University of Miami – The Dr. John T. Macdonald Foundation …

Our mission is to become a world renowned Center of Excellence in the areas of human genetics, genomic research and clinical genomic medicine. Using clinically advanced technology, state-of-the-art equipment and highly trained professionals, we aim to uncover the genetic contributions to disease, apply our findings to better patient care, and educate the geneticists and genomicists of tomorrow.

Established through the generous support of the Dr. John T. Macdonald Foundation, we are committed to the identification of genes and gene networks that cause diseases. We are in an extraordinary period of growth, especially since the completion of the Human Genome Project in 2003. Our recognition spans far beyond traditional single-gene disorders such as sickle cell anemia and cystic fibrosis, and now encompasses knowledge associated with complex conditions such as autism, Alzheimers disease and Parkinson disease.

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University of Miami – The Dr. John T. Macdonald Foundation …

Home | HMS Department of Genetics

BCH Division of Genetics and Genomics Seminar

Generating Cartilage from Human Pluripotent Stem Cells: A Developmental Approach.

Special Seminar

How Neurons Talk to the Blood: Sensory Regulation of Hematopoiesis in the Drosophila Model

Genetics Seminar Series

Neural Reprogramming of Germline Cells and Trans-Generational Memory in Drosophila

BCH Division of Genetics and Genomics Seminar

Genetics Seminar Series – Focused Seminars

Reflecting the breadth of the field itself, the Department of Genetics at Harvard Medical School houses a faculty working on diverse problems, using a variety of approaches and model organisms, unified in their focus on the genome as an organizing principle for understanding biological phenomena. Genetics is not perceived simply as a subject, but rather as a way of viewing and approaching biological phenomena.

While the range of current efforts can best be appreciated by reading the research interests of individual faculty, the scope of the work conducted in the Department includes (but is by no means limited to) human genetics of both single gene disorders and complex traits, development of genomic technology, cancer biology, developmental biology, signal transduction, cell biological problems, stem cell biology, computational genetics, immunology, synthetic biology, epigenetics, evolutionary biology and plant biology.

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Department of Genetics – Stanford University School of …

Altman Lab

The Helix Group at Stanford is directed by Russ Altman.

The Ashley lab is focused on the application of genomics to medicine.

Attardi Lab

The overarching goal of our research is to better define the mechanisms by which the p53 protein promotes different responses in different settings.

Baker Lab

Cellular differentiation is governed by dynamic changes occurring in the genome.

Barna Lab

We study how the genome is translated into morphology through a ribosome code and single cell imaging of tissue patterning.

Bhatt Lab

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Department of Genetics – Stanford University School of …

Medical Genetics at University of Washington

Medical Genetics Faculty, Fellows & Staff: 2014

The University of Washington Department of Medicine is recruiting for one (1) full-time faculty position at the Associate Professor, or Professor level in the Division of Medical Genetics, Department of Medicine. This position is offered with state tenure funding.

Successful candidates for this position will have an M.D./Ph.D. or M.D. degree (or foreign equivalent), clinical expertise in genetics, and will be expected to carry out a successful research program. Highly translational PhD (or foreign equivalent) scientists may be considered. Although candidates with productive research programs in translational genetics/genomics and/or precision medicine will be prioritized, investigators engaged in gene therapy research may also be considered.

The position will remain open until filled. Send CV and 1-2 page letter of interest to:

Medical Genetics Faculty Search c/o Sara Carlson Division of Medical Genetics University of Washington seisner@u.washington.edu

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Medical Genetics at University of Washington

ESPERITE (ESP) validates SERENITY, the breast and ovarian cancer risk screening test that sequences the entire BRCA1 …

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ESPERITE (ESP) validates SERENITY, the breast and ovarian cancer risk screening test that sequences the entire BRCA1 …

NorthShore University HealthSystem Launches Comprehensive Center for Personalized Medicine, Ushering in New Era in …

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NorthShore University HealthSystem Launches Comprehensive Center for Personalized Medicine, Ushering in New Era in …

Genelex Enables Genetic Risk Analysis and Precision Medicine in EHRs and Population Health Software with New APIs

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Genelex Enables Genetic Risk Analysis and Precision Medicine in EHRs and Population Health Software with New APIs

Aetna, Cigna balk as Angelina effect spurs genetic cancer testing

Medical researchers call it the “Angelina Effect,” the surge in demand for genetic testing attributable to movie star Angelina Jolie’s public crusade for more aggressive detection of hereditary breast and ovarian cancer.

But there’s a catch: Major insurance companies including Aetna, Anthem and Cigna are declining to pay for the latest generation of tests, known as multi-gene panel tests, Reuters has learned. The insurers say that the tests are unproven and may lead patients to seek out medical care they don’t need.

That’s a dangerous miscalculation, a range of doctors, genetic counselors, academics and diagnostics companies said. While they acknowledge that multi-gene tests produce data that may not be useful from a diagnostic standpoint, they say that by refusing or delaying coverage, insurance companies are endangering patients who could be undergoing screenings or changing their diets if they knew about the possible risks.

The tests have come a long way since Jolie, 39, went public in 2013, revealing that she underwent a double mastectomy after a genetic test found she carried mutations in the BRCA1 and BRCA2 genes, indicating a high risk of breast and ovarian cancer. She disclosed last month that she had her ovaries and fallopian tubes removed.

The new panel tests, which can cost between $2,000 to $4,900, analyze 20 or more genes at once. That allows healthcare professionals to establish possible DNA links to other cancer-related conditions such as Lynch syndrome and Li-Fraumeni Syndrome earlier. Humans have about 23,000 genes.

Susan Kutner, a surgeon at a Kaiser Permanente hospital in San Jose, California, who serves on a U.S. Centers for Disease Control and Prevention advisory committee on young women and breast cancer, said more women with a family history of cancer should be able get these tests.

“If we have members who are not being tested in a timely manner, we know that their risk of cancer in the long run costs us and them a lot more,” Kutner said.

Kaiser, which insures its own members, covers panel tests for patients with family histories of cancer.

That’s not so at three of the four largest managed care companies. Aetna Inc, Anthem Inc and Cigna Corp state in their policies that in most cases they don’t cover multi-gene panel tests. The fourth, UnitedHealth Group, covers the tests if patients meet certain criteria.

All insurers cover screenings for BRCA1 and BRCA2 and for certain other genes for women who have family histories of cancer. Indeed, such coverage is mandated by the Affordable Care Act, known as Obamacare.

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Aetna, Cigna balk as Angelina effect spurs genetic cancer testing

Likely genetic source of muscle weakness found in six previously undiagnosed children

Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.

The child was one of six cases in which TGen sequenced — or decoded — the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms, according to a study published April 8 in the journal Molecular Genetics & Genomic Medicine.

“In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing — often over many years — without a successful diagnosis, until they enrolled in our study,” said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.

This is a prime example of the type of “personalized medicine” TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.

“Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,” said Dr. Baumbach-Reardon. “This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.”

In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.

“To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,” said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.

Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease.

In another closely related case, TGen’s genetic testing found a pathogenic variant in the RYR1 gene in a case of calcium channel myopathy. When the brain sends an electrical signal, CACNA1S opens the RYR1 calcium channel flooding muscles with calcium and causing them to contract. When either partner of this duo doesn’t function correctly, devastating muscle weakness results.

Five of the six cases involved patients under the care of Dr. Saunder Bernes, a neurologist at Barrow Neurological Institute at Phoenix Children’s Hospital. Dr. Bernes referred all five cases to TGen for genetic sequencing in an effort to find the causes of the children’s muscle weakness.

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Likely genetic source of muscle weakness found in six previously undiagnosed children

TGen finds likely genetic source of muscle weakness in 6 previously undiagnosed children

Simple genetic test by TGen reveals likely causes of disease, after other extensive testing failed; 1 child’s case produces discovery

PHOENIX, Ariz. — April 9, 2015 — Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.

The child was one of six cases in which TGen sequenced — or decoded — the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms, according to a study published April 8 in the journal Molecular Genetics & Genomic Medicine.

“In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing — often over many years — without a successful diagnosis, until they enrolled in our study,” said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.

This is a prime example of the type of “personalized medicine” TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.

“Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,” said Dr. Baumbach-Reardon. “This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.”

In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.

“To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,” said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.

Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease.

In another closely related case, TGen’s genetic testing found a pathogenic variant in the RYR1 gene in a case of calcium channel myopathy. When the brain sends an electrical signal, CACNA1S opens the RYR1 calcium channel flooding muscles with calcium and causing them to contract. When either partner of this duo doesn’t function correctly, devastating muscle weakness results.

Originally posted here:

TGen finds likely genetic source of muscle weakness in 6 previously undiagnosed children

TGen scientists discover the likely cause of rare type of muscle weakness in six children

Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.

The child was one of six cases in which TGen sequenced — or decoded — the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms, according to a study published April 8 in the journal Molecular Genetics & Genomic Medicine.

“In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing — often over many years — without a successful diagnosis, until they enrolled in our study,” said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.

This is a prime example of the type of “personalized medicine” TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.

“Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,” said Dr. Baumbach-Reardon. “This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.”

In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.

“To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,” said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.

Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease.

In another closely related case, TGen’s genetic testing found a pathogenic variant in the RYR1 gene in a case of calcium channel myopathy. When the brain sends an electrical signal, CACNA1S opens the RYR1 calcium channel flooding muscles with calcium and causing them to contract. When either partner of this duo doesn’t function correctly, devastating muscle weakness results.

Five of the six cases involved patients under the care of Dr. Saunder Bernes, a neurologist at Barrow Neurological Institute at Phoenix Children’s Hospital. Dr. Bernes referred all five cases to TGen for genetic sequencing in an effort to find the causes of the children’s muscle weakness.

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TGen scientists discover the likely cause of rare type of muscle weakness in six children

UK biotech Silence Therapeutics raises $58 million for its RNA drive

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UK biotech Silence Therapeutics raises $58 million for its RNA drive

Silence Therapeutics raises 38 million pounds for its RNA drive

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Silence Therapeutics raises 38 million pounds for its RNA drive

It Takes Two To Tango: Combine Diagnostics And Drugs For Precision Medicine

Personalization is the New Name of the Game

Precision medicine, also known as personalized medicine, is a concept of combining a drug with a test that is modified to a persons genetic disposition. The test has the ability to predict disease risk, diagnose disease and monitor therapeutic response. Given the huge problem of drug failure rates, the concept of companion diagnostics in the realm of precision medicine has gained huge momentum since 2010. Precision medicine involves the selection of diagnostic tests (companion diagnostics) that have the potential to identify changes in each patients cells. The use of that knowledge may help prevent and treat diseases through the development of treatment strategies to target these specific molecular alterations. Ultimately, the goal of precision medicine is to improve patient outcomes.

Figure 1 shows the failure rates for drugs in several disease categories today. Personalized medicine can help save billions of dollars for the healthcare economy globally.

How Big is the Opportunity?

By 2020, the companion diagnostics market will experience a growth of 20.4 percent globally. In 2014, the market for test sales and test services alone was $2.4 billion and is expected to reach $6.9 billion globally.

Figure 2 shows the percentage distribution of partnerships by type of therapeutic area from 2011 to 2013. Companion diagnostics for oncology is obviously leading the way, but there are several other therapeutic areas, including neurology and cardiovascular, that have started to develop drug/diagnostics combo treatments. The challenges in adopting personalized medicine are boundless. The first and foremost challenge affecting the precision medicine landscape is coordinating the timelines. Aligning the development of a drug and diagnostic design program requires a lot of careful planning. This also closely ties into the fact that the current regulations must be modified to support this idea. Current regulations and the three-tier approval process significantly drives up the cost of delivering drugs to market ($800 million $2 billion per molecule) with times-to-market of seven to 10 years. This does not lend itself to driving the agility that is imperative for personalized medicine to become mainstream. A radical redesign of the drug approval process is imperative for personalized medicine to flourish.

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It Takes Two To Tango: Combine Diagnostics And Drugs For Precision Medicine

Study identifies genetic variants linked to Hirschsprungs disease

Rare disorder can spring from common mutations that affect nerve development

Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprungs disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the Hirschsprungs disease that direct it.

The results appear in the April 2 issue of the American Journal of Human Genetics.

About one in every 5,000 babies is born with Hirschsprungs disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.

The genetic causes of Hirschsprungs disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicines McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.

But while Chakravartis and other groups have identified several genetic variants associated with Hirschsprungs, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprungs disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.

The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.

It looks like the semaphorin variant doesnt by itself lead to Hirschsprungs, but when theres a variant in Ret too, it causes the pathway to malfunction and can cause disease, Chakravarti says. Weve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.

Chakravarti notes that the genetic puzzle of Hirschsprungs is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases.

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Study identifies genetic variants linked to Hirschsprungs disease

Genetic studies reveal cause of Hirschsprung's disease

Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.

The results appear in the April 2 issue of the American Journal of Human Genetics.

About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.

The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.

But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.

The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.

“It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,” Chakravarti says. “We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.”

Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases.

See the article here:

Genetic studies reveal cause of Hirschsprung's disease

New genetic clues emerge on origin of Hirschsprung's disease

Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.

The results appear in the April 2 issue of the American Journal of Human Genetics.

About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.

The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.

But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.

The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.

“It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,” Chakravarti says. “We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.”

Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases.

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Other authors on the paper are Qian Jiang, Stacey Arnold, Betty Doan, Ashish Kapoor, Albee Yun Ling, Maria X. Sosa, Moltu Guy, Krishna Praneeth Kilambi, Qingguang Jiang, Grzegorz Burzynski, Kristen West, Seneca Bessling, Jeffrey J. Gray and Andrew S. McCallion of The Johns Hopkins University; Tiffany Heanue and Vassilis Pachnis of the MRC National Institute for Medical Research; Paola Griseri and Isabella Ceccherini of the Istituto Gaslini; Jeanne Amiel and Stanislas Lyonnet of the French National Institute of Health and Medical Research and Paris Descartes University-Sorbonne Paris Cite; Raquel M. Fernandez and Salud Borrego of the University of Seville; Joke B.G.M. Verheij of the University of Groningen; and Robert M.W. Hofstra of the University of Rotterdam.

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New genetic clues emerge on origin of Hirschsprung's disease

Researchers produce iPSC model to better understand genetic lung/liver disease

(Boston)–Using patient-derived stem cells known as induced pluripotent stem cells (iPSC) to study the genetic lung/liver disease called alpha-1 antitrypsin (AAT) deficiency, researchers have for the first time created a disease signature that may help explain how abnormal protein leads to liver disease.

The study, which appears in Stem Cell Reports, also found that liver cells derived from AAT deficient iPSCs are more sensitive to drugs that cause liver toxicity than liver cells derived from normal iPSCs. This finding may ultimately lead to new treatments for the condition.

IPSC’s are derived from the donated skin or blood cells of adults and, with the reactivation of four genes, are reprogrammed back to an embryonic stem cell-like state. Like embryonic stem cells, iPSC can be differentiated toward any cell type in the body, but they do not require the use of embryos. Alpha-1 antitrypsin deficiency is a common genetic cause of both liver and lung disease affecting an estimated 3.4 million people worldwide.

Researchers from the Center for Regenerative Medicine (CReM) at Boston University and Boston Medical Center (BMC) worked for several years in collaboration with Dr. Paul Gadue and his group from Children’s Hospital of Philadelphia to create iPSC from patients with and without AAT deficiency. They then exposed these cells to certain growth factors in-vitro to cause them to turn into liver-like cells, in a process that mimics embryonic development. Then the researchers studied these “iPSC-hepatic cells” and found the diseased cells secrete AAT protein more slowly than normal cells. This finding demonstrated that the iPSC model recapitulates a critical aspect of the disease as it occurs in patients. AAT deficiency is caused by a mutation of a single DNA base. Correcting this single base back to the normal sequence fixed the abnormal secretion.

“We found that these corrected cells had a normal secretion kinetic when compared with their diseased, parental cells that are otherwise genetically identical except for this single DNA base,” explained lead author Andrew A. Wilson, MD, assistant professor of medicine at Boston University School of Medicine and Director of the Alpha-1 Center at Bu and BMC.

They also found the diseased (AAT deficient) iPSC-liver cells were more sensitive to certain drugs (experience increased toxicity) than those from normal individuals. “This is important because it suggests that the livers of actual patients with this disease might be more sensitive in the same way,” said Wilson, who is also a physician in pulmonary, critical care and allergy medicine at BMC.

According to Wilson, while some patients are often advised by their physicians to avoid these types of drugs, these recommendations are not based on solid scientific evidence. “This approach might now be used to generate that sort of evidence to guide clinical decisions,” he added.

The researchers believe that studies using patient-derived stem cells will allow them to better understand how patients with AAT deficiency develop liver disease. “We hope that the insights we gain from these studies will result in the discovery of new potential treatments for affected patients in the near future,” said Wilson.

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Funding was provided by an ARRA stimulus grant (1RC2HL101535-01) awarded by the National Institutes of Health (NIH) to Boston University School of Medicine, Boston Medical Center and the Children’s Hospital of Philadelphia. Additional funding was provided by K08 HL103771, FAMRI 062572_YCSA, an Alpha-1 Foundation Research Grant and a Boston University Department of Medicine Career Investment Award. Additional grants from NIH 1R01HL095993 and 1R01HL108678 and an ARC award from the Evans Center for Interdisciplinary Research at Boston University supported this work.

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Researchers produce iPSC model to better understand genetic lung/liver disease