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Archive for the ‘Chemical Biology and its relations to Metabolic Disease’ Category

Bipolar Disorder now understood by Markers Identified of the Gene Expression for this Diagnosis

Reporter: Aviva Lev-Ari, PhD, RN

Published: 

Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways

Abstract

Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls and the transcriptional effects of BD-associated genetic variants. We found two coexpressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the postsynaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (QTL) (eQTL), and these data converged on several individual genes, including SCN2A and GRIN2A. Thus, these data implicate specific genes and pathways that may contribute to the pathology of BP.

SOURCE

https://www.nature.com/articles/s41593-022-01024-6

Gene Expression Markers for Bipolar Disorder Pinpointed

The work was led by researchers at Johns Hopkins’ Lieber Institute for Brain Development. The findings, published this week in Nature Neuroscience, represent the first time that researchers have been able to apply large-scale genetic research to brain samples from hundreds of patients with bipolar disorder (BD). They used 511 total samples from 295 unique donors.

“This is the first deep dive into the molecular biology of the brain in people who died with bipolar disorder—studying actual genes, not urine, blood or skin samples,” said Thomas Hyde of the Lieber Institute and a lead author of the paper. “If we can figure out the mechanisms behind BD, if we can figure out what’s wrong in the brain, then we can begin to develop new targeted treatments of what has long been a mysterious condition.”

Bipolar disorder is characterized by extreme mood swings, with episodes of mania alternating with episodes of depression. It usually emerges in people in their 20s and 30s and remains with them for life. This condition affects approximately 2.8% of the adult American population, or about 7 million people. Patients face higher rates of suicide, poorer quality of life, and lower productivity than the general population. Some estimates put the annual cost of the condition in the U.S. alone at $219.1 billion.

While drugs can be useful in treating BD, many patients find they have bothersome side effects, and for some patients, current medications don’t work at all.

In this study, researchers measured levels of messenger RNA in the brain samples. They observed almost eight times more differentially expressed gene features in the sACC versus the amygdala, suggesting that the sACC may play an especially prominent role—both in mood regulation in general and BD specifically.

In patients who died with BD, the researchers found abnormalities in two families of genes: one containing genes related to the synapse and the second related to immune and inflammatory function.

“There finally is a study using modern technology and our current understanding of genetics to uncover how the brain is doing,” Hyde said. “We know that BD tends to run in families, and there is strong evidence that there are inherited genetic abnormalities that put an individual at risk for bipolar disorder. Unlike diseases such as sickle-cell anemia, bipolar disorder does not result from a single genetic abnormality. Rather, most patients have inherited a group of variants spread across a number of genes.”

“Bipolar disorder, also known as manic-depressive disorder, is a highly damaging and paradoxical condition,” said Daniel R. Weinberger, chief executive and director of the Lieber Institute and a co-author of the study. “It can make people very productive so they can lead countries and companies, but it can also hurl them into the meat grinder of dysfunction and depression. Patients with BD may live on two hours of sleep a night, saving the world with their abundance of energy, and then become so self-destructive that they spend their family’s fortune in a week and lose all friends as they spiral downward. Bipolar disorder also has some shared genetic links to other psychiatric disorders, such as schizophrenia, and is implicated in overuse of drugs and alcohol.”

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The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

Reporter: Stephen J. Williams, Ph.D.

It has been a while since I have added to this series but there have been a plethora of exciting biotech startups in the Philadelphia area, and many new startups combining technology, biotech, and machine learning. One such exciting biotech is Proteovant Therapeutics, which is combining the new PROTAC (Proteolysis-Targeting Chimera) technology with their in house ability to utilize machine learning and artificial intelligence to design these types of compounds to multiple intracellular targets.

PROTACs (which actually is under a trademark name of Arvinus Operations, but is also refered to as Protein Degraders. These PROTACs take advantage of the cell protein homeostatic mechanism of ubiquitin-mediated protein degradation, which is a very specific targeted process which regulates protein levels of various transcription factors, protooncogenes, and receptors. In essence this regulated proteolyic process is needed for normal cellular function, and alterations in this process may lead to oncogenesis, or a proteotoxic crisis leading to mitophagy, autophagy and cellular death. The key to this technology is using chemical linkers to associate an E3 ligase with a protein target of interest. E3 ligases are the rate limiting step in marking the proteins bound for degradation by the proteosome with ubiquitin chains.

Model of PROTAC Ternarary Complex

A review of this process as well as PROTACs can be found elsewhere in articles (and future articles) on this Open Access Journal.

Protevant have made two important collaborations:

  1. Oncopia Therapeutics: came out of University of Michigan Innovation Hub and lab of Shaomeng Wang, who developed a library of BET and MDM2 based protein degraders. In 2020 was aquired by Riovant Sciences.
  2. Riovant Sciences: uses computer aided design of protein degraders

Proteovant Company Description:

Proteovant is a newly launched development-stage biotech company focusing on discovery and development of disease-modifying therapies by harnessing natural protein homeostasis processes. We have recently acquired numerous assets at discovery and development stages from Oncopia, a protein degradation company. Our lead program is on track to enter IND in 2021. Proteovant is building a strong drug discovery engine by combining deep drugging expertise with innovative platforms including Roivant’s AI capabilities to accelerate discovery and development of protein degraders to address unmet needs across all therapeutic areas. The company has recently secured $200M funding from SK Holdings in addition to investment from Roivant Sciences. Our current therapeutic focus includes but is not limited to oncology, immunology and neurology. We remain agnostic to therapeutic area and will expand therapeutic focus based on opportunity. Proteovant is expanding its discovery and development teams and has multiple positions in biology, chemistry, biochemistry, DMPK, bioinformatics and CMC at many levels. Our R&D organization is located close to major pharmaceutical companies in Eastern Pennsylvania with a second site close to biotech companies in Boston area.

Protein degradation

Source: Protevant

The ubiquitin proteasome system (UPS) is responsible for maintaining protein homeostasis. Targeted protein degradation by the UPS is a cellular process that involves marking proteins and guiding them to the proteasome for destruction. We leverage this physiological cellular machinery to target and destroy disease-causing proteins.

Unlike traditional small molecule inhibitors, our approach is not limited by the classic “active site” requirements. For example, we can target transcription factors and scaffold proteins that lack a catalytic pocket. These classes of proteins, historically, have been very difficult to drug. Further, we selectively degrade target proteins, rather than isozymes or paralogous proteins with high homology. Because of the catalytic nature of the interactions,  it is possible to achieve efficacy at lower doses with prolonged duration while decreasing dose-limiting toxicities.

Biological targets once deemed “undruggable” are now within reach.

About Riovant Sciences: from PRNewsWire https://www.prnewswire.com/news-releases/roivant-unveils-targeted-protein-degradation-platform-301186928.html

Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch “Vants” – nimble and focused biopharmaceutical and health technology companies. These Vants include Proteovant but also Dermovant, ImmunoVant,as well as others.

Roivant’s drug discovery capabilities include the leading computational physics-based platform for in silico drug design and optimization as well as machine learning-based models for protein degradation.

The integration of our computational and experimental engines enables the rapid design of molecules with high precision and fidelity to address challenging targets for diseases with high unmet need.

Our current modalities include small molecules, heterobifunctionals and molecular glues.

Roivant Unveils Targeted Protein Degradation Platform

– First therapeutic candidate on track to enter clinical studies in 2021

– Computationally-designed degraders for six targets currently in preclinical development

– Acquisition of Oncopia Therapeutics and research collaboration with lab of Dr. Shaomeng Wang at the University of Michigan to add diverse pipeline of current and future compounds

Clinical-stage degraders will provide foundation for multiple new Vants in distinct disease areas

– Platform supported by $200 million strategic investment from SK Holdings

Other articles in this Vibrant Philly Biotech Scene on this Online Open Access Journal include:

The Vibrant Philly Biotech Scene: PCCI Meeting Announcement, BioDetego Presents Colon Cancer Diagnostic Tool

The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

Philly Biotech Scene: Biobots and 3D BioPrinting (Now called Allevi)

Philly Biotech Scene: November 2015 PCCI Meeting Showcasing ViFant (Penn Center For Innovation)

Spark Therapeutics’ $4.8Billion deal Confirmed as Biggest VC-backed Exit in Philadelphia

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Two brothers with MEPAN Syndrome: A Rare Genetic Disorder

Reporter: Amandeep Kaur

In the early 40s, a married couple named Danny and Nikki, had normal pregnancy and delivered their first child in October 2011.  The couple was elated after the birth of Carson because they were uncertain about even conceiving a baby. Soon after birth, the parents started facing difficulty in feeding the newborn and had some wakeful nights, which they used to called “witching hours”. For initial six months, they were clueless that something was not correct with their infant. Shortly, they found issues in moving ability, sitting, and crawling with Carson. Their next half year went in visiting several behavioral specialists and pediatricians with no conclusion other than a suggestion that there is nothing to panic as children grow at different rates.

Later in early 2013, Caron was detected with cerebral palsy in a local regional center. The diagnosis was based on his disability to talk and delay in motor development. At the same time, Carson had his first MRI which showed no negative results. The parents convinced themselves that their child condition would be solved by therapies and thus started physical and occupational therapies. After two years, the couple gave birth to another boy child named Chase in 2013. Initially, there was nothing wrong with Chase as well. But after nine months, Chase was found to possess the same symptoms of delaying in motor development as his elder brother. It was expected that Chase may also be suffering from cerebral palsy. For around one year both boys went through enormous diagnostic tests starting from karyotyping, metabolic screen tests to diagnostic tests for Fragile X syndrome, lysosomal storage disorders, Friedreich ataxia and spinocerebellar ataxia. Gene panel tests for mitochondrial DNA and Oxidative phosphorylation (OXPHOS) deficiencies were also performed. No conclusion was drawn because each diagnostic test showed the negative results.

Over the years, the condition of boys was deteriorating as their movements became stiffer and ataxic, they were not able to crawl anymore. By the end of 2015, the boys had an MRI which showed some symmetric anomalies in their basal ganglia indicating a metabolic condition. The symptoms of Carson and Chase was not even explained by whole exome sequencing due to the absence of any positive result. The grievous journey of visits to neurologist, diagnostic tests and inconclusive results led the parents to rethink about anything happened erroneous due to them such as due to their lifestyle, insufficient intake of vitamins during pregnancy or exposure to toxic agents which left their sons in that situation.

During the diagnostic odyssey, Danny spent many restless and sleepless nights in searching PubMed for any recent cases with symptoms similar to his sons and eventually came across the NIH’s Undiagnosed Diseases Network (UDN), which gave a light of hope to the demoralized family. As soon as Danny discovered about the NIH’s Diseases Network, he gathered all the medical documents of both his sons and submitted the application. The submitted application in late 2015 got accepted a year later in December 2016 and they got their first appointment in early 2017 at the UDN site at Stanford. At Stanford, the boys had gone through whole-genome sequencing and some series of examinations which came back with inconclusive results. Finally, in February 2018, the family received some conclusive results which explained that the two boys suffer from MEPAN syndrome with pathogenic mutations in MECR gene.

  • MEPAN means Mitochondrial Enoyl CoA reductase Protein-Associated Neurodegeneration
  • MEPAN syndrome is a rare genetic neurological disorder
  • MEPAN syndrome is associated with symptoms of ataxia, optic atrophy and dystonia
  • The wild-type MECR gene encodes a mitochondrial protein which is involved in metabolic processes
  • The prevalence rate of MEPAN syndrome is 1 in 1 million
  • Currently, there are 17 patients of MEPAN syndrome worldwide

The symptoms of Carson and Chase of an early onset of motor development with no appropriate biomarkers and T-2 hyperintensity in the basal ganglia were matching with the seven known MEPAN patient at that time. The agonizing journey of five years concluded with diagnosis of rare genetic disorder.

Despite the advances in genetic testing and their low-cost, there are many families which still suffer and left undiagnostic for long years. To shorten the diagnostic journey of undiagnosed patients, the whole-exome and whole-genome sequencing can be used as a primary tool. There is need of more research to find appropriate treatments of genetic disorders and therapies to reduce the suffering of the patients and families. It is necessary to fill the gap between the researchers and clinicians to stimulate the development in diagnosis, treatment and drug development for rare genetic disorders.

The family started a foundation named “MEPAN Foundation” (https://www.mepan. org) to reach out to the world to educate people about the mutation in MECR gene. By creating awareness among the communities, clinicians, and researchers worldwide, the patients having rare genetic disorder can come closer and share their information to improve their condition and quality of life.

Reference: Danny Miller, The diagnostic odyssey: our family’s story, The American Journal of Human Genetics, Volume 108, Issue 2, 2021, Pages 217-218, ISSN 0002-9297, https://doi.org/10.1016/j.ajhg.2021.01.003 (https://www.sciencedirect.com/science/article/pii/S0002929721000033)

Sources:

https://www.variantyx.com/2020/02/26/in-silico-panel-expansion/

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=508093

https://www.mepan. org

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

Effect of mitochondrial stress on epigenetic modifiers

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/05/07/effect-of-mitochondrial-stress-on-epigenetic-modifiers/

The Three Parent Technique to Avoid Mitochondrial Disease in Embryo

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

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

New Insights into mtDNA, mitochondrial proteins, aging, and metabolic control

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/04/20/new-insights-into-mtdna-mitochondrial-proteins-aging-and-metabolic-control/

Mitochondrial Isocitrate Dehydrogenase and Variants

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/02/mitochondrial-isocitrate-dehydrogenase-and-variants/

Update on mitochondrial function, respiration, and associated disorders

Larry H. Benstein, MD, FCAP, Gurator and writer

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-disorders/

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First single-course ‘curative’ CRISPR Shot by Intellia rivals Alnylam, Ionis and Pfizer

Reporter: Aviva Lev-Ari, PhD, RN

 

Intellia to kick-start first single-course ‘curative’ CRISPR shot, as it hopes to beat rivals Alnylam, Ionis and Pfizer

It’s been a good year for Intellia: One of its founders, Jennifer Doudna, Ph.D., nabbed the Nobel Prize in Chemistry for her CRISPR research.

Now, the biotech she helped build is putting that to work, saying it now plans the world’s first clinical trial for a single-course therapy that “potentially halts and reverses” a condition known as hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

This genetic disorder occurs when a person is born with a specific DNA mutation in the TTR gene, which causes the liver to produce a protein called transthyretin (TTR) in a misfolded form and build up in the body.

hATTR can manifest as polyneuropathy (hATTR-PN), which can lead to nerve damage, or cardiomyopathy (hATTR-CM), which involves heart muscle disease that can lead to heart failure.

This disorder has seen a lot of interest in recent years, with an RNAi approach from Alnylam seeing an approval for Onpattro a few years back, specifically for hATTR in adults with damage to peripheral nerves.

Ionis Pharmaceuticals and its rival RNAi drug Tegsedi also saw an approval in 2018 for a similar indication.

They both battle with Pfizer’s older med tafamidis, which has been approved in Europe for years in polyneuropathy, and the fight could spread to the U.S. soon.

The drug, now marketed as Vyndaqel and Vyndamax, snatched up an FDA nod last May to treat both hereditary and wild-type ATTR patients with a heart condition called cardiomyopathy.

While coming into an increasingly crowed R&D area, Intellia is looking for a next-gen approach, and has been given the go-ahead by regulators ion the U.K, to start a phase 1 this year.

The idea is for Intellia’s candidate NTLA-2001, which is also partnered with Regeneron, to go beyond its rivals and be the first curative treatment for ATTR.

By applying the company’s in vivo liver knockout technology, NTLA-2001 allows for the possibility of lifelong transthyretin (TTR) protein reduction after a single course of treatment. If this works, this could in essence cure patients of the their disease.

The 38-patient is set to start by year’s end.

“Starting our global NTLA-2001 Phase 1 trial for ATTR patients is a major milestone in Intellia’s mission to develop medicines to cure severe and life-threatening diseases,” said Intellia’s president and chief John Leonard, M.D.

“Our trial is the first step toward demonstrating that our therapeutic approach could have a permanent effect, potentially halting and reversing all forms of ATTR. Once we have established safety and the optimal dose, our goal is to expand this study and rapidly move to pivotal studies, in which we aim to enroll both polyneuropathy and cardiomyopathy patients.”

SOURCE

https://www.fiercebiotech.com/biotech/intellia-to-kickstart-first-single-course-curative-crispr-shot-as-it-hopes-to-beat-rivals

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

 

Familial transthyretin amyloid polyneuropathy

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/06/10/familial-transthyretin-amyloid-polyneuropathy/

 

Stabilizers that prevent transthyretin-mediated cardiomyocyte amyloidotic toxicity

Reporter and curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/12/02/stabilizers-that-prevent-transthyretin-mediated-cardiomyocyte-amyloidotic-toxicity/

 

Transthyretin amyloid cardiomyopathy (ATTR-CM): U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ for this Rare and Fatal Disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/10/29/transthyretin-amyloid-cardiomyopathy-attr-cm-u-s-fda-approves-vyndaqel-and-vyndamax-for-this-rare-and-fatal-disease/

 

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/13/alnylam-announces-first-ever-fda-approval-of-an-rnai-therapeutic-onpattro-patisiran-for-the-treatment-of-the-polyneuropathy-of-hereditary-transthyretin-mediated-amyloidosis-in-adults/

 

 

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

 

Obesity is a global concern that is associated with many chronic complications such as type 2 diabetes, insulin resistance (IR), cardiovascular diseases, and cancer. Growing evidence has implicated the digestive system, including its microbiota, gut-derived incretin hormones, and gut-associated lymphoid tissue in obesity and IR. During high fat diet (HFD) feeding and obesity, a significant shift occurs in the microbial populations within the gut, known as dysbiosis, which interacts with the intestinal immune system. Similar to other metabolic organs, including visceral adipose tissue (VAT) and liver, altered immune homeostasis has also been observed in the small and large intestines during obesity.

 

A link between the gut microbiota and the intestinal immune system is the immune-derived molecule immunoglobulin A (IgA). IgA is a B cell antibody primarily produced in dimeric form by plasma cells residing in the gut lamina propria (LP). Given the importance of IgA on intestinal–gut microbe immunoregulation, which is directly influenced by dietary changes, scientists hypothesized that IgA may be a key player in the pathogenesis of obesity and IR. Here, in this study it was demonstrate that IgA levels are reduced during obesity and the loss of IgA in mice worsens IR and increases intestinal permeability, microbiota encroachment, and downstream inflammation in metabolic tissues, including inside the VAT.

 

IgA deficiency alters the obese gut microbiota and its metabolic phenotype can be recapitulated into microbiota-depleted mice upon fecal matter transplantation. In addition, the researchers also demonstrated that commonly used therapies for diabetes such as metformin and bariatric surgery can alter cellular and stool IgA levels, respectively. These findings suggested a critical function for IgA in regulating metabolic disease and support the emerging role for intestinal immunity as an important modulator of systemic glucose metabolism.

 

Overall, the researchers demonstrated a critical role for IgA in regulating intestinal homeostasis, metabolic inflammation, and obesity-related IR. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease. This research further emphasized the importance of the intestinal adaptive immune system and its interactions with the gut microbiota and innate immune system within the larger network of organs involved in the manifestation of metabolic disease.

 

Future investigation is required to determine the impact of IgA deficiency during obesity in humans and the role of metabolic disease in human populations with selective IgA deficiency, especially since human IgA deficiency is associated with an altered gut microbiota that cannot be fully compensated with IgM. However, the research identified IgA as a critical immunological molecule in the intestine that impacts systemic glucose homeostasis, and treatments targeting IgA-producing immune populations and SIgA may have therapeutic potential for metabolic disease.

 

References:

 

https://www.nature.com/articles/s41467-019-11370-y?elqTrackId=dc86e0c60f574542b033227afd0fdc8e

 

https://www.jci.org/articles/view/88879

 

https://www.nature.com/articles/nm.2353

 

https://diabetes.diabetesjournals.org/content/57/6/1470

 

https://www.sciencedirect.com/science/article/pii/S1550413115001047?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1550413115002326?via%3Dihub

 

https://www.sciencedirect.com/science/article/pii/S1931312814004636?via%3Dihub

 

https://www.nature.com/articles/nature15766

 

https://www.sciencedirect.com/science/article/pii/S1550413116000371?via%3Dihub

 

https://www.nature.com/articles/nm.2001

 

https://www.sciencedirect.com/science/article/abs/pii/S1550413118305047?via%3Dihub

 

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Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

 

Reporter: Aviva Lev-Ari, PhD, RN

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” said Alessio Fasano, HMS professor of pediatrics at Mass General, director of MIBRC and co-senior author of the paper.

https://hms.harvard.edu/news/major-shift?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_3&utm_content=HMNews05132019

 

 

Image Source: iStock/wildpixel

Article OPEN Published: 

Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease

Scientific Reports volume 9, Article number: 7029 (2019Download Citation

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

Mass. General researchers develop 3D “mini-gut” model to study autoimmune response to gluten in celiac and non-celiac patient tissue

Gene expression of intestinal organoids reflects functional differences found in celiac disease

In pursuit of a novel tool for the research and treatment of celiac disease, scientists at the Mucosal Immunology and Biology Research Center (MIBRC) at Massachusetts General Hospital (MGH) have validated the use of intestinal organoids. These three-dimensional tissue cultures are miniature, simplified versions of the intestine produced in vitro. Taking tissue from duodenal biopsies of celiac and non-celiac patients, researchers created the “mini-guts” to explore how the gut epithelium and microbiota-derived molecules respond to gluten, a complex class of proteins found in wheat and other grains.

“We currently have no animal model that can recapitulate the response to gluten that we see in humans,” says Stefania Senger, PhD, co-senior author of the study published in Scientific Reports this week. “Using this human tissue model, we observed that intestinal organoids express the same molecular markers as actual epithelium in the celiac tissue, and the signature gene expression reflects the functional differences that occur when epithelia of celiac disease patients are exposed to gliadin.” Gliadin and glutenin proteins are main components of gluten.

Celiac disease is triggered when genetically predisposed individuals consume gluten. The condition affects approximately 1 percent of the U.S. population. Based on current data, the onset of celiac disease is thought to be preceded by the release of the protein zonulin, which is triggered by the activation of undigested gliadin to induce an autoimmune response. This leads to increased intestinal permeability and a disrupted barrier function. Novel evidence suggests that the microorganisms in the gastrointestinal tract may play a role in the onset of celiac disease.

Earlier studies from the MIBRC group and others have shown that human organoids “retain a gene expression that recapitulates the expression of the tissue of origin, including a diseased state,” the authors write. Through RNA sequencing, the new findings validate the organoid model as a “faithful in vitro model for celiac disease,” Senger says.
Using whole-transcriptome analysis, the researchers identified 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids. These included novel genes associated with epithelial functions related to the pathogenesis of celiac disease – including gut barrier maintenance, stem cell regeneration and innate immune response. A second finding of the study shows that bioproducts derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and co-senior author.

Senger adds, “We believe our observations represent a major shift in the study of celiac disease. We are confident that with adequate funding we could achieve major goals that include the development and implementation of high-throughput drug screenings to quickly identify new treatments for patients and expand the organoid repository to develop more complex models and pursue personalized treatment.”
Additional co-authors of the paper are first author Rachel Freire, PhD, along with Laura Ingano and Gloria Serena, PhD, of the MGH MIBRC; Murat Cetinbas, PhD, and Ruslan Sadreyev, PhD, MGH Department of Molecular Biology; Anthony Anselmo, PhD, formerly of MGH Molecular Biology and now with PatientsLikeMe, Cambridge, Mass.; and Anna Sapone, MD, PhD, Takeda Pharmaceuticals International. Support for the study includes National Institutes of Health grants RO1 DK104344-01A1 and 1U19 AI082655-02 and the Egan Family Foundation.

SOURCE

https://www.massgeneral.org/about/pressrelease.aspx?id=2403

 

Other related articles and e-Books by LPBI Group’s Authors published on this Open Access Online Scientific Journal include the following:

 

Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases

  • Metabolomics 

VOLUME 1: Metabolic Genomics and Pharmaceutics. On Amazon.com since 7/21/2015

http://www.amazon.com/dp/B012BB0ZF0

Gluten-free Diets

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

 

Breakthrough Digestive Disorders Research: Conditions affecting the Gastrointestinal Tract.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/12/breakthrough-digestive-disorders-research-conditions-affecting-the-gastrointestinal-tract/

 

Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and subepithelial myofibroblasts

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/25/collagen-binding-molecular-chaperone-hsp47-role-in-intestinal-fibrosis-colonic-epithelial-cells-and-subepithelial-myofibroblasts/

Expanding area of Tolerance-inducing Autoimmune Disease Therapeutics: Key Players

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/17/expanding-area-of-tolerance-inducing-autoimmune-disease-therapeutics-key-players/

 

What is the key method to harness Inflammation to close the doors for many complex diseases?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

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

 

The bacterial makeup of human milk is influenced by the mode of breastfeeding, according to a new study. Although previously considered sterile, breast milk is now known to contain a low abundance of bacteria. While the complexities of how maternal microbiota influence the infant microbiota are still unknown, this complex community of bacteria in breast milk may help to establish the infant gut microbiota. Disruptions in this process could alter the infant microbiota, causing predisposition to chronic diseases such as allergies, asthma, and obesity. While it’s unclear how the breast milk microbiome develops, there are two theories describing its origins. One theory speculates that it originates in the maternal mammary gland, while the other theory suggests that it is due to retrograde inoculation by the infant’s oral microbiome.

 

To address this gap in knowledge scientists carried out bacterial gene sequencing on milk samples from 393 healthy mothers three to four months after giving birth. They used this information to examine how the milk microbiota composition is affected by maternal factors, early life events, breastfeeding practices, and other milk components. Among the many factors analyzed, the mode of breastfeeding (with or without a pump) was the only consistent factor directly associated with the milk microbiota composition. Specifically, indirect breastfeeding was associated with a higher abundance of potential opportunistic pathogens, such as Stenotrophomonas and Pseudomonadaceae. By contrast, direct breastfeeding without a pump was associated with microbes typically found in the mouth, as well as higher overall bacterial richness and diversity. Taken together, the findings suggest that direct breastfeeding facilitates the acquisition of oral microbiota from infants, whereas indirect breastfeeding leads to enrichment with environmental (pump-associated) bacteria.

 

The researchers argued that this study supports the theory that the breast milk microbiome is due to retrograde inoculation. Their findings indicate that the act of pumping and contact with the infant oral microbiome influences the milk microbiome, though they noted more research is needed. In future studies, the researchers will further explore the composition and function of the milk microbiota. In addition to bacteria, they will profile fungi in the milk samples. They also plan to investigate how the milk microbiota influences both the gut microbiota of infants and infant development and health. Specifically, their projects will examine the association of milk microbiota with infant growth, asthma, and allergies. This work could have important implications for microbiota-based strategies for early-life prevention of chronic conditions.

 

References:

 

https://www.genomeweb.com/sequencing/human-breast-milk-microbiome-affected-mode-feeding#.XIOH0igzZPY

 

http://childstudy.ca/2019/02/13/breastmilk-microbiome-linked-to-method-of-feeding/

 

https://gizmodo.com/pumping-breast-milk-changes-its-microbiome-1832568169

 

https://www.sciencedaily.com/releases/2019/02/190213124445.htm

 

https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30049-6

 

https://www.unicef.org.uk/babyfriendly/news-and-research/baby-friendly-research/infant-health-research/epigenetics-microbiome-research/

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

 

Research about marijuana and fertility is limited but some previous studies suggested that it might harm semen quality. Smoking of any type is also known to be a risk factor for male infertility. So, men who have smoked cannabis are expected to have worse measures of fertility but the data from a recent study suggested the opposite. The finding contradicts all conventional knowledge on how weed affects sperm. This may be because previous research typically focused on men with drug abuse history but this present study simply asked men if they had smoked more than two joints in their life.

 

Analysis of 1,143 semen samples from 662 men collected between 2000 and 2017 at the Fertility Clinic at Massachusetts General Hospital showed that those who had smoked weed at some point in their life had a mean sperm concentration of 62.7 million sperm per milliliter (mL) of ejaculate, while men who avoided marijuana entirely had mean concentrations of 45.4 million/mL. Added to this only 5% of weed smokers had sperm concentrations below the 15 million/mL threshold the World Health Organization has set for a “normal” sperm count, versus 12% of men who never smoked marijuana.

 

The study has some imperfections such as the participants are not necessarily representative of the general population. They were predominantly college educated men with a mean age of 36, and were all seeking treatment at a fertility center. Further research is needed to support the findings. Two possibilities are put forward by the researchers as the reason behind such data. The first is that low levels of marijuana could have a positive effect on the endocannabinoid system, the neurotransmitters in the nervous system that bind to cannabinoid receptors, and are known to regulate fertility. The second is that may be weed-smokers are just bigger risk takers and men with higher testosterone levels and thus have better sperm count.

 

But, there’s certainly no medical recommendation to smoke weed as a fertility treatment but this study, at least, suggests that a little marijuana doesn’t hurt and might benefit sperm production in some way. But, the researchers specified that their finding does not necessarily mean that smoking cannabis increases the chances of fatherhood.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/30726923

 

https://www.bloomberg.com/amp/news/articles/2019-02-06/cannabis-smoking-associated-with-higher-sperm-count-study-finds?__twitter_impression=true

 

https://qz.com/1543564/smoking-weed-linked-to-higher-sperm-count-in-a-harvard-study/

 

https://www.thestar.com.my/news/world/2019/02/06/cannabis-smoking-associated-with-higher-sperm-count-study-finds/

 

http://time.com/5520421/smoking-marijuana-sperm-fertility/

 

https://www.health.com/infertility/marijuana-sperm-count

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

 

The relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research. Bidirectional microbiota–gut–brain communication has mostly been explored in animal models, with human research lagging behind. Large-scale metagenomics studies could facilitate the translational process, but their interpretation is hampered by a lack of dedicated reference databases and tools to study the microbial neuroactive potential.

 

Out of all the many ways, the teeming ecosystem of microbes in a person’s gut and other tissues might affect health. But, its potential influences on the brain may be the most provocative for research. Several studies in mice had indicated that gut microbes can affect behavior, and small scale studies on human beings suggested this microbial repertoire is altered in depression. Studies by two large European groups have found that several species of gut bacteria are missing in people with depression. The researchers can’t say whether the absence is a cause or an effect of the illness, but they showed that many gut bacteria could make substances that affect the nerve cell function—and maybe the mood.

 

Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Together with DialisterCoprococcus spp. was also depleted in depression, even after correcting for the confounding effects of antidepressants. Two kinds of microbes, Coprococcus and Dialister, were missing from the microbiomes of the depressed subjects, but not from those with a high quality of life. The researchers also found the depressed people had an increase in bacteria implicated in Crohn disease, suggesting inflammation may be at fault.

 

Looking for something that could link microbes to mood, researchers compiled a list of 56 substances important for proper functioning of nervous system that gut microbes either produce or break down. They found, for example, that Coprococcus seems to have a pathway related to dopamine, a key brain signal involved in depression, although they have no evidence how this might protect against depression. The same microbe also makes an anti-inflammatory substance called butyrate, and increased inflammation is implicated in depression.

 

Still, it is very much unclear that how microbial compounds made in the gut might influence the brain. One possible channel is the vagus nerve, which links the gut and brain. Resolving the microbiome-brain connection might lead to novel therapies. Some physicians and companies are already exploring typical probiotics, oral bacterial supplements, for depression, although they don’t normally include the missing gut microbes identified in the new study.

 

References:

 

https://www.sciencemag.org/news/2019/02/evidence-mounts-gut-bacteria-can-influence-mood-prevent-depression?utm_source=Nature+Briefing

 

https://www.nature.com/articles/s41564-018-0337-x

 

https://www.ncbi.nlm.nih.gov/pubmed/22968153

 

https://www.ncbi.nlm.nih.gov/pubmed/24888394

 

https://www.ncbi.nlm.nih.gov/pubmed/27067014

 

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The second annual PureTech Health BIG (Brain-Immune-Gut) Summit 2019 – By invitation only –

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

 

January 30 – February 1, 2019

The second annual PureTech Health BIG Summit brings together an elite ensemble of leading scientific researchers, investors, and CEOs and R&D leaders from major pharmaceutical, technology, and biotech companies.

The BIG Summit is designed to stimulate ideas that will have an impact on existing pipelines and catalyze future interactions among a group of delegates that represent leaders and innovators in their fields.

Please follow the discussion on Twitter using #BIGAxisSummit

By invitation only; registration is non-transferable.

For more information, please contact PureTechHealthSummit@PureTechHealth.com

 

HOST COMMITTEE

Participants

 

BIG SUMMIT AGENDA

(Subject to Change)

PureTech Health BIG Summit 2019 Agenda_FINALv2_WEBSITE.jpg

“Almost starting to understand immunology at this thought-provoking @PureTechh #BIGAxisSummit. Great Speakers.”

-tweet by Simone Fishburn, BioCentury @SimoneFishburn

SOURCE

https://bigsummit2019.com/agenda/

 

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Gail S. Thornton Selections

Luke Timmerman‏ @ldtimmerman 7h7 hours ago

Back for final sessions at #BIGAxisSummit. @PureTechH Jim Harper of Sonde Health talking about how voice data — pacing, fine motor articulation, oscillation — can point the way to objective, quantitative measures for detecting and monitoring depression.

 

Eddie Martucci

 @EddieMartucci 5h5 hours ago

Paul Biondi at #BIGAxisSummit : What makes big deals happen is financial, and *deep conviction* of a big future fit. Disproportionate valuation from bidders is expected.

Love this. We often reduce everything to mathematical analyses to champion or ridicule deals. Not that simple

 

PureTech Health Plc‏ @PureTechH Jan 31

Bob Langer (@MIT) asks how #lymphatics affected by #aging. Santambrogio: typically blame aging #immune cells for increased disease, but aging affects lymphatics too (less efficient trafficking shown). Rejuvenating these could affect several aging-related diseases #BigAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Viviane Labrie (@VAInstitute) discusses why the appendix has been identified as a potential starting point for #parkinsons #BIGAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Chris Porter (@MIPS_Australia) notes #lymphatics is major route for trafficking #immune cells that surveil gut and respond to immune & #autoimmune stimuli. This is key in #BIGAxis interactions and why lymphatics-targeted therapies could enhance #immunomodulation #BIGAxisSummit

 

Dr. Stephen J. Williams Selections

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Dr. Irina Robu Selection

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Dr. Sudipta Saha Selection

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