Category Archives: Gene Medicine

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Newswise NEW YORK, NY (February 19, 2015)Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases. The newly associated gene, called TBK1, plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec, and HudsonAlpha Institute for Biotechnology, was published today in the online edition of Science.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn, PhD, Chief Scientist for The ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.

This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts, said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which were only beginning to discover. The more of these mutations we identify, the better we can decipherand influencethe pathways that lead to disease. The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

These findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS, said Dr. Harris. The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing.

Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec. Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha, said Dr. Myers. I love this research model because it doesnt happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done."

Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patientsa large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS, said Dr. Goldstein. Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients.

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New ALS Gene and Signaling Pathways Identified

Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases. The newly associated gene, called TBK1, plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec, and HudsonAlpha Institute for Biotechnology, was published today in the online edition of Science.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn, PhD, Chief Scientist for The ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.

"This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts," said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. "ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we're only beginning to discover. The more of these mutations we identify, the better we can decipher--and influence--the pathways that lead to disease." The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

"These findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS," said Dr. Harris. "The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing."

"Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec. Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha, said Dr. Myers. "I love this research model because it doesn't happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done."

Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

"Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS," said Dr. Goldstein. "Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients."

The researchers are currently using patient-derived induced pluripotent embryonic stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates. Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival.

"This is a great example of the potential of precision medicine," said Tom Maniatis, PhD, the Isidore S. Edelman Professor, chair of biochemistry and molecular biophysics, and coauthor on the paper. Dr. Maniatis is also a member of the Zuckerman Mind Brain Behavior Institute and director of Columbia's university-wide precision medicine initiative. "It now seems clear that future ALS treatments will not be equally effective for all patients because of the disease's genetic diversity. Ultimately, as candidate therapies become available, we hope to be able to use the genetic data from each ALS patient to direct that person to the most appropriate clinical trials and, ultimately, use the data to prescribe treatment."

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New ALS gene, signaling pathways identified

Cancer Center News

Duke Medicine researchers have shown how gene mutations may cause common forms of cartilage tumors. In a study published in the Feb. 16, 2015, issue of the Proceedings of the National Academy of Sciences, Duke researchers and their colleagues revealed that mutations in the isocitrate dehydrogenase (IDH) gene contribute to the formation of benign tumors in cartilage that can be a precursor to malignancies.

Click here to read the full press release.

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Among the research institutions NCI funds across the United States, it currently designates 68 as Cancer Centers. Largely based in research universities, these facilities are home to many of the NCI-supported scientists who conduct a wide range of intense, laboratory research into cancers origins and development. The Cancer Centers Program also focuses on trans-disciplinary research, including population science and clinical research. The centers research results are often at the forefront of studies in the cancer field.

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Duke scientists find that gene mutation drives cartilage tumor formation

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Newswise While genomics is the study of all of the genes in a cell or organism, epigenomics is the study of all the genomic add-ons and changes that influence gene expression but arent encoded in the DNA sequence. A variety of new epigenomic information is now available in a collection of studies published Feb. 19 in Nature by the National Institutes of Health (NIH) Roadmap Epigenomics Program. This information provides a valuable baseline for future studies of the epigenomes role in human development and disease.

Two of these studies, led by researchers at University of California, San Diego School of Medicine and Ludwig Cancer Research, address the differences between chromosome pairs (one inherited from mom, the other from dad) and how chromosome folding influences gene expression.

Both of these studies provide important considerations for clinicians and researchers who are developing personalized medicines based on a patients genomic information, said Bing Ren, PhD, professor of cellular and molecular medicine at UC San Diego, Ludwig Cancer Research member and senior author of both studies.

The first paper by Rens group takes a look at differences in our chromosome pairs. Each of us inherits one set from our mother and the other from our father. Chromosome pairs are often thought to be identical, one just a backup for the other. But this study found widespread differences in how genes are regulated (turned on and off) between the two chromosomes in a pair. It turns out that we all have biases in our chromosomes. In other words, different traits have a stronger contribution from one parent than the other. The study also suggests that these biases are rooted in inherited sequence variations and that they are not randomly distributed. These findings help explain why, for example, all kids in a family may have their fathers hair but their mothers eyes.

The second paper by Rens group tackles how the genome is organized and how it changes as stem cells differentiate (specialize). DNA strands in every cell are tightly wound and folded into chromosomes. Yet chromosomal structures, and how they influence gene expression, are not well understood. In this study, Ren and team mapped chromosomal structures in stem cells and several different differentiated cell types derived from stem cells. First, they induced differentiation in the stem cells. Then they used molecular tools to examine how the structure of the cells chromosomes changed and how that change is associated with gene activity. The team found that chromosomes are partitioned into relatively stable structural units known as topologically associating domains (TADs), and that TAD boundaries remain constant in different cell types. Whats more, the researchers found that the changes in chromosomal architecture mostly take place within the TADs in a way that correlates with changes in the epigenome.

The epigenome chemical modifications to chromosomes and 3D chromosomal structure is not just a linear object, Ren said. The epigenome is a 3D object, folded in a hierarchical way, and that should affect how we think about many aspects of human development, health and disease.

Co-authors on the paper Integrative Analysis of Haplotype-Resolved Epigenomes Across Human Tissues include Danny Leung, Inkyung Jung, Nisha Rajagopal, Anthony Schmitt, Siddarth Selvaraj, Ah Young Lee, Chia-An Yen, Yunjiang Qiu, Samantha Kuan, Lee Edsall, Ludwig Cancer Research; Shin Lin, Yiing Lin, Stanford University and Washington University School of Medicine; Wei Xie, formerly at Ludwig Cancer Research and now at Tsinghua University; Feng Yue, formerly at Ludwig Cancer Research and now at Pennsylvania State University; Manoj Hariharan, Joseph R. Ecker, Howard Hughes Medical Institute and Salk Institute for Biological Studies; Pradipta Ray, University of Texas; Hongbo Yang, Neil C. Chi, UC San Diego; and Michael Q. Zhang, University of Texas, Dallas and Tsinghua University.

Co-authors on the paper Chromatin Architecture Reorganization during Stem Cell Differentiation include Jesse R. Dixon, Siddarth Selvaraj, Ludwig Cancer Research and UC San Diego; Inkyung Jung, Yin Shen, Ah Young Lee, Zhen Ye, Audrey Kim, Nisha Rajagopal, Yarui Diao, Ludwig Cancer Research; Jessica E. Antosiewicz-Bourget, Morgridge Institute for Research; Wei Xie, Tsinghua University; Jing Liang, Huimin Zhao, University of Illinois at Urbana-Champaign; Victor V. Lobanenkov, National Institute of Allergy and Infectious Diseases; Joseph R. Ecker, Howard Hughes Medical Institute and Salk Institute for Biological Studies; James Thomson, Morgridge Institute for Research, University of Wisconsin and University of California, Santa Barbara.

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New Insights into 3D Genome Organization and Genetic Variability

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Newswise An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, has identified the microtubule-associated protein tau (MAPT) gene as increasing the risk for developing Alzheimers disease (AD). The MAPT gene encodes the tau protein, which is involved with a number of neurodegenerative disorders, including Parkinsons disease (PD) and AD. These findings provide novel insight into Alzheimers neurodegeneration, possibly opening the door for improved clinical diagnosis and treatment.

The findings are published in the February 18 online issue of Molecular Psychiatry.

Alzheimers disease, which afflicts an estimated 5 million Americans, is typically characterized by progressive decline in cognitive skills, such as memory and language and behavioral changes. While some recent AD genome-wide association studies (GWAS), which search the entire human genome for small variations, have suggested that MAPT is associated with increased risk for AD, other studies have found no association. In comparison, a number of studies have found a strong association between MAPT and other neurodegenerative disorders, such as PD.

Though a tremendous amount of work has been conducted showing the involvement of the tau protein in Alzheimers disease, the role of the tau-associated MAPT gene is still unclear, said Rahul S. Desikan, MD, PhD, research fellow and radiology resident at the UC San Diego School of Medicine and the studys first author.

In the new Molecular Psychiatry paper, conducted with collaborators across the country and world, Desikan and colleagues narrowed their search. Rather than looking at all possible loci (specific gene locations), the authors only focused on loci associated with PD and assessed whether these loci were also associated with AD, thus increasing their statistical power for AD gene discovery.

By using this approach, they found that carriers of the deleterious MAPT allele (an alternative form of the gene) are at increased risk for developing AD and more likely to experience increased brain atrophy than non-carriers.

"This study demonstrates that tau deposits in the brains of Alzheimer's disease subjects are not just a consequence of the disease, but actually contribute to development and progression of the disease," said Gerard Schellenberg, PhD, professor of pathology and laboratory medicine at the University of Pennsylvania, principal investigator of the Alzheimers Disease Genetics Consortium and a study co-author.

An important aspect was the collaborative nature of this work. Thanks to our collaborators from the Consortium, the International Parkinsons Disease Genetics Consortium, the Genetic and Environmental Risk in Alzheimers Disease, the Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE Genetics and the DemGene cohort, we had tremendous access to a large number of Alzheimers and Parkinsons genetic datasets that we could use to identify and replicate our MAPT finding, said Ole A. Andreassen, MD, PhD, professor of biological psychiatry at the University of Oslo and a senior co-author.

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Tau-Associated MAPT Gene Increases Risk for Alzheimer's Disease

Claremont, CA (PRWEB) February 17, 2015

Precision medicine is a hot topic in health care and scientific research. President Obama spoke about it in his State of the Union Address on January 22, and the White House quickly followed up with details about the Presidents Precision Medicine Initiative a $215 million investment that is aimed at accelerating biomedical discoveries and dramatically improving treatment options for a number of diseases, including those classified as rare.

In recognition of the potential of precision medicine to revolutionize the treatment of rare disease, the theme of Keck Graduate Institutes 6th Annual Rare Disease Day on Friday, February 27, is Precision Medicine for Rare Disease. Rare Disease Day is an international advocacy day to bring widespread recognition of rare diseases as a global health challenge. Each year, KGIs Center for Rare Disease Therapies recognizes the day with a speaker series, panel discussion and the showing of a documentary film on rare disease.

This years keynote speaker is Dr. Stanley Crooke, a pioneer in the field of precision medicine known as antisense therapy. Antisense gene therapy is a gene silencing technique. The therapy is called a gene silencing technique because, instead of repairing the gene that causes disease, it aims to silence the genes effect. As the founder, chairman and CEO of Isis Pharmaceuticals, Dr. Crooke has led the scientific development of antisense technology and engineered the creation of one of the largest and more advanced development pipelines in the biotechnology industry. Isis has achieved commercialization of the first two antisense drugs to reach the market, Vitravene and KYNAMRO. KYNAMRO, approved in January 2013, is the first systemically administered antisense drug to be approved and the first to be approved for lifelong treatment of a chronic rare disease, Homozygous Familial Hypercholesterolemia, disorder of high LDL (bad) cholesterol that is passed down through families.

Precision medicine is the new trend for gene therapies and antisense therapies. It involves utilizing very precise methods for replacing or inhibiting mutant genes known to cause a disease, said Dr. Ian Phillips, director of KGIs Center for Rare Disease Therapies. Having Dr. Crooke as a speaker at this years Rare Disease Day is an incredible opportunity for our students and members of our community to hear firsthand how Isis has been at the forefront of this research and technology.

Chris Garabedian, CEO of Sarepta Pharmaceuticals, is also slated to speak at the event. He will talk about the development of antisense therapy to treat Duchenne muscular dystrophy, a rare disease affecting around 1 in 3,600 males, which results in muscle degeneration and eventual death. His talk will also cover medical countermeasures (MCMs) against the Ebola, Marburg and flu viruses, and against antibacterial resistance.

The Rare Disease Day event will also include the showing of the film Silent Angels: The Rett Syndrome Story. Narrated by actress Julia Roberts, the documentary film explores the lives of children (primarily girls) living with this rare disorder of the nervous system that leads to developmental reversals, especially in the areas of expressive language and hand use.

Rare Disease Day at KGI will also include a panel discussion with Dr. Tim Cot, the founder of Cot Orphan Consulting and a former director of the FDAs Office of Orphan Product Development; Dr. Jon Bui, associate professor at UC San Diego School of Medicines Department of Neurosciences; Dr. Sukirti Bagal, director, US & Global Medical Affairs and Clinical Development, Pfizer; and Barbara Lavery, board member, Global Genes. Global Genes is one of the leading rare disease patient advocacy organizations in the world.

KGIs 6th Annual Rare Disease Day will take place on Friday, February 27 at KGIs campus in Claremont, CA. For more information contact Kelly Esperias at Kelly_Esperias(at)kgi(dot)edu or 909-607-9651.

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2015 Rare Disease Day at KGI to Explore the Use of Precision Medicine for the Treatment of Rare Disease

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Newswise BOSTON President Barack Obama is requesting an increase of $215 million in the 2016 federal budget to launch the Precision Medicine Initiative. This boost in funding for research will give genetic causes of cancer a national focus specifically around precision or personalized treatments for cancer in the future.

Here are some facts about precision medicine:

1) What is precision or personalized medicine?

Physicians have long recognized that the same disease can behave differently from one patient to another, and that there is no one-size-fits-all treatment. Precision medicine makes diagnosis and treatment of cancer and other diseases more accurate, using the specific genetic makeup of patients (and, in cancer, of their tumors) to select the safest and most effective treatments for them.

In cancer, precision medicine involves testing DNA from patients tumors to identify the mutations or other changes that drive their cancer. Then a treatment for a particular patients cancer that best matches, or targets, the culprit mutations in the tumor DNA is used. While such therapies are not widespread yet, many cancer specialists believe precision treatments will be central to the future of cancer care.

2) Do all patients receive precision or targeted treatment?

Not all patients need targeted therapy to treat their type of cancer. The use of targeted therapies is meant for patients whose tumors have specific gene mutations that can be blocked by available drug compounds. Patients who have mutations in certain types of genes, who have mutations that are beyond the reach of available drugs, or whose tumor cells lack identifiable mutations generally would not be candidates for personalized medicine treatments.

According to the National Cancer Institute, a patient is a candidate for a targeted therapy only if he or she meets specific criteria, which vary depending on the disease. These criteria are set by the Federal Drug Administration (FDA) when it approves a specific targeted therapy.

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Dana-Farber Experts Share Five Things You Should Know About Precision Medicine

Duke Medicine researchers have shown how gene mutations may cause common forms of cartilage tumors.

In a study published in the Feb. 16, 2015, issue of the Proceedings of the National Academy of Sciences, Duke researchers and their colleagues revealed that mutations in the isocitrate dehydrogenase (IDH) gene contribute to the formation of benign tumors in cartilage that can be a precursor to malignancies.

These benign tumors, known as enchondromas, are associated with severe pain, fractures, and skeletal deformities. They also have the potential to evolve into a cancerous form known as chondrosarcomas. Over 40% of primary bone cancers are chondrosarcomas, according to the American Cancer Society.

"These findings are important for cancer treatments, as currently there are no drug therapies for enchondromas and there are no universally effective chemotherapies for chondrosarcomas," said senior author Benjamin Alman, M.D., chair of the Orthopaedic Surgery Department at Duke University Medical Center.

All bones begin as cartilage tissue, and some of this tissue becomes growth-plate cartilage, which is responsible for bone growth. Over time, the growth-plate cells become replaced with bone. When development is complete, only the joint cartilage at the tips of the bone typically remains.

"About five percent of people have some kind of cartilage tumor in their bones, and in most cases it's because the growth-plate cartilage cells weren't fully replaced by bone tissue," Alman said. "Our study sought to understand what happens to make those growth-plate cartilage cells remain, and this work will ultimately be used to determine what causes those benign tumors to become malignant."

The researchers identified a broad range of mutations in the IDH gene in cartilage tumors. They used mice and cartilage cells in a dish to study one mutant form of IDH that is identified only in cartilage cells. They found that mutations in the IDH gene alter the way cartilage cells function during bone formation, leaving some cells behind. This is apparently what leads to enchondromas.

Previous work on cartilage tumors has been done using models based on genetic mutations that occurred only rarely in enchondromas; however, IDH mutations are present in a high percentage of enchondromas.

The researchers hope these findings will aid in developing new treatments by using animal models that more closely represent the types of mutations apparent in the vast majority of patients with enchrondromas.

For instance, the study provides evidence that drugs designed to block the function of IDH might be useful in treating benign cartilage tumors to possibly prevent their transformation to malignancy.

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Gene mutation drives cartilage tumor formation

23 hours ago by Amanda Siegfried Dr. Leonidas Bleris (left), assistant professor of bioengineering at UT Dallas,and Richard Taplin Moore MS11 helped create a new delivery system that may change gene therapy.

Bioengineers at The University of Texas at Dallas have created a novel gene-delivery system that shuttles a gene into a cell, but only for a temporary stay, providing a potential new gene-therapy strategy for treating disease.

The approach offers distinct advantages over other types of gene therapies under investigation, said Richard Taplin Moore MS'11, a doctoral student in bioengineering in the Erik Jonsson School of Engineering and Computer Science. He is lead author of a study describing the new technique in the Jan. 30 issue of the journal Nucleic Acids Research.

"In other gene therapy approaches, the therapeutic genetic messages being delivered can persist for a long time in the patient, potentially lasting for the patient's entire lifetime," Moore said. "This irreversibility is one reason gene therapies are so difficult to get approved."

The UT Dallas study describes proof-of-concept experiments in which a gene carrying instructions for making a particular protein is ordered to self-destruct once the cell has "read" the instructions and made a certain quantity of the protein. In its experiments with isolated human kidney cells, the research team successfully deliveredand then destroyeda test gene that makes a red fluorescent protein.

More research is needed to determine whether and how well the system might work in living organisms. But Moore said the ultimate goal is to refine the method to deliver genes that produce therapeutic proteins or drugs. The nature of the gene delivery system offers more control over how much protein the gene produces in cells or tissues. Because it does not alter the cell permanently, the method also sidesteps potential health problems that can occur if a gene is delivered to the wrong place in a cell's genome.

"Our goal was to create a delivery system for therapeutic genes that would self-destruct, giving us more control over the delivered DNA by limiting the time it resides in cells," Moore said.

Located in the nucleus of each human cell, genes are made of DNA and contain instructions for making proteins. Machinery inside each cell "reads" the instructions and builds those proteins, which then carry out various functions needed to sustain life. Defective or mutated genes can result in malfunctioning or missing proteins, leading to disease.

Gene therapy aims to replace defective genes with healthy versions. Typically the good genes are packaged with a delivery mechanism called a vector, which transports the genetic material inside cells. With traditional approaches, once in the cell, the gene permanently integrates itself into the cell's DNA.

Although promising, this type of gene therapy also has risks. If a therapeutic gene is inserted in the wrong place in the cell's DNA, such as too close to a cancer-related gene, the process could activate additional disease-causing genes, resulting in lifelong health problems for the patient. While many gene therapy clinical trials are underway worldwide, the Food and Drug Administration has not approved for sale any human gene therapy product in the U.S.

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Synthetic biology yields new approach to gene therapy

Investigators with the National Institutes of Health have discovered the genomic switches of a blood cell key to regulating the human immune system. The findings, published in Nature today, open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis.

The senior author of the paper, John J. O'Shea, M.D., is the scientific director at NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases. The lead author, Golnaz Vahedi, Ph.D., is a postdoctoral fellow in Dr. O'Shea's lab in the Molecular Immunology and Inflammation Branch. The study was performed in collaboration with investigators led by NIH Director, Francis S. Collins, M.D., Ph.D., in the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute.

Autoimmune diseases occur when the immune system mistakenly attacks its own cells, causing inflammation. Different tissues are affected in different diseases, for example, the joints become swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis. The causes of these diseases are not well understood, but scientists believe that they have a genetic component because they often run in families.

"We now know more about the genetics of autoimmune diseases," said NIAMS Director Stephen I. Katz, M.D., Ph.D. "Knowledge of the genetic risk factors helps us assess a person's susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual."

Identifying autoimmune disease susceptibility genes can be a challenge because in most cases a complex mix of genetic and environmental factors is involved. Genetic studies have shown that people with autoimmune diseases possess unique genetic variants, but most of the alterations are found in regions of the DNA that do not carry genes. Scientists have suspected that the variants are in DNA elements called enhancers, which act like switches to control gene activities.

Dr. O'Shea's team wondered if the alterations might lie in a newly discovered type of enhancer called a super-enhancer (SE). Earlier work in the laboratory of Dr. Collins and others had shown that SEs are especially powerful switches, and that they control genes important for the function and identity of each individual cell type. In addition, a large number of disease-associated genetic alterations were found to fall within SEs, suggesting that disease occurs when these switches malfunction.

Dr. O'Shea's team began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease.

"Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach," said Dr. O'Shea. "From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets--their key proteins--and thereby where we are most likely to find genetic alterations that confer disease susceptibility."

Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokine and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response.

But the researchers' most striking observation was that a large fraction of previously identified alterations associated with rheumatoid arthritis and other autoimmune diseases localized to these T cell SEs. Additional experiments provided further evidence for a central role for SEs in rheumatoid arthritis. When the scientists exposed human T cells to a drug used to treat the disease, tofacitinib, the activities of genes controlled by SEs were profoundly affected compared to other genes without SEs. This result suggests that tofacitinib may bring about its therapeutic effects in part by acting on SEs to alter the activities of important T cell genes.

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Link between powerful gene regulatory elements and autoimmune diseases