuse to foot the bill for kitchens and cooks.

In 2012 the health ministry made a modest investment of 100m yuan to provide supplements to 270,000 babies in 100 counties. This year 400,000 babies in 300 counties are meant to get them. Later this year Mr Lu’s charity will begin a tiny pilot of an early-parenting programme, akin to America’s Head Start, in 50 villages, with 50 more villages being used for controlled comparison. James Heckman, an economist and Nobel laureate who has researched early-childhood development, is helping design the study. Such programmes look promising. But they are tiny.

Part of the problem in getting local or provincial governments to spend money on childhood nutrition is that the payoffs are years in the making. And the returns might not go to the village or province, but to cities miles away, in the form of more skilled workers who move there. Central ministries are keen to invest, Mr Lu says, but they want to spend their cash on things that officials crave more than children do—like buildings in villages for each ministry.

For Mr Lu one kind of building does promise a big payoff—village early-education centres, or preschools. His charity has set them up in 677 villages, often using redundant elementary schools. In Songjia village Tian Lin, 22, and her older sister, Tian Hongjiao, teach 26 children aged three to six, including the younger sister’s own three-year-old son. They cook lunch with whatever the children bring from home. Those with migrant-worker parents, who are a bit better off, may have a chunk of pork; others bring a meagre potato or vegetable. Either way all the children get a ying yang bao with their lunch.

In 2012 a study found the anaemia rate among the three- to five-year-olds in this county was close to 18%, more than twice the average for poor rural areas nationwide, according to Mr Lu’s CDRF. He reckons that, on coming to the centres, the children show only 20% of the memory retention of their urban counterparts and 40-60% of their language abilities and cognition. But nutritional supplements help. A study of nine- and ten-year olds, co-written by Mr Rozelle, found that taking a daily chewable vitamin with iron for six months not only cut anaemia levels. It also improved their maths.

pre-school centre in Songjia

pre-school centre in Songjia

Malnutrition Plagues Children of Rural China
China became an economic superpower in only a matter of decades. Forbes Magazine’s annual rich list reported that China has had 152 billionaires this past year. The once struggling nation has shown promising improvement. According to the World Bank, the number of impoverished people living in China dropped from 683 million in 1990 to 157 million in 2009. This improvement is a result of the rapid urbanization in China in recent years. Greater economic opportunity and government assistance is now available in cities. However, children in rural villages are stuck in a seemingly unbreakable cycle of poverty.

The children of rural China face a variety of challenges that are virtually nonexistent in the cities. Among one of the most glaring is the struggle against malnutrition. UNICEF estimates that there are 12.7 million stunted children in China; this life-long condition that results from severe malnutrition plagues children most during early childhood.

stunted due to malnutrition during his first two years of life.

Lttle Han’s elder brother (right) is 9-years-old and stands barely 1.2 meter tall. It is likely that he is stunted due to malnutrition during his first two years of life.

Back home, noodles without beef and porridge are the staple foods. For an average rural family in Hualong, potato is almost their sole source of vegetable.  Beef and mutton are only consumed during rare festive occasions.

Many families cannot afford to keep any sheep or cattle, therefore both milk and meat can be rarely found on the dining table.

“Babies eat the same food as their mothers after breastfeeding stops – we all know there is not enough nutrition for them, but we didn’t know what to do,” said Dr. Wang Chunhua, from the  township hospital,. She has delivered over 500 babies during her 10 years’ service in Hualong.

In addition to malnutrition, anemia takes a tremendous toll on rural Chinese children. Stanford University conducted a test on 1824 babies in China’s Shaanxi Province. Forty nine percent of the babies tested were anemic and 28 percent were near anemic. Furthermore, of all the babies tested, 40 percent displayed cognitive or motor problems.

Why are rates of anemia so high? Stanford reports that while the parents were generally willing to spend additional money on food for their children, they were uninformed on what type of nutritional value the food should have. Many micronutrients, such as iron, were missing, indicating that fresh fruits and vegetables were consumed infrequently. Additionally, further investigation revealed that mothers stopped breastfeeding after six months. From that point on, the child would typically eat rice porridge or soups.

Misinformed parents are often responsible for their children’s poor health. Parents often do not introduce solid food into children’s diets until they are 12 to 18 months old, though it is recommended that solid food make up half of a one-year-old’s diet. Many parents believe myths that babies cannot digest hard foods or that particular foods, like rice, are better for cognitive development.

Treating anemia and replenishing nutrients is actually quite easy. Stanford researchers state that simply taking iron supplements can counter anemia. To address the rampant malnutrition in China’s poor, rural provinces, UNICEF has begun to distribute a nutrition supplement called Ying Yang Bao. Ying Yang Bao is a small packet of powdered vitamins, minerals and proteins that can be mixed into solid foods like porridge.

Many rural Chinese families cannot afford to buy fresh fruits, vegetables and proteins like beef. Dairy products are also expensive and difficult to access. Often, noodles, porridge, rice and starches like potatoes constitute meals. Fortunately, the micronutrients in Ying Yang Bao are easily dissolved in porridges and soups.

UNICEF reports that, between 2008 and 2011, more than 30,000 rural children received Ying Yang Bao. After consumption, anemia levels were cut in half. A long-term solution to malnutrition is still in the works. While aid from UNICEF and other organizations is improving the health of rural children, education is a key issue to be addressed. Parents are misguided by myths and superstitions, which has led to the silent suffering on many children. A public education program has not been officially instituted, but would be another component of China’s long-term solution for malnutrition.

– Bridget Tobin

Child: Care, Health and Development

Volume 31Issue 4pages 417–423July 2005

Abstract

Background  China has the largest population in the world with more than 70% of the people living in rural areas. Over 34% of children under the age of 5 years are responded to show moderate or severe growth stunting, so United Nations International Children’s Emergency Fund and Chinese Ministry of Health conducted this large-scale survey in China. This study aimed to learn the feeding practice, to find the problems in child-feeding practice and to provide evidence for the government to develop an approach to child malnutrition in rural China.

Methods  A structured  questionnaire  was  used  to  survey  21 036  mothers  of  children  with  age  of 0–24 months.

Results  Of the 20 915 children, 98.22% were breastfeeding and 24.36% were exclusively breastfeeding. The proportion of children with weekly protein intake was 78.47%. Among the infants under 4 months, the risk of pneumonia in the group of exclusive breastfeeding was 1.69%, while in the group of non-exclusive breastfeeding was 3.63%, showing a statistically significant difference between the two groups. The risk of diarrhoea in the group of exclusive breastfeeding and in the group of non-exclusive breastfeeding among the infants under 4 months was 24.37% and 40.86%, respectively, also showing a statistically significant difference between the two groups. For children with age 4–6 months, the complementary feeding contributed to a higher prevalence of diarrhoea, but not pneumonia.

Conclusions  The breastfeeding was very common, but the exclusive breastfeeding was quite low and the exclusive breastfeeding for children under the age of 4 months decreased the risks of pneumonia and diarrhoea. For children with age 4–6 months, the exclusive breastfeeding could decrease the risk of diarrhoea, too. Protein intake was insufficient for children in rural China. The rural people lacked health knowledge and were greatly influenced by traditional feeding practices.

Physical growth of children and adolescents in China over the past 35 years

Xin-Nan Zong a & Hui Li a

  1. Department of Growth and Development, Capital Institute of Pediatrics, No. 2 Yabao Road, Chaoyang District, Beijing 100020, China.

Correspondence to Hui Li (email: huiligrowth@163.com).

(Submitted: 18 June 2013 – Revised version received: 10 December 2013 – Accepted: 14 January 2014 – Published online: 05 June 2014.)

Bulletin of the World Health Organization 2014; 92:555-564. doi: http://dx.doi.org/10.2471/BLT.13.126243

Introduction

In 1978, the Government of China introduced economic reforms to convert the country’s planned economy into a free-market system. Since then, sustained economic productivity has greatly increased the food supply, average household income and personal expenditure on food.1,2 With increasing urbanization, the average Chinese diet has become higher in fat and calories, and lower in dietary fibre.3 Also, the level of physical activity during work and leisure time has declined.4In short, dietary changes after these economic reforms have been accompanied by a rise in diseases related to affluence.5,6

Child-growth assessments are useful not only for monitoring a population’s nutritional status, but also for gauging inequalities in human development among different populations.7 Although many growth and nutrition surveys among children and adolescents have been carried out in China,8,9 few have tried to link trends in child growth and nutrition to changes in economic development. One study that evaluated the effects of China’s economic reforms on the growth of children showed an increase in the average height of children in both rural and urban areas. However, the increase in urban areas was five times that of rural areas.10

Since the economic reforms, income inequalities have increased between western rural areas and coastal areas, as well as between and within rural and urban areas.11These inequalities have probably influenced the regional distribution of malnutrition and how this distribution has changed over time.12

The objective of this paper is to give an overall picture of long-term trends in the growth and nutritional status of Chinese children and adolescents by examining the results of seven large surveys conducted over the past 35 years. We focused on regional disparities in child and adolescent growth and nutritional status, as well as on changes in the pattern and rates of malnutrition after the transition to a more high-fat, high-energy-density and low-fibre diet in an attempt to determine if these changes were associated with the country’s economic development.

Methods

Data procurement

Growth and nutrition data

Data on the growth and nutritional status of children and adolescents between 0 and 18 years of age were extracted from published data and raw datasets of seven large surveys undertaken in one or more areas with different economic characteristics in China between 1975 and 2010. The following surveys were included: National Growth Survey of Children under 7 years in the Nine Cities of China; National Growth Survey for Rural Children under 7 years in the Ten Provinces of China; National Epidemiological Survey on Simple Obesity in Childhood; Chinese National Survey on Students’ Constitution and Health; China National Nutrition Survey; Chinese Food and Nutrition Surveillance system and China Health and Nutrition Survey. A summary of these surveys can be found in Table 1.

Classification of economic areas was based on five indices: regional gross domestic product (GDP), total yearly income per capita, average food consumption per capita, natural growth rate of population, and the regional social welfare index.8 The areas were categorized from highest to lowest economic status as large coastal cities, high, medium or low cities, high, medium or low rural areas and poor western rural areas.

Economic data

Development indicators for China were obtained from the World Bank;29 GDP per capita, the Gini index and the percentage of the population living in urban areas between 1970 and 2012.

Mortality data

Mortality rates for infants and for children less than 5 years of age between 1990 and 2013 were obtained from the Global Burden of Disease study.30

Dietary data

Dietary data for children and adolescents – daily intake of calories, fats, and protein – were obtained from the China Health and Nutrition Survey24 and the China National Nutrition Survey.20

Sedentary behaviour and physical activity

To describe trends in the level of physical activity, data on sedentary behaviour (hours per day watching television or videos or using the computer) and on passive commuting to and from school were obtained from replies to the China Health and Nutrition Survey questionnaire.25,26

Data analysis

Since the study designs, location and demographic characteristics of the population vary among the surveys, data from subsequent rounds of the same survey were used to assess trends. We assessed undernutrition using data for underweight and stunting. Underweight was defined as less than minus two standard deviations from the median weight-for-age of the reference population. Stunting was defined as less than minus two standard deviations from median height-for-age of the reference population. We assessed obesity using data for both overweight and obesity as defined by the Working Group on Obesity in China, adjusted for each year of age.31

We examined the statistical associations between physical growth and economic development using ecological comparisons and trends. To explore the relationship between height and GDP and urbanization and infant and child mortality rates, we calculated Pearson’s correlation coefficients (r), adjusting for sex. Trends in the prevalence of underweight, stunting, overweight and obesity were assessed using the χ2 test. SPSS version 13.0 (SPSS Inc., Chicago, United States of America) was used for the statistical analyses.

Results

Secular trends in growth

Between 1975 and 2010, the average height of children and adolescents increased steadily, without any tendency to plateau. The largest increment was noted around puberty, particularly among males, e.g. an increase of 11.9 cm in 13-year-old urban boys. The difference in height between the sexes at 18 years of age increased from 10.3 cm to 12.3 cm during this same period.

Body weight increased in both sexes and all age groups from 1985–2010. After 2005, in all age categories boys were heavier than girls (Fig. 1). To assess whether the increase in adolescents’ average height was associated with economic development – as captured by urbanization, GDP per capita and the Gini index – (Fig. 2), we looked for correlations between two of these indicators and the average height of adolescents 17–18 years of age.

Fig. 1. Changes in physical height and body weight of children and adolescents living in Chinese urban areas, 1975–2010

Fig. 1. Changes in physical height and body weight of children and adolescents living in Chinese urban areas, 1975–2010

Fig. 1. Changes in physical height and body weight of children and adolescents living in Chinese urban areas, 1975–2010

Sample size: n = 140 229 aged 0–18 years in 1975; n = 79 194 for children less than 7 years of age in 1985; n = 79 154 for children less than 7 years of age in 1995; n = 69 760 for children less than 7 years of age in 2005; n = 204 973 aged 7–18 years in 1985; n = 105 409 aged 7–18 years in 1995; n = 117 997 aged 7–18 years in 2005 and n = 107 574 aged 7–18 years in 2010.
Data sources: National Growth Survey of Children under 7 years in the Nine Cities of China13 and Chinese National Survey on Students Constitution and Health.32

Fig. 2. Trends in gross domestic product (GDP) per capita, Gini index, urban population and child mortality rate in China, 1975–2010

Height showed a close correlation with GDP

Height showed a close correlation with GDP

US$, United States dollars.
Data sources: GDP, Gini index and urban population from the World Bank;29 infant mortality and under-5 years mortality rates from the World population prospects: the 2010 revision.30

Height showed a close correlation with GDP per capita (r = 0.90, P < 0.0001) and with urbanization (r = 0.92, P < 0.0001). We also looked for a correlation between the decline in infant and under-5 mortality rates (Fig. 2) and average height and observed that they were both negatively correlated (r = −0.95; P < 0.0001), even after sex adjustment (r = −0.94; P < 0.0001).

Geographical disparities

Differences in height were observed in areas having different economic characteristics. Data from the National Growth Survey of Children under 7 years in Nine Cities of China and the National Growth Survey for Rural Children under 7 years in Ten Provinces of China showed that, on average, children of both sexes in rural areas were 2.1 cm (standard deviation, SD: 1.2) shorter than those in suburban areas and 3.6 cm (SD: 2.0) shorter than those in urban areas.

According to the Chinese National Survey on Students’ Constitution and Health, children and adolescents between 7 and 18 years of age who lived in a coastal city were taller, on average, than those living in other provincial capitals. They were also markedly taller, on average, than those living in medium-sized or small cities. Similar differences were observed among rural areas showing high, moderate and poor economic development (Fig. 3).

Fig. 3. Physical heighta in children and adolescents of different economic status groups, China, 2005

National Growth Survey of Children under 7 years in the Nine Cities of China

National Growth Survey of Children under 7 years in the Nine Cities of China

a Height was measured as length for children less than 3 years of age.
Sample size: n = 69 760 urban children less than 7 years of age; n = 69 015 suburban children less than 7 years of age; n = 95 925 rural children less than 7 years of age;n = 81 438 urban children and adolescents aged 7–18 years; n = 111 584 rural children and adolescents aged 7–18 years.
Data sources: National Growth Survey of Children under 7 years in the Nine Cities of China,13 National Growth Survey for Rural Children under 7 years in the Ten Provinces of China9 and Chinese National Survey on Students Constitution and Health.17,18

Trends in malnutrition

The prevalence of undernutrition in children less than 5 years of age was highest in poor rural areas. Compared with the 1990s, the overall prevalence of undernutrition has declined sharply – by 74% for underweight and 70% for stunting. Significant downward trends in the prevalence of both underweight and stunting were observed for all areas (P < 0.001). However, in poor rural areas in 2010, the prevalence of underweight and stunting was still high, at 8.0% and 20.3%, respectively (Fig. 4).

Fig. 4. Trends in underweighta and stuntingb in children less than 5 years of age, China, 1990–2010

below minus two standard deviations from median weight-for-age of the reference population

below minus two standard deviations from median weight-for-age of the reference population

a Underweight was defined as below minus two standard deviations from median weight-for-age of the reference population.
b Stunting was defined as below minus two standard deviations from median height-for-age of the reference population.
Sample size: n = 3200 rural children and n = 1130 urban children in 1990; n = 2139 rural children and n = 765 urban children in 1995; n = 10 729 rural children and n = 5770 urban children in 2000; n = 10 501 rural children and n = 5535 urban children in 2005; n = 10 596 rural children and n = 4803 urban children in 2010.
Data source: Chinese Food and Nutrition Surveillance System.21–23

In 2010, the combined prevalence of overweight and obesity was found to be highest among urban boys (23.2%), followed by rural boys (13.8%), urban girls (12.7%) and rural girls (8.6%). Significant increases were noted in the combined prevalence of overweight and obesity in all groups (P < 0.001) (Fig. 5). Between 1985 and 2010, the proportion of obese males increased faster than that of obese females. In urban areas, male obesity increased 0.34 percentage points per year, compared with 0.15 for female obesity. In rural areas, the increase was 0.18 percentage points per year for male obesity, compared with 0.10 for female obesity. The increase in obesity in urban areas between 1985 and 2000 was twice that of the increase in rural areas during the same time period. However, between 2005 and 2010, the annual increase in obesity in rural areas has outpaced that of urban areas (0.34 versus 0.30 percentage points in males and 0.17 versus 0.10 percentage points in females).

Fig. 6 (not shown) illustrates the burden of obesity in areas with different economic characteristics. Large coastal cities were the first to exhibit a rise in overweight and obesity and had the largest increase in prevalence – 32.6% (males) and 19.1% (females) in 2010. Similar increases followed in other areas: first in large, prosperous cities, followed by medium-sized cities with a large middle class and, finally, by the more affluent rural areas. Although an increase in obesity was noted between 1985 and 2010 in western rural areas with low economic development, these areas still had the lowest prevalence of obesity in 2010.

Trends in nutrition and physical activity

To assess whether factors associated with increased body weight in children and adolescents were affected by China’s economic reforms, we obtained data on fat and protein intake and level of physical activity. Between 1991 and 2009, people’s diets in China changed considerably. For children and adolescents between 7 and 17 years of age, the average daily fat intake increased from 55 to 66 g and the average daily protein intake decreased from 66 to 58 g. There was also an increase in fats as a proportion of total caloric intake and an increase in the proportion of children and adolescents obtaining more than 30% of their energy from fat. In addition, during this period time spent in front of a television, video or computer also increased, as did the proportion of children and adolescents who commuted to school in a motorized vehicle (Fig. 7)(not shown).

The economic transition

In the wake of the 1978 reforms, China underwent many changes in its social structures, living conditions and diet. This has been accompanied by a positive trend in the physical growth of children.33 An empirical division of China’s economic development into stages based on the time cycle of China growth surveys facilitates the analysis of its association with trends in children’s growth. In Stage I (before 1975) – out of scope of this analysis – a previous subtle upward trend in growth ceased and even reversed owing to the detrimental effects of famine. In Stage II (1975–1985), children’s growth began to improve again with the recovery of the national economy, and positive trends emerged in older age groups of children in the major cities. In Stage III (1985–1995), physical growth continued to improve in parallel with sustained economic growth. The increment in height among children in rural areas exceeded that seen in children living in urban areas because of improved living standards, health care and increased food supply in the rural areas in the mid-1980s.9 In Stage IV (1995–2005), even higher growth increments were documented among both urban and rural residents. According to data from 2005 to 2010 (Stage V), the increment has continued and does not seem to be levelling off.34

The growth of children in China has improved in recent decades and this improvement is more pronounced at puberty than at earlier or later ages, consistent with other population-based studies.35 The increase in height at the age of 18 years is already present in younger ages and the eventual increase in adult height is established during the first 2 years of life.

In the Netherlands, the secular increase in growth has come to a halt after 150 years, with males now 13.1 cm taller on average than females.36 Since sex difference in adult height widens gradually as secular increases in growth continue, the difference of 12.3 cm between the sexes in 2010 suggests that the positive trend in Chinese children may continue.

Before the economic reforms, food had been in short supply,3 but after 1978, when a policy of liberal food production was introduced and annual economic growth improved, people began to eat more meat and grains and less vegetables. Child growth and nutrition improved and overweight and obesity were still rare. In 1985 and 1986, the prevalence of obesity in children and adolescents was below 1% in large cities.15,19

In 1986, China started its first specific survey on obesity and found that the Chinese diet had become richer in fats and calories and lower in fibre, a change that was introducing an increased risk of chronic diseases.37,38 Obesity among infants and preschool children increased by a factor of 2.8 between 1986 and 2006.15 And between 1985 and 2010, overweight among school-aged children and adolescents increased from 1.11% to 9.62% and obesity from 0.13% to 4.95%.16 Additionally, between 1993 and 2009 the prevalence of obesity rose from 6.1% to 13.1% among children between the ages of 6 and 17 years.39 The higher prevalence of overweight males contrasts with the situation in some non-Asian countries.40

In 2012, for the first time in history, China’s urban population outnumbered its rural population.41 This urbanization can be seen as a double-edged sword. Although it has brought increased access to health care and improvements in basic health infrastructure for many, it has also brought about changes in diet and lifestyle, such as an increase in the availability of sweets and fast-food restaurants and in the use of television, personal computers and cars, all of which can pose substantial health risks.42,43

We have shown that in recent decades fat intake and physical inactivity have risen among Chinese children, with a resulting increase in childhood obesity and a documented decline in physical fitness. For instance, the capacity for endurance running among Chinese students declined significantly between 1985 and 2010.32,44

Dual burden of malnutrition

Large discrepancies still exist between rural and urban areas both in health conditions and in health care.45 Decades of observation suggest that despite improved growth in children belonging to all economic groups, a large growth disparity persists between the rural and suburban areas and the urban areas,9 and among different economic subgroups within these areas.17,18

Compared with the late 1980s and early 1990s,46 in 2010, malnutrition in childhood declined dramatically, owing to sustained economic development, sound nutrition policies, improved health services for women and children and broad implementation of child nutritional interventions.23 However, in the same year, nutrition in rural areas was still poor, with a high prevalence of underweight and stunting among children less than5 years of age. Another survey in 2009 reported 15.9% prevalence for stunting, 7.8% for underweight and 3.7% for wasting in poor rural ares.47

We have also observed a paradoxical situation: in 2006, prevalence of overweight children was as high as 16.8%, while that of stunting was 57.6% among the children in the same poor areas of China’s midwestern provinces.48 The coexistence of stunting and overweight in the same child is a result of protein and energy malnutrition, which retards height despite increased body weight,49 and Chinese rural children have a lower daily protein intake than urban children.24

Childhood obesity has become a serious public health problem in China.19,50 The current strategies for preventing and controlling malnutrition need to be re-examined. Research on obesity prevention and control needs to be improved and nutrition policies need to be aligned with appropriate obesity prevention strategies. Cross-sectoral collaboration such as between health and agriculture, needs to be promoted.

Our study has shown that regional inequalities in child growth and nutrition in China accompany regional economic disparities. Therefore, to promote equitable growth for all children in China, strategies for optimal nutrition need to focus more closely on disadvantaged groups in the poor and underdeveloped areas.

References

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listless child who was among many kwashiorkor cases

listless child who was among many kwashiorkor cases

This late 1960s photograph shows a seated, listless child who was among many kwashiorkor cases found in Nigerian relief camps during the Nigerian-Biafran war. Kwashiorkor is a disease brought on due to a severe dietary protein deficiency, and this child, whose diet fit such a deficiency profile, presented with symptoms including edema of legs and feet, light-colored, thinning hair, anemia, a pot-belly, and shiny skin. Image courtesy of Dr. Lyle Conrad and the CDC Public Health Image Library.

anemia

anemia

Even where children get the calories they need—as most do in rural China—they are not being fed the right things. In one study of 1,800 infants in rural Shaanxi province in China’s north-west, 49% were anemic and 40% were significantly hampered in developing either cognitive or motor skills. Fewer than one in ten were stunted or wasting, meaning that in most cases the problem was not lack of calories, but lack of micronutrients.

Part of the problem in getting local or provincial governments to spend money on childhood nutrition is that the payoffs are years in the making. And the returns might not go to the village or province, but to cities miles away, in the form of more skilled workers who move there. Central ministries are keen to invest, Mr Lu says, but they want to spend their cash on things that officials crave more than children do—like buildings in villages for each ministry.

For Mr Lu one kind of building does promise a big payoff—village early-education centres, or preschools. His charity has set them up in 677 villages, often using redundant elementary schools. In Songjia village Tian Lin, 22, and her older sister, Tian Hongjiao, teach 26 children aged three to six, including the younger sister’s own three-year-old son. They cook lunch with whatever the children bring from home. Those with migrant-worker parents, who are a bit better off, may have a chunk of pork; others bring a meagre potato or vegetable. Either way all the children get a ying yang bao with their lunch.

In 2012 a study found the anemia rate among the three- to five-year-olds in this county was close to 18%, more than twice the average for poor rural areas nationwide, according to Mr Lu’s CDRF. He reckons that, on coming to the centres, the children show only 20% of the memory retention of their urban counterparts and 40-60% of their language abilities and cognition. But nutritional supplements help. A study of nine- and ten-year olds, co-written by Mr Rozelle, found that taking a daily chewable vitamin with iron for six months not only cut anaemia levels. It also improved their maths.

children under the age of five, wasting and stunting

children under the age of five, wasting and stunting

Despite progress, malnutrition remains a challenge

http://www.irinnews.org/photo/Download.aspx?Source=Details&Year=2011&ImageID=201108100909210715

AKARTA, 30 August 2012 (IRIN) – While Indonesia in relative terms is cutting the number of malnourished children under the age of five, wasting and stunting – especially in certain pockets of the country – remain a major concern, say health experts.

Children_under_height_for_age_UN_HDR_2007-2008

Children_under_height_for_age_UN_HDR_2007-2008

Vitamin A deficiency

A few salient facts

  • An estimated 250 million preschool children are vitamin A deficient and it is likely that in vitamin A deficient areas a substantial proportion of pregnant women is vitamin A deficient.
  • An estimated 250 000 to 500 000 vitamin A-deficient children become blind every year, half of them dying within 12 months of losing their sight.

A collateral challenge

Vitamin A deficiency (VAD) is the leading cause of preventable blindness in children and increases the risk of disease and death from severe infections. In pregnant women VAD causes night blindness and may increase the risk of maternal mortality.

Vitamin A deficiency is a public health problem in more than half of all countries, especially in Africa and South-East Asia, hitting hardest young children and pregnant women in low-income countries.

Crucial for maternal and child survival, supplying adequate vitamin A in high-risk areas can significantly reduce mortality. Conversely, its absence causes a needlessly high risk of disease and death.

http://www.goldenrice.org/Content3-Why/why1_vad.php

The most damaging micronutrient deficiencies in the world are the consequence of low dietary intake of iron, vitamin A, iodine and zinc. Vitamin A deficiency (VAD) is prevalent among the poor whose diets are based mainly on rice or other carbohydrate-rich, micronutrient-poor calory sources. Rice does not contain any β-carotene (provitamin A), which their body could then convert into vitamin A. Dependence on rice as the predominant food source, therefore, necessarily leads to VAD, most severely affecting small children and pregnant women. In 2012 the World Health Organization reported that about 250 million preschool children are affected by VAD, and that providing those children with vitamin A could prevent about a third of all under-five deaths, which amounts to up to 2.7 million children that could be saved from dying unnecessarily.

VAD compromises the immune systems of approximately 40 percent of children under five in the developing world, greatly increasing the severeness of common childhood infections, often leading to deadly outcomes. VAD is most severe in Southeast Asia and Africa. For the 400 million rice-consuming poor, the medical consequences are fatal: impaired vision—, in extreme cases irreversible blindness; impaired epithelial integrity, exposing the affected individuals to infections; reduced immune response; impaired haemopoiesis (and hence reduced capacity to transport oxygen in the blood) and skeletal growth; among other debilitating afflictions.

Rice containing provitamin A could substantially reduce the problems described above. This can only be achieved using genetic engineering because there is no provitamin A in the rice seeds, even though it is present in the leaves. Thousands of rice varieties have been screened for this trait without success. Existing coloured rice varieties contain pigments that belong to a different chemical class.

Small children are most susceptible to micronutrient deficiencies. Initially a VAD affects their eyesight, but at the same time it impairs their immune system, and children fall prey to common infectious diseases. Vitamin A and zinc alone could save more thn a third of the 12 million children who die annually because of malnutrition worldwide.

Golden Rice has the potential to complement existing efforts that seek to reduce blindness and other VAD induced diseases. Those efforts include industrial fortification of basic foodstuffs with vitamin A, distribution of vitamin supplements, and increasing consumption of other foods rich in vitamin A.

Distribution of Vitamin A Deficiency (WHO, 2009)

Distribution of Vitamin A Deficiency (WHO, 2009)

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