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Archive for the ‘Liver & Digestive Diseases Research’ Category


Hypertriglyceridemia: Evaluation and Treatment Guideline

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications. Patients with primary hypertriglyceridemia must be assessed for other cardiovascular risk factors, such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction. The aim of this study was to develop clinical practice guidelines on hypertriglyceridemia.

The diagnosis of hypertriglyceridemia should be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of >1000 mg/dl) be considered a risk for pancreatitis. The patients with hypertriglyceridemia must be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease.

The treatment goal in patients with moderate hypertriglyceridemia should be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification, physical activity and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate can be used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

Three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins may be considered as treatment options in patients with moderate to severe triglyceride levels. Statins are not be used as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/77242?xid=NL_CardioEndoConnection_2019-01-21

https://www.ncbi.nlm.nih.gov/pubmed/19307519

https://www.ncbi.nlm.nih.gov/pubmed/23009776

https://www.ncbi.nlm.nih.gov/pubmed/6827992

https://www.ncbi.nlm.nih.gov/pubmed/22463676

https://www.ncbi.nlm.nih.gov/pubmed/17635890

 

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The assessment of liver function using breath tests @Hadassah Medical Center

Reporter: Aviva Lev-Ari, PhD, RN

 

Unresolved issues of breath testing

Similar to many other diagnostic tests, several issues remain unresolved in breath testing. The first is the role of hypoxia, which may contribute to impaired liver function and interfere with the results of liver function tests. In patients with cirrhosis, cytochrome P‐450‐mediated metabolism is facilitated in the presence of supplemental oxygen. The effect of oxygen supplementation on hepatic microsomal function as assessed by MBT in patients with cirrhosis of different severities and degrees of anaemia has been evaluated.47 In patients who breathe room air, the total amount of 13C exhaled is weakly correlated with the CTP score and haemoglobin concentrations. Oxygen supplementation increased the total amount of 13C exhaled by 68 ± 90%. Preliminary data suggest that MBT results are independent of the patient’s pulmonary function and can be performed in ventilated patients (G. Lalazar, Hebrew University–Hadassah Medical Center, Jerusalem, unpublished data). The second issue affecting the MBT is that endogenous CO2 production changes with age, motor activity and nutrition. Recent unpublished data suggest that MBT results are independent of gastrointestinal function. Thirdly, the intra‐hepatic resistance index, as measured by Doppler‐pulsed wave analysis, was increased in elderly subjects, and this index was inversely correlated with the results of the MBT.46 Finally, although several studies have suggested that MBT can distinguish between early cirrhotic (Child A) and non‐cirrhotic patients, the ability of the MBT to detect the early‐stages of fibrosis remains yet unproven.16

Table 1. Clinical situations where assessment of liver reserve with the breath test system may be beneficial
Patients with acute liver disease Follow‐up of patients with fulminant or subfulminant liver disease to determine the need for liver transplantation or to predict recovery.
Patients with chronic liver disease Follow‐up and prediction of complications and prognosis in patients with chronic liver disease.
A non‐invasive tool for assessment of degree of liver fibrosis.
Follow‐up of response to treatment (anti‐virals in chronic hepatitis B and C viruses; steroids in autoimmune hepatitis).
Deciding the timing of liver transplantation and prioritizing patients on the waiting list.
Assessment of liver reserve in patients with cholestatic liver diseases.
Distinguishing non‐alcoholic fatty liver disease from non‐alcoholic steatohepatitis.
Before and after procedures Assessment of liver reserve before hepatectomy.
Assessment of liver reserve in living donors and of brain death donors with marginal livers.
Determining liver reserve before insertion of transjugular intrahepatic portosystemic stent shunt.
Pre‐ and postchemoembolizations.
Follow‐up of graft function after liver transplantation.
Determining the liver impairment prior to bariatric surgery or any non‐hepatic major surgery in patients with chronic liver disease.
Screening of healthy population Screening test for occult liver disease in seemingly healthy populations.

SOURCE

Review article: the assessment of liver function using breath tests

First published: 15 September 2007
Cited by: 36
Prof. Y. Ilan, Hebrew University, Hadassah Medical Center, PO Box 12000, Jerusalem, Israel.
E‐mail: deborah@hadassah.org.il

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2036.2007.03519.x

 

Patient success story

http://www.hadassah.org/news-stories/grateful-patient-returns-to-thank-hadassah.html

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3D Liver Model in a Droplet

Curator: Marzan Khan, BSc

Recently, a Harvard University Professor of Physics and Applied Physics, David Weitz and his team of researchers have successfully generated 3D models of liver tissue composed of two different kinds of liver cells, precisely compartmentalized in a core-shell droplet, using the microfluidics approach(1). Compared to alternative in-vitro methods, this approach comes with more advantages – it is cost-effective, can be quickly assembled and produces millions of organ droplets in a second(1). It is the first “organ in a droplet” technology that enables two disparate liver cells to physically co-exist and exchange biochemical information, thus making it a good mimic of the organ in vivo(1).

Liver tissue models are used by researchers to investigate the effect of drugs and other chemical compounds, either alone or in combination on liver toxicity(2). The liver is the primary center of drug metabolism, detoxification and removal and all of these processes need to be carried out systematically in order to maintain a homeostatic environment within the body(2) Any deviation from the steady state will shift the dynamic equilibrium of metabolism, leading to production of reactive oxygen species (ROS)(2). These are harmful because they will exert oxidative stress on the liver, and ultimately cause the organ to malfunction. Drug-induced liver toxicity is a critical problem – 10% of all cases of acute hepatitis, 5% of all hospital admissions, and 50% of all acute liver failures are caused by it(2).

Before any novel drug is launched into the market, it is tested in-vitro, in animal models, and then progresses onto human clinical trials(1). Weitz’s system can produce up to one-thousand organ droplets per second, each of which can be used in an experiment to test for drug toxicity(1). Clarifying further, he asserts that “Each droplet is like a mini experiment. Normally, if we are running experiments, say in test tubes, we need a milliliter of fluid per test tube. If we were to do a million experiments, we would need a thousand liters of fluid. That’s the equivalent of a thousand milk jugs! Here, each droplet is only a nanoliter, so we can do the whole experiment with one milliliter of fluid, meaning we can do a million more experiments with the same amount of fluid.”

Testing hepatocytes alone on a petri dish is a poor indicator of liver-specific functions because the liver is made up of multiple cells systematically arranged on an extracellular matrix and functionally interdependent(3). The primary hepatocytes, hepatic stellate cells, Kupffer cells, endothelial cells and fibroblasts form the basic components of a functioning liver(3). Weitz’s upgraded system contains hepatocytes (that make up the majority of liver cells and carry out most of the important functions) supported by a network of fibroblasts(3). His microfluidic chip is comprised of a network of constricted, circular channels spanning the micrometer range, the inner phase of which contains hepatocytes mixed in a cell culture solution(3). The surrounding middle phase accommodates fibroblasts in an alginate solution and the two liquids remain separated due to differences in their chemical properties as well as the physics of fluids travelling in narrow channels. Addition of a fluorinated carbon oil interferes with the two aqueous layers, forcing them to become individual monodisperse droplets(3). The hydrogel shell is completed when a 0.15% solution of acetic acid facilitates the cross-linking of alginate to form a gelatinous shell, locking the fibroblasts in place(3). Thus, the aqueous core of hepatocytes are encapsulated by fibroblasts confined to a strong hydrogel network, creating a core-shell hydrogel scaffold of 3D liver micro-tissue in a droplet(3). Using empirical analysis, scientists have shown that albumin secretion and urea synthesis (two important markers of liver function) were significantly higher in a co-culture of hepatocytes and fibroblasts 3D core-shell spheroids compared to a monotypic cell-culture of hepatocyte-only spheroids(3). These results validate the theory that homotypic as well as heterotypic communication between cells are important to achieve optimal organ function in vitro(3).

This system of creating micro-tissues in a droplet with enhanced properties is a step-forward in biomedical science(3). It can be used in experiments to test for a myriad of drugs, chemicals and cosmetics on different human tissue samples, as well as to understand the biological connectivity of contrasting cells(3).

diagram

Image source: DOI: 10.1039/c6lc00231

A simple demonstration of the microfluidic chip that combines different solutions to create a core-shell droplet consisting of two different kinds of liver cells.

References:

  1. National Institute of Biomedical Imaging and Bioengineering. (2016, December 13). New device creates 3D livers in a droplet.ScienceDaily. Retrieved February 9, 2017 from https://www.sciencedaily.com/releases/2016/12/161213112337.htm
  2. Singh, D., Cho, W. C., & Upadhyay, G. (2015). Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants: An Overview.Frontiers in Physiology,6, 363. http://doi.org/10.3389/fphys.2015.00363
  3. Qiushui Chen, Stefanie Utech, Dong Chen, Radivoje Prodanovic, Jin-Ming Lin and David A. Weitz; Controlled assembly of heterotypic cells in a core– shell scaffold: organ in a droplet; Lab Chip, 2016, 16, 1346; DOI: 10.1039/c6lc00231

Other related articles on 3D on a Chip published in this Open Access Online Scientific Journal include the following:

 

What could replace animal testing – ‘Human-on-a-chip’ from Lawrence Livermore National Laboratory

Reporter: Aviva Lev-Ari, PhD, RN

AGENDA for Second Annual Organ-on-a-Chip World Congress & 3D-Culture Conference, July 7-8, 2016, Wyndham Boston Beacon Hill by SELECTBIO US

Reporter: Aviva Lev-Ari, PhD, RN

Medical MEMS, BioMEMS and Sensor Applications

Curator and Reporter: Aviva Lev-Ari, PhD, RN

Contribution to Inflammatory Bowel Disease (IBD) of bacterial overgrowth in gut on a chip

Larry H. Bernstein, MD, FCAP, Curator

Current Advances in Medical Technology

Larry H. Bernstein, MD, FCAP, Curator

 

Other related articles on Liver published in this Open Access Online Scientific Journal include the following:

 

Alnylam down as it halts development for RNAi liver disease candidate

by Stacy Lawrence

LIVE 9/21 8AM to 2:40PM Targeting Cardio-Metabolic Diseases: A focus on Liver Fibrosis and NASH Targets at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

Reporter: Aviva Lev-Ari, PhD, RN

2016 Nobel in Economics for Work on The Theory of Contracts to winners: Oliver Hart and Bengt Holmstrom

Reporter: Aviva Lev-Ari, PhD, RN

LIVE 9/20 2PM to 5:30PM New Viruses for Therapeutic Gene Delivery at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

Reporter: Aviva Lev-Ari, PhD, RN

Seven Cancers: oropharynx, larynx, oesophagus, liver, colon, rectum and breast are caused by Alcohol Consumption

Reporter: Aviva Lev-Ari, PhD, RN

 

Other related articles on 3D on a Chip published in this Open Access Online Scientific Journal include the following:

 

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute,  Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

Trovagene’s ctDNA Liquid Biopsy urine and blood tests to be used in Monitoring and Early Detection of Pancreatic Cancer

Reporters: David Orchard-Webb, PhD and Aviva Lev-Ari, PhD, RN

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

Real Time Coverage of the AGENDA for Powering Precision Health (PPH) with Science, 9/26/2016, Cambridge Marriott Hotel, Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

 

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LIVE 9/21 8AM to 2:40PM Targeting Cardio-Metabolic Diseases: A focus on Liver Fibrosis and NASH Targets at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

#BostonDOT16

@BostonDOT

 

Nonalcoholic Steatohepatitis (NASH)

 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

 

Wednesday, September 21

7:30 am Registration Open and Morning Coffee

8:00 Chairperson’s Opening Remarks

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

  • Epidemic of NASH,
  • approaches to treating NASH – Fibrosis
  • NASH is a metabolic Disease of the Liver
  • Treating the HCV will treat the Fibrosis

8:10 FEATURED PRESENTATION: The Epidemic of Fatty Liver Disease: Silent, Serious and Still Growing?

Lee Kaplan, M.D., Ph.D., Director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School

  • Silent, Serious and Growing
  • Obesity the Disease = BMI>30: Medical Complicastions for BMI >%) – On ANti-Obisity and Bariatric SUrgery, Type 2 Diabetis .. NAFLD .. NASH .. Cirrhosis .. HCC
  • Parkinson’s Disease
  • HIV/AIDS
  1. Medical Complications of Obisity =197 :
  2. NAFLD – Nonalcoholic Fatty Liver Disease >>> Liver transplantation replacing HCV
  3. Associated with obesity and type 2 diabetes
  4. NAFLD is UP 90% wiht Severe Obesity
  5. Viral hepatitis and Hemochromatosis
  6. NAFLD: Steatosis, Inflamamtion, Hepatocellular Necrosis, Fibrosis, Cirrhosis
  7. NASH: insulin resistence .. metabolic syndrom .. interaction
  8. Alternative Model: Metabolis Syndrom.. Steatosis .. NASH … FIbrosis
  9. Genetics of Liver DIsease
  10. PNPLA3 Associated with NAFLD – Not Weight Gain
  11. Other genes: A Partial List:
  12. Diagnosis of NASH: Liver biopsy macrovescicular fatty change: InflammationMollery bodies
  13. 75% Patients with Cirrhousis have obisity
  14. Alcoholoc hepatisis >> Progression to Cirrhousis
  15. Macrovesicular Steatosis
  16. NASH – inflammation
  17. Sinusoidal Pericellular Fibrosis –
  18. LAB Features of NAFLD
  • Transaminase elevation
  • Akaline phosphate
  1. Biomarkers – NASH – associated cirrhousis with lower rate 30% of elevation
  2. Fibrosure
  • Clinical Features of NASH: none presentation, Bright, Echo Fibroscan FibroscanScreen for HCC, Varices if Gray zone: Biopsy
  • Treatment of NASH
  • Treat liver disease: Treat steatosis then Inflamamtion and fibrosis
  1. NAFLD Treatment Strategy: Stepwise Approach
  • Treat the steatosis Piodlitazone
  • PPARalpha, delta,
  • Treat Inflammation: ANtioxidant
  • CCR2/CCR% inhibitors
  • Metabolic SUrgery
  • Weigh-independent for bariatric
  • Bariatic: improvrment of steatosis,effect on inflammationless clear
  • dramatic on weigh loss
  • NO clear is surgery improved cirhousis
  • If NASH developed >>>> progression s the rule
  • No great treatment of NASH

Medication-assciated NASH: Glucocorti

 

8:40 Non-Alcoholic Steatohepatitis and Cardiovascular Disease: Modulation by Novel PPAR Agonists

Bart Staels, Ph.D., Professor, INSERM, University of Lille, Pasteur Institute

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. In this presentation, we will review recent findings on the pathophysiological role of PPARs in the different stages of non-alcoholic fatty liver disease (NAFLD), from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidences for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis towards irreversible, more advanced lesions. Large controlled trials of long duration to assess the long-term clinical benefits of PPAR agonists in humans are ongoing.

Non-Alcoholic Steatohepatisis and CVD – Meta inflammatory disease

  • NAFL — abnormal Lipid accumulation
  • NASH >> Balooning, FIbrosis inflamation
  • Resolution of NASH is associated with reduction of Fibrosis (Golden – 505 trial)

CVD is linked to NAFLD: Lipids elevated and therosclerosis

  • TG – elevated, APO B elevated, VLDL – elevated HDL decrease
  • PPAR Alpha
  • Gamma
  • PPAR Beta/Delta agonist: GENFIT – Elafibranor
  • SPPARM

Trans-activation: Lipid and Glucose homeostasis: Trans-repression – anti-inflammatory properties

  • Hapatic mitochondrial activity deseases upon progression from NAFL to NASH: Obese NAFL and NASH
  1. Upregulated hepatic respiratory in obese humans with or without NAFL
  2. Impaired
  3. Hepatic PPARalpha Expression Decreases upon Progression of Nash and Fibrosis
  4. hepatic PPARalpha expression – target genes increase in patients with improved NASH histology after 1 year
  5. Metabolic Regualtion by thehepatic JNK Signaling Pathway
  6. Target gene transcription – miR-21 expression increases in human
  7. PPAR Delta: Elafibbranor: – effect on plasma lipids: A Dual PPAR alpha/Delts (GFT505): 80mg vs placebo and 120mg vs placebo, improves plasma apolipolipids and glucose HbA1C – insulin sensitivity
  8. efficacy in NASH acting on: Steatosis, fibrosis and cirrhosis
  9. inflammatory markers: RESOLVE-IT Phase 3 Study Desing: NASH ressolution without adverse on FIbrosis and Cirrhosis

GOLDEN505 Trial: Improves plasma lipid levels: Triglycerides

Inclusion Criteria:

ALT, AST, GGT, ALP

Improve atherogenic dyslipidemia

  • APOC3 – associated with CVD

9:10 PANEL DISCUSSION: Liver Fibrosis and NASH Targets

Moderator: H. James Harwood, Ph.D., Delphi BioMedical Consultants, LLC

Panelists:

Lee Kaplan, M.D., Ph.D., Director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School

Bart Staels, Ph.D., Professor, INSERM, University of Lille, Pasteur Institute

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

Weilin Xie, Ph.D., Senior Principal Scientist, Biotherapeutics, Celgene Corp.

  • FDA’s view on surrogate endpoints
  • Biomarkers of NASH
  • Regulatory challenges
  1. Liver biopsy: gold standard, invasive direct measure of endpoints pros/cons
  2. non-invasive functional tests – plasma bioamrkers
  3. non-invasisve liver imaging techniques: MRI to assess hepatic fat content MRE to assess hepatic fibrosis, Fibroscan,
  4. Endpoints acceptable by FDA: Current vs Future
  • Pre clinical Translational animal models

Discussion by Panel members

Progression from NAFLD to NASH: Oxidative stress and toxic lipids

NASH and Steatosis are different populations

Alcoholoc Steatosis vs Non-Alcoholic Steatosis

  • Obesity cause of Fatty liver
  • NASH in Diabetes
  • NASH progresses
  • Steatosis is associated with NASH
  • Different types of NASH: HTN, Dislipedemia,
  • GENETICS underlining factors, more genes are discovered
  • Limitations of Animal Studies for inference on Humans – careful in over generalizing results
  • Metabolic SYndrom -not all progresses to NASH
  • Nonalcoholic Steatohepatitis (NASH) depend on Steatosis

 

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Targeting Fibroblast Activation Protein (FAP) and FGF21 to Treat Fatty Liver Disease

Diana Ronai Dunshee, Ph.D., Department of Molecular Biology, Senior Scientific Researcher, Genentech, Inc.

FGF21 is a hormone with anti-obesity and hepatoprotective properties. However, the beneficial effects of FGF21 are limited by a relatively short half-life in circulation. We discovered that fibroblast activation protein (FAP), an endopeptidase overexpressed in liver with cirrhosis, cleaves and inactivates FGF21. Pharmacological inhibition of FAP increases endogenous levels of active FGF21, thus making FAP a promising target for the treatment of non-alcoholic-steatohepatitis (NASH).

  • Medical complications of obisity: NASH and DM-2
  • energy consumption
  • white adipose tissue – energy storage
  • brown adipose tissue matochondia’s energy
  • FGF21 – Human activation of protein cleavage: A Homone beneficial on metabolic health circulation, weigh loss
  • it suppreses hepatic Steatohepatitis
  • One singleinjection in mice — leads to energy expenditure induced weigh loss and metabolic improvement in Obese Humans
  • Negative FGF21 is Rapidly Eliminated from the body – renal degradation and Inactivation of FGF21 Endopeptidase Cleavage Site – Fibroblast Activation Protein Matched FAP Endopeptidease Specificity
  • Closest relative of DPP4 upregulted during tissue injury in NASH
  • FAP is SUfficient to Cleave FGF21
  • Recombinant FGF21 with Recombinant FAP in Serum or Plasma
  • FAP Protease – Serum Immunodepleted Ablates FGF21 Cleavage Activity: Peptide IgG vs anti-FAP
  • FAP Cleavage Inactivates Human FGF21 dependent on KLB-FGFR1c placed on the site
  • hFGF21 in Not Cleaved in FAP KO Mice
  • Fc-hFGF21 is more stable in FAP KO mice
  • FAR cleaves Endogenously Produced FGF21 In Vivo in monkeys and in dogs
  • The FAP Cleavage Consensus GLY-Pro is COnserved in most mammalian FGF21
  • FAP Does not Cleave the C-Terminal Residues of Mouse FGF21
  • Human: FAP, DPPIV
  • Mouse: FAP, DPP4
  • FAP INhibition
  • FAP is Overexpressed in Liver with Steatohepatitis: Early NASH vs Late NASH
  • Proposal: FAP Inhibition for FGF21 Stabilization in NASH
  1. Fatty hepatocytes – e.g. NASH
  2. Activated stellate cells, e.g. NASH

 

10:55 Thyroid Hormone Receptor Beta (THR-ß) Agonist for NASH: Correcting a Primary Deficiency in NASH Livers

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

NASH patients typically have metabolic syndrome including diabetes, dyslipidemia, obesity, and primarily die of cardiovascular disease. Hypothyroidism at the level of the thyroid gland and liver-specific hypothyroidism are common in NASH. Based on clinical and preclinical data, Thyroid receptor beta agonists decrease insulin resistance, reduce LDL-C, triglycerides fatty liver, inflammation and fibrosis in NASH. The target will also provide CV benefit to patients with NASH. MGL-3196 is a highly THR-ß selective liver-directed once daily oral medication that has shown excellent safety and lipid-lowering efficacy in humans; unlike prior thyroid receptor agonist(s), no cartilage findings in chronic toxicology or ALT increases in human studies. MGL-3196 is being advanced in Phase II studies in patients with genetic dyslipidemia or NASH.

Madrigal Portfolio of drugs:

  • MGL-3196: First-in-Class THR-Beta Agonist – discovered first at ROCHE – THR-beta selective targeted to the Liver – regulated by THR-Alpha  – in Phase II – no side effects on bone
  • Large & underserved Markets in NASH
  • Phase 2 HeFH Patients
  1. Hypothyroidism common in NASH patients
  2. Liver-specific Hypothyroidism present in human NASH degradation of thyroid hormone increases deiodised 9DIO) 3 produced by Stelllate cells in NASH liver
  3. Treating NASHrather than fibrosis is key in addressing the disease – approvable endpoint
  4. THR – Thyroid hormone reduces Cholesterol
  5. Thyroid hormone T3 thyroxine – treatment amy cause osteoporosis
  6. MGL 0 3196: Liver size, Live Triglycerides, Improve Insulin tolerance, decrease ALT
  7. Reduction of key NASH, Fibrosis Pathway Genes at Human Comparable Drug levels
  8. THR-beta: Decreased Liver Fibrosis, Apoptosis in mice:

HUMAN DATA

  • Single ascending dose study
  • Multiple – ascending studies: LDL and TG decrease
  • decrease Non-HDL CHolesterol
  • Decrease Apolipoprotein B
  • Pleiotropic Pioglitazone Effect in NASH at 6 month treatment and biopsy of liver – dramatic effect in NASH – ten years ago study
  • PPAR gamma agonist – NEGATIVE SIDE EFFECTS: weight gain, CHF, Bone osteoporosis
  • Anti-inflammatory: well tolerated

No Single NASH Therapeutics – Conbination agents

MGL – 3196 Phase 2 – Study: Proposed Phase 2 Proof of COncepts NASH Protocol

  • Unmet needs in FH, a severeGenetic Dyslipedemia
  • Weight loss in 6 weeksreduction in cholesterol and TG
  • Likelihood of Success
  • second study after 9 months
  • is different on NASH Patients in 12 weeks using MRI on Liver
  • prevalence
  • HeFH, PCSK9 inhibitors plus standard care
  • Unique and Complementary Lipid Lowering Profile
  1. Lowers Lp(a) and severely atherogenic practice
  2. Proposed Phase 2 HeFH Patients

 

11:25 Enjoy Lunch on Your Own

 

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Marcela’s Story:  A Liver Transplant Gives the Gift of Life

Patient is HCV Positive, liver transplanted from a 22-year-old donor performed at age 70. Interview conducted 14 years post-liver transplant.

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

For Marcela Almada Calles of Valle de Bravo, Mexico, a picturesque town on the shores of Lake Avándaro about two hours outside of Mexico City where she has lived for 30 years, life is about seizing the moment and having “an open mind and positive attitude.”  An active woman in her 80’s, Marcela’s days are full of professional and personal achievements and a long list of activities still to accomplish. However, life wasn’t always so positive as she put her life on hold for two-and-a-half years to relocate to Los Angeles, California, so that she could have a liver transplant.

“My spirit and attitude have always been what has carried me through life and difficult situations. This time was no different.”

Image SOURCE: Photographs courtesy of Marcela Almada Calles.   

Marcela’s story started 20 years ago during a time when she operated a successful event planning and catering business for high-profile government and social dignitaries, pharmaceutical companies, and luxury department stores.

“I normally worked long hours from early morning until evening, until one day, I felt exceptionally tired and it became a huge effort to concentrate. My ankles were swollen and I was out of breath all the time and my skin was yellow. I felt sleepy and would sometimes become tired during the day. This was unusual for me. I knew something was not right.”

At that point, Marcela decided to make an appointment with her local physician and friend, Dr. Sergio Ulloa, a highly regarded rheumatologist and corporate and government affairs leader in Mexico, who examined her and took several blood tests. When the blood results came back, Dr. Ulloa immediately referred her to Dr. Sergio Kershenovich, a well-regarded hepatologist, at his private clinic, who checked her for symptoms of Hepatitis C. After that Marcela decided to get another opinion and went to see Dr. Fernando Quijano, a general surgeon, who immediately wanted her to have surgery because he had found a cancerous tumor in her liver.

“My doctors’ opinions were that I needed to have a liver transplant immediately because I was in liver failure. It appeared that I had a failing liver — and a tumor there as well and my liver was not working properly.”

Relocating Life to the United States

At that point, my six children – Marcela, Luis, Diego, Rodolfo, Gabriela, Mario — who live in parts of Mexico and Singapore became involved in my health care decisions and treatment plan.

“My son, Luis, believed the best treatment for me was to see a liver specialist in the United States so that I received the best care from a leading liver transplantation hospital. He made some connections with friends and that next day, Dr. Francisco Durazo, chief of Transplant Hepatology and medical director of the Dumont UCLA Liver Transplant Center in Los Angeles, told me to come immediately to see him. I remember my children were supportive and concerned, but were afraid for me as we all knew that I had a long road ahead of me.”

At that time, she was put on a national liver transplant list by the UCLA Transplant Center.

“What I didn’t know was that more than 9,000 potential recipients are currently awaiting liver transplants.”  http://transplants.ucla.edu/site.cfm?id=397

“Dr. Durazo was very concerned and told me that my liver was not working at all and I had to have a liver transplant as soon as possible, so he asked me to stay in Los Angeles, since I was now part of a transplant list.”

Evaluation By Transplant Team

Marcela’s case is no different than any other patient awaiting a liver transplant. According to their web site, the UCLA Transplant Center conducts evaluations over two or three days. During this time, the patients meets with a social worker, transplant hepatologist, surgeon, transplant coordinator, psychiatrist and dietitian, as well as other specialists as needed. The evaluation is customized to each patient’s medical condition. Once the evaluation is completed, each patient’s case is presented at a weekly meeting of the UCLA Liver Transplant Consultation Team. This group includes specialists from surgery, adult and pediatric hepatology, cardiology, pulmonary, nephrology, hematology, infectious disease, as well as transplant coordinators and social workers. At this time, the team determines if any other tests are required to ensure the patient’s candidacy for transplant, then the patient and the physician are notified of the recommendation made by the transplant team. http://transplants.ucla.edu/site.cfm?id=401

Waiting For Answers

Marcela arrived at UCLA in Los Angeles with her family on Mother’s Day — May 10, 1999 — for what she describes as “the best time in her life to be alive with the help of medicine and technology.” That meant that she needed to rent an apartment and live near the hospital in case the doctors received an anonymous donor who would give her the gift of life.

“I had to wear a beeper 24 hours a day and I was never alone. My children took turns over the next two-and-a-half years to give up their lives with their families to live with me and help me navigate the health care system and my upcoming surgery.”

Marcela filled her days at her new apartment in Los Angeles reading about her condition, meditating to quiet her mind, watching television, and talking with family, friends and neighbors.

“The doctors called me two times over the next few months, saying they had an anonymous liver donor and I needed to come now to the hospital for tests. Unfortunately, those blood tests and other diagnostic tests showed that I was not a good match, so the doctors sent me home. It was a frustrating time because I wanted to have the liver transplant surgery and move on with my life.”

Finally, after waiting eight months for a liver transplant, Marcela’s outlook on life was greatly improved when an anonymous donor gave her the gift of life – a new, healthy liver.

“The donor’s blood type was a match for me. The surgery took eight hours and it was successful. The doctors told me that my immune system might reject my new liver, so I was given a cocktail of medicines, such as anti-rejection drugs, corticosteroids, calcinurin inhibitors, mTOR inhibitors, and antibiotics and watched very closely in the hospital.”

Marcela was then permitted to leave the hospital only a week after her surgery.

“That was the happiest day of my life. My spirits were high and I had a life to live.”

Her children served as her strength.

“My children took turns flying back and forth to Los Angeles to stay with me. They had a long list of instructions from the doctor. I could take some walks and eat small meals for the next few weeks, but I couldn’t exert myself in any way. I developed a cold over the next few weeks, as my immune system was low, so I had to take special care to eat right, get enough sleep and, most of all, relax. My body, spirit and mind had much healing to do.”

For the next 1 ½ years, Los Angeles was my “second” home.

“I needed to remain there after the procedure so my doctors could monitor my progress. During that time, I felt stronger each day. The support of my family was a true blessing for me. They were my eyes and ears – and my greatest advocates. My doctor recommended that I come weekly for check-ups and go through a physical therapy program so that I could regain my liver function and physical strength. I followed all my doctor’s orders.”

Day by day, Marcela believed as if she could conquer the world.

“I decided, one day many months after the surgery, to become ‘irresponsible’ and spent time with a few good friends, Gabriela and Guadalupe, who traveled to see me. For a weekend, we went to Las Vegas to see shows and go to the casinos. I laughed, played and walked all I could. My children didn’t even know what I was up to, but I felt good and wanted to enjoy the world and my new freedom.”

Marcela was able to return home to Valle de Bravo with a fresh perspective, a long list of things to do, and many happy memories.

“Since that time, I have kept myself active and busy; I never let my mind and heart rest. I am also forever grateful to my anonymous liver donor because it is because of a 22-year-old young man who died in an unfortunate automobile accident that I am here today.”

Liver Transplant Facts

The liver is the body’s vital organ that you cannot live without. It serves many critical functions, including metabolism of drugs and toxins, removing degradation products of normal body metabolism and synthesis of many proteins and enzyme, which are necessary for blood to clot. Transplantation is the only cure for liver insufficiency or liver failure because no device or machine reliably performs all the functions of the liver. http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

According to a hospital transplant web site, overall, outcomes for liver transplantation are very good, but vary significantly depending on the indication for liver transplant as well as factors associated with the donor. Currently, the overall patient survival one year after liver transplant is 88 percent. Patient survival five years after liver transplant is 73 percent. These results vary significantly based on the indication for liver transplantation. The encouraging trend is that over the past 20 years short- and long-term patient survival has continued to improve. With advances in surgical technique, organ preservation, peri-operative care, and immunosuppression, survival will hopefully continue to improve in the future. http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

Life For Marcela Today

Science is helping rebalance medicine with the most innovative discoveries and new ways of treating illness.

“I am happy to be part of the solution with a happy ending, too.”

Today, Marcela leads a rich and full life.

“It’s been 14 years since my liver transplant. I continue to feel healthy and alive. Nothing will keep me from doing what I want to do.”

Marcela has an active social life. She takes frequent vacations around the world, including a three-month holiday to Asia, where she travels multiple times to Bali, Cambodia, China and Singapore, where her daughter lives. She is an avid golfer and organizes tournaments in many private golf courses. She is learning to speak French, which is an easy transition (she says) from speaking Spanish. She plays cards with a group of friends weekly, sings in a musical group, and takes dance lessons, too. Life is very, very good.

Editor’s note: We would like to thank Gabriela Contreras, a global communications consultant and patient advocate, for the tremendous help and support that she provided in locating and scheduling time to talk with Marcela Almada Calles.

Marcela Almada Calles provided her permission to publish this interview on July 21, 2016.

 

REFERENCE/SOURCE 

http://www.webmd.com/digestive-disorders/digestive-diseases-liver-transplantation

Other related articles:

Retrieved from http://transplants.ucla.edu/site.cfm?id=397

Retrieved from http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

Retrieved from http://transplant.surgery.ucsf.edu/conditions–procedures/liver-transplantation.aspx

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

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https://pharmaceuticalintelligence.com/2016/07/15/adoptive-t-cell-therapy-delivering-car-tcr-and-til-from-research-to-reality-chis-4th-annual-immuno-oncology-summit-september-1-2-2016-marriott-long-wharf-hotel-boston-ma/

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https://pharmaceuticalintelligence.com/2015/08/16/newly-discovered-cells-regenerate-liver-tissue-without-forming-tumors/

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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.
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  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.
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  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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Image Tools

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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Microbe meets cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Microbes Meet Cancer

Understanding cancer’s relationship with the human microbiome could transform immune-modulating therapies.

By Kate Yandell | April 1, 2016  http://www.the-scientist.com/?articles.view/articleNo/45616/title/Microbes-Meet-Cancer

 © ISTOCK.COM/KATEJA_FN; © ISTOCK.COM/FRANK RAMSPOTT  http://www.the-scientist.com/images/April2016/feature1.jpg

In 2013, two independent teams of scientists, one in Maryland and one in France, made a surprising observation: both germ-free mice and mice treated with a heavy dose of antibiotics responded poorly to a variety of cancer therapies typically effective in rodents. The Maryland team, led by Romina Goldszmidand Giorgio Trinchieri of the National Cancer Institute, showed that both an investigational immunotherapy and an approved platinum chemotherapy shrank a variety of implanted tumor types and improved survival to a far greater extent in mice with intact microbiomes.1 The French group, led by INSERM’s Laurence Zitvogel, got similar results when testing the long-standing chemotherapeutic agent cyclophosphamide in cancer-implanted mice, as well as in mice genetically engineered to develop tumors of the lung.2

The findings incited a flurry of research and speculation about how gut microbes contribute to cancer cell death, even in tumors far from the gastrointestinal tract. The most logical link between the microbiome and cancer is the immune system. Resident microbes can either dial up inflammation or tamp it down, and can modulate immune cells’ vigilance for invaders. Not only does the immune system appear to be at the root of how the microbiome interacts with cancer therapies, it also appears to mediate how our bacteria, fungi, and viruses influence cancer development in the first place.

“We clearly see shifts in the [microbial] community that precede development of tumors,” says microbiologist and immunologist Patrick Schloss, who studies the influence of the microbiome on colon cancer at the University of Michigan.

But the relationship between the microbiome and cancer is complex: while some microbes promote cell proliferation, others appear to protect us against cancerous growth. And in some cases, the conditions that spur one cancer may have the opposite effect in another. “It’s become pretty obvious that the commensal microbiota affect inflammation and, through that or through other mechanisms, affect carcinogenesis,” says Trinchieri. “What we really need is to have a much better understanding of which species, which type of bug, is doing what and try to change the balance.”

Gut feeling

In the late 1970s, pathologist J. Robin Warren of Royal Perth Hospital in Western Australia began to notice that curved bacteria often appeared in stomach tissue biopsies taken from patients with chronic gastritis, an inflammation of the stomach lining that often precedes the development of stomach cancer. He and Barry J. Marshall, a trainee in internal medicine at the hospital, speculated that the bacterium, now called Helicobacter pylori, was somehow causing the gastritis.3 So committed was Marshall to demonstrating the microbe’s causal relationship to the inflammatory condition that he had his own stomach biopsied to show that it contained no H. pylori, then infected himself with the bacterium and documented his subsequent experience of gastritis.4 Scientists now accept that H. pylori, a common gut microbe that is present in about 50 percent of the world’s population, is responsible for many cases of gastritis and most stomach ulcers, and is a strong risk factor for stomach cancer.5 Marshall and Warren earned the 2005 Nobel Prize in Physiology or Medicine for their work.

H. pylori may be the most clear-cut example of a gut bacterium that influences cancer development, but it is likely not the only one. Researchers who study cancer in mice have long had anecdotal evidence that shifts in the microbiome influence the development of diverse tumor types. “You have a mouse model of carcinogenesis. It works beautifully,” says Trinchieri. “You move to another institution. It works completely differently,” likely because the animals’ microbiomes vary with environment.

IMMUNE INFLUENCE: In recent years, research has demonstrated that microbes living in and on the mammalian body can affect cancer risk, as well as responses to cancer treatment. Although the details of this microbe-cancer link remain unclear, investigators suspect that the microbiome’s ability to modulate inflammation and train immune cells to react to tumors is to blame.
See full infographic: WEB | PDF
© AL GRANBERG

Around the turn of the 21st century, cancer researchers began to systematically experiment with the rodent microbiome, and soon had several lines of evidence linking certain gut microbes with a mouse’s risk of colon cancer. In 2001, for example, Shoichi Kado of the Yakult Central Institute for Microbiological Research in Japan and colleagues found that a strain of immunocompromised mice rapidly developed colon tumors, but that germ-free versions of these mice did not.6 That same year, an MIT-based group led by the late David Schauer demonstrated that infecting mice with the bacterium Citrobacter rodentium spurred colon tumor development.7 And in 2003, MIT’s Susan Erdman and her colleagues found that they could induce colon cancer in immunocompromised mice by infecting them with Helicobacter hepaticus, a relative of? H. pylori that commonly exists within the murine gut microbiome.8

More recent work has documented a similar link between colon cancer and the gut microbiome in humans. In 2014, a team led by Schloss sequenced 16S rRNA genes isolated from the stool of 90 people, some with colon cancer, some with precancerous adenomas, and still others with no disease.9 The researchers found that the feces of people with cancer tended to have an altered composition of bacteria, with an excess of the common mouth microbes Fusobacterium or Porphyromonas. A few months later, Peer Bork of the European Molecular Biology Laboratory performed metagenomic sequencing of stool samples from 156 people with or without colorectal cancer. Bork and his colleagues found they could predict the presence or absence of cancer using the relative abundance of 22 bacterial species, including Porphyromonas andFusobacterium.10 They could also use the method to predict colorectal cancer with about the same accuracy as a blood test, correctly identifying about 50 percent of cancers while yielding false positives less than 10 percent of the time. When the two tests were combined, they caught more than 70 percent of cancers.

Whether changes in the microbiota in colon cancer patients are harbingers of the disease or a consequence of tumor development remained unclear. “What comes first, the change in the microbiome or tumor development?” asks Schloss. To investigate this question, he and his colleagues treated mice with microbiome-altering antibiotics before administering a carcinogen and an inflammatory agent, then compared the outcomes in those animals and in mice that had received only the carcinogenic and inflammatory treatments, no antibiotics. The antibiotic-treated animals had significantly fewer and smaller colon tumors than the animals with an undisturbed microbiome, suggesting that resident bacteria were in some way promoting cancer development. And when the researchers transferred microbiota from healthy mice to antibiotic-treated or germ-free mice, the animals developed more tumors following carcinogen exposure. Sterile mice that received microbiota from mice already bearing malignancies developed the most tumors of all.11

Most recently, Schloss and his colleagues showed that treating mice with seven unique combinations of antibiotics prior to exposing them to carcinogens yielded variable but predictable levels of tumor formation. The researchers determined that the number of tumors corresponded to the unique ways that each antibiotic cocktail modulated the microbiome.12

“We’ve kind of proven to ourselves, at least, that the microbiome is involved in colon cancer,” says Schloss, who hypothesizes that gut bacteria–driven inflammation is to blame for creating an environment that is hospitable to tumor development and growth. Gain or loss of certain components of the resident bacterial community could lead to the release of reactive oxygen species, damaging cells and their genetic material. Inflammation also involves increased release of growth factors and blood vessel proliferation, potentially supporting the growth of tumors. (See illustration above.)

Recent research has also yielded evidence that the gut microbiota impact the development of cancer in sites far removed from the intestinal tract, likely through similar immune-modulating mechanisms.

Systemic effects

In the mid-2000s, MIT’s Erdman began infecting a strain of mice predisposed to intestinal tumors withH. hepaticus and observing the subsequent development of colon cancer in some of the animals. To her surprise, one of the mice developed a mammary tumor. Then, more of the mice went on to develop mammary tumors. “This told us that something really interesting was going on,” Erdman recalls. Sure enough, she and her colleagues found that mice infected with H. hepaticus were more likely to develop mammary tumors than mice not exposed to the bacterium.13The researchers showed that systemic immune activation and inflammation could contribute to mammary tumors in other, less cancer-prone mouse models, as well as to the development of prostate cancer.

MICROBIAL STOWAWAYS: Bacteria of the human gut microbiome are intimately involved in cancer development and progression, thanks to their interactions with the immune system. Some microbes, such as Helicobacter pylori, increase the risk of cancer in their immediate vicinity (stomach), while others, such as some Bacteroides species, help protect against tumors by boosting T-cell infiltration.© EYE OF SCIENCE/SCIENCE SOURCE
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© DR. GARY GAUGLER/SCIENCE SOURCE  http://www.the-scientist.com/images/April2016/immune3.jpg

At the University of Chicago, Thomas Gajewski and his colleagues have taken a slightly different approach to studying the role of the microbiome in cancer development. By comparing Black 6 mice coming from different vendors—Taconic Biosciences (formerly Taconic Farms) and the Jackson Laboratory—Gajewski takes advantage of the fact that the animals’ different origins result in different gut microbiomes. “We deliberately stayed away from antibiotics, because we had a desire to model how intersubject heterogeneity [in cancer development] might be impacted by the commensals they happen to be colonized with,” says Gajewski in an email to The Scientist.

Last year, the researchers published the results of a study comparing the progression of melanoma tumors implanted under the mice’s skin, finding that tumors in the Taconic mice grew more aggressively than those in the Jackson mice. When the researchers housed the different types of mice together before their tumors were implanted, however, these differences disappeared. And transferring fecal material from the Jackson mice into the Taconic mice altered the latter’s tumor progression.14

Instead of promoting cancer, in these experiments the gut microbiome appeared to slow tumor growth. Specifically, the reduced tumor growth in the Jackson mice correlated with the presence of Bifidobacterium, which led to the greater buildup of T?cells in the Jackson mice’s tumors. Bifidobacteriaactivate dendritic cells, which present antigens from bacteria or cancer cells to T?cells, training them to hunt down and kill these invaders. Feeding Taconic mice bifidobacteria improved their response to the implanted melanoma cells.

“One hypothesis going into the experiments was that we might identify immune-suppressive bacteria, or commensals that shift the immune response towards a character that was unfavorable for tumor control,” says Gajewski.  “But in fact, we found that even a single type of bacteria could boost the antitumor immune response.”

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Drug interactions

Ideally, the immune system should recognize cancer as invasive and nip tumor growth in the bud. But cancer cells display “self” molecules that can inhibit immune attack. A new type of immunotherapy, dubbed checkpoint inhibition or blockade, spurs the immune system to attack cancer by blocking either the tumor cells’ surface molecules or the receptors on T?cells that bind to them.

CANCER THERAPY AND THE MICROBIOME

In addition to influencing the development and progression of cancer by regulating inflammation and other immune pathways, resident gut bacteria appear to influence the effectiveness of many cancer therapies that are intended to work in concert with host immunity to eliminate tumors.

  • Some cancer drugs, such as oxaliplatin chemotherapy and CpG-oligonucleotide immunotherapy, work by boosting inflammation. If the microbiome is altered in such a way that inflammation is reduced, these therapeutic agents are less effective.
  • Cancer-cell surface proteins bind to receptors on T cells to prevent them from killing cancer cells. Checkpoint inhibitors that block this binding of activated T cells to cancer cells are influenced by members of the microbiota that mediate these same cell interactions.
  • Cyclophosphamide chemotherapy disrupts the gut epithelial barrier, causing the gut to leak certain bacteria. Bacteria gather in lymphoid tissue just outside the gut and spur generation of T helper 1 and T helper 17 cells that migrate to the tumor and kill it.

As part of their comparison of Jackson and Taconic mice, Gajewski and his colleagues decided to test a type of investigational checkpoint inhibitor that targets PD-L1, a ligand found in high quantities on the surface of multiple types of cancer cells. Monoclonal antibodies that bind to PD-L1 block the PD-1 receptors on T?cells from doing so, allowing an immune response to proceed against the tumor cells. While treating Taconic mice with PD-L1–targeting antibodies did improve their tumor responses, they did even better when that treatment was combined with fecal transfers from Jackson mice, indicating that the microbiome and the immunotherapy can work together to take down cancer. And when the researchers combined the anti-PD-L1 therapy with a bifidobacteria-enriched diet, the mice’s tumors virtually disappeared.14

Gajewski’s group is now surveying the gut microbiota in humans undergoing therapy with checkpoint inhibitors to better understand which bacterial species are linked to positive outcomes. The researchers are also devising a clinical trial in which they will give Bifidobacterium supplements to cancer patients being treated with the approved anti-PD-1 therapy pembrolizumab (Keytruda), which targets the immune receptor PD-1 on T?cells, instead of the cancer-cell ligand PD-L1.

Meanwhile, Zitvogel’s group at INSERM is investigating interactions between the microbiome and another class of checkpoint inhibitors called CTLA-4 inhibitors, which includes the breakthrough melanoma treatment ipilimumab (Yervoy). The researchers found that tumors in antibiotic-treated and germ-free mice had poorer responses to a CTLA-4–targeting antibody compared with mice harboring unaltered microbiomes.15 Particular Bacteroides species were associated with T-cell infiltration of tumors, and feedingBacteroides fragilis to antibiotic-treated or germ-free mice improved the animals’ responses to the immunotherapy. As an added bonus, treatment with these “immunogenic” Bacteroides species decreased signs of colitis, an intestinal inflammatory condition that is a dangerous side effect in patients using checkpoint inhibitors. Moreover, Zitvogel and her colleagues showed that human metastatic melanoma patients treated with ipilimumab tended to have elevated levels of B. fragilis in their microbiomes. Mice transplanted with feces from patients who showed particularly strong B. fragilis gains did better on anti-CTLA-4 treatment than did mice transplanted with feces from patients with normal levels of B. fragilis.

“There are bugs that allow the therapy to work, and at the same time, they protect against colitis,” says Trinchieri. “That is very exciting, because not only [can] we do something to improve the therapy, but we can also, at the same time, try to reduce the side effect.”

And these checkpoint inhibitors aren’t the only cancer therapies whose effects are modulated by the microbiome. Trinchieri has also found that an immunotherapy that combines antibodies against interleukin-10 receptors with CpG oligonucleotides is more effective in mice with unaltered microbiomes.1He and his NCI colleague Goldszmid further found that the platinum chemotherapy oxaliplatin (Eloxatin) was more effective in mice with intact microbiomes, and Zitvogel’s group has shown that the chemotherapeutic agent cyclophosphamide is dependent on the microbiota for its proper function.

Although the mechanisms by which the microbiome influences the effectiveness of such therapies remains incompletely understood, researchers once again speculate that the immune system is the key link. Cyclophosphamide, for example, spurs the body to generate two types of T?helper cells, T?helper 1 cells and a subtype of T?helper 17 cells referred to as “pathogenic,” both of which destroy tumor cells. Zitvogel and her colleagues found that, in mice with unaltered microbiomes, treatment with cyclophosphamide works by disrupting the intestinal mucosa, allowing bacteria to escape into the lymphoid tissues just outside the gut. There, the bacteria spur the body to generate T?helper 1 and T?helper 17 cells, which translocate to the tumor. When the researchers transferred the “pathogenic” T?helper 17 cells into antibiotic-treated mice, the mice’s response to chemotherapy was partly restored.

Microbiome modification

As the link between the microbiome and cancer becomes clearer, researchers are thinking about how they can manipulate a patient’s resident microbial communities to improve their prognosis and treatment outcomes. “Once you figure out exactly what is happening at the molecular level, if there is something promising there, I would be shocked if people don’t then go in and try to modulate the microbiome, either by using pharmaceuticals or using probiotics,” says Michael Burns, a postdoc in the lab of University of Minnesota genomicist Ran Blekhman.

Even if researchers succeed in identifying specific, beneficial alterations to the microbiome, however, molding the microbiome is not simple. “It’s a messy, complicated system that we don’t understand,” says Schloss.

So far, studies of the gut microbiome and colon cancer have turned up few consistent differences between cancer patients and healthy controls. And the few bacterial groups that have repeatedly shown up are not present in every cancer patient. “We should move away from saying, ‘This is a causal species of bacteria,’” says Blekhman. “It’s more the function of a community instead of just a single bacterium.”

But the study of the microbiome in cancer is young. If simply adding one type of microbe into a person’s gut is not enough, researchers may learn how to dose people with patient-specific combinations of microbes or antibiotics. In February 2016, a team based in Finland and China showed that a probiotic mixture dubbed Prohep could reduce liver tumor size by 40 percent in mice, likely by promoting an anti-inflammatory environment in the gut.16

“If it is true that, in humans, we can alter the course of the disease by modulating the composition of the microbiota,” says José Conejo-Garcia of the Wistar Institute in Philadelphia, “that’s going to be very impactful.”

Kate Yandell has been a freelance writer living Philadelphia, Pennsylvania. In February she became an associate editor at Cancer Today.

GENETIC CONNECTION

The microbiome doesn’t act in isolation; a patient’s genetic background can also greatly influence response to therapy. Last year, for example, the Wistar Institute’s José Garcia-Conejo and Melanie Rutkowski, now an assistant professor at the University of Virginia, showed that a dominant polymorphism of the gene for the innate immune protein toll-like receptor 5 (TLR5) influences clinical outcomes in cancer patients by changing how the patients’ immune cells interact with their gut microbes (Cancer Cell, 27:27-40, 2015).

More than 7 percent of people carry a specific mutation in TLR5 that prevents them from mounting a full immune response when exposed to bacterial flagellin. Analyzing both genetic and survival data from the Cancer Genome Atlas, Conejo-Garcia, Rutkowski, and their colleagues found that estrogen receptor–positive breast cancer patients who carry the TLR5 mutation, called the R392X polymorphism, have worse outcomes than patients without the mutation. Among patients with ovarian cancer, on the other hand, those with the TLR5 mutation were more likely to live at least six years after diagnosis than patients who don’t carry the mutation.

Investigating the mutation’s contradictory effects, the researchers found that mice with normal TLR5produce higher levels of the cytokine interleukin 6 (IL-6) than those carrying the mutant version, which have higher levels of a different cytokine called interleukin 17 (IL-17). But when the researchers knocked out the animals’ microbiomes, these differences in cytokine production disappeared, as did the differences in cancer progression between mutant and wild-type animals.

“The effectiveness of depleting specific populations or modulating the composition of the microbiome is going to affect very differently people who are TLR5-positive or TLR5-negative,” says Conejo-Garcia. And Rutkowski speculates that many more polymorphisms linked to cancer prognosis may act via microbiome–immune system interactions. “I think that our paper is just the tip of the iceberg.”

References

  1. N. Iida et al., “Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment,” Science, 342:967-70, 2013.
  2. S. Viaud et al., “The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide,” Science, 342:971-76, 2013.
  3. J.R. Warren, B. Marshall, “Unidentified curved bacilli on gastric epithelium in active chronic gastritis,”Lancet, 321:1273-75, 1983.
  4. B.J. Marshall et al., “Attempt to fulfil Koch’s postulates for pyloric Campylobacter,” Med J Aust, 142:436-39, 1985.
  5. J. Parsonnet et al., “Helicobacter pylori infection and the risk of gastric carcinoma,” N Engl J Med, 325:1127-31, 1991.
  6. S. Kado et al., “Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor β chain and p53 double-knockout mice,” Cancer Res, 61:2395-98, 2001.
  7. J.V. Newman et al., “Bacterial infection promotes colon tumorigenesis in ApcMin/+ mice,” J Infect Dis, 184:227-30, 2001.
  8. S.E. Erdman et al., “CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice,” Am J Pathol, 162:691-702, 2003.
  9. J.P. Zackular et al., “The human gut microbiome as a screening tool for colorectal cancer,” Cancer Prev Res, 7:1112-21, 2014.
  10. G. Zeller et al., “Potential of fecal microbiota for early-stage detection of colorectal cancer,” Mol Syst Biol, 10:766, 2014.
  11. J.P. Zackular et al., “The gut microbiome modulates colon tumorigenesis,” mBio, 4:e00692-13, 2013.
  12. J.P. Zackular et al., “Manipulation of the gut microbiota reveals role in colon tumorigenesis,”mSphere, doi:10.1128/mSphere.00001-15, 2015.
  13. V.P. Rao et al., “Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice,” Cancer Res, 66:7395, 2006.
  14. A. Sivan et al., “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy,” Science, 350:1084-89, 2015.
  15. M. Vétizou et al., “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota,”Science, 350:1079-84, 2015.

……..

 

Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation

Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, …., Julia Tchou,  Gabriel A. Rabinovich, Jose R. Conejo-Garcia
Cancer cell    12 Jan 2015; Volume 27, Issue 1, p27–40  http://dx.doi.org/10.1016/j.ccell.2014.11.009
Figure thumbnail fx1
  • TLR5-dependent IL-6 mobilizes MDSCs that drive galectin-1 production by γδ T cells
  • IL-17 drives malignant progression in IL-6-unresponsive tumors
  • TLR5-dependent differences in tumor growth are abrogated upon microbiota depletion
  • A common dominant TLR5 polymorphism influences the outcome of human cancers

The dominant TLR5R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.

see also… Immune Influence

In recent years, research has demonstrated that microbes living in and on the mammalian body can affect cancer risk, as well as responses to cancer treatment.

By Kate Yandell | April 1, 2016

http://www.the-scientist.com/?articles.view/articleNo/45644/title/Immune-Influence

Although the details of this microbe-cancer link remain unclear, investigators suspect that the microbiome’s ability to modulate inflammation and train immune cells to react to tumors is to blame. Here are some of the hypotheses that have come out of recent research in rodents for how gut bacteria shape immunity and influence cancer.

HOW THE MICROBIOME PROMOTES CANCER

Gut bacteria can dial up inflammation locally in the colon, as well as in other parts of the body, leading to the release of reactive oxygen species, which damage cells and DNA, and of growth factors that spur tumor growth and blood vessel formation.

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Helicobacter pylori can cause inflammation and high cell turnover in the stomach wall, which may lead to cancerous growth.

HOW THE MICROBIOME STEMS CANCER

Gut bacteria can also produce factors that lower inflammation and slow tumor growth. Some gut bacteria (e.g., Bifidobacterium)
appear to activate dendritic cells,
which present cancer-cell antigens to T cells that in turn kill the cancer cells.

http://www.the-scientist.com/images/April2016/ImmuneInfluence3_310px1.jpg

http://www.the-scientist.com/images/April2016/ImmuneInfluence4_310px1.jpg

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