Category Archives: Gene Medicine

PUBLIC RELEASE DATE:

13-Nov-2014

Contact: Service de presse AFM-Tlthon gmonfort@afm-telethon.fr AFM-Tlthon @AfmPresse

Duchenne muscular dystrophy is the most common neuromuscular disease of children (affecting 1 boy in 3500-5000 births). It is caused by a genetic defect in the DMD gene residing on the X chromosome, which results in the absence of the dystrophin protein essential to the proper functioning of muscles.

The treatment being developed by researchers at Atlantic Gene Therapies, Gnthon and the Institute of Myology, is based on the use of an AAV vector (Adeno Associated Virus) carrying a transgene for the skipping of a specific exon which allows functional dystrophin production in the muscle of the patient.

Safety, efficacy and stability of the treatment in dogs

In GRMD (Golden Retriever Muscular Dystrophy) dogs the treatment aimed at skipping exons 6, 7 and 8 of the dystrophin gene. The product was given by loco-regional administration in the forelegs of 18 dogs who were followed for 3.5 months after injection. It was well tolerated by all treated dogs; no immune response against the synthesized dystrophin was observed. Exon skipping resulted in high levels of expression of dystrophin in the treated muscles. The results of this treatment also indicate that, once injected into the muscle tissue a prolonged and stable effect is produced over the observation time of the study and, unlike antisense oligonucleotides already used clinically for exon skipping, it does not need to be re- administered regularly. The synthesis of "new" dystrophin is dependent on the dose of vector injected: the higher the dose, the greater the exon skipping is effective. Muscle strength also increases with dose. 80% of muscle fibers expressed the "new" dystrophin at the highest dose. This is a very encouraging result because a minimum of 40% of dystrophin in muscle fibers is believed to be necessary for the muscle force to be significantly improved.

A phase I/II clinical trial phase

These results open the way for a phase I / II clinical trial by loco-regional administration in the upper limb of non-ambulatory Duchenne muscular dystrophy patients which are amenable to treatment by the specific skipping of exon 53. The regulatory toxicology and biodistribution studies have just ended and the filing of an application with regulatory authorities is planned for 2015.

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Effectiveness of innovative gene therapy treatment demonstrated in canine model of DMD

PUBLIC RELEASE DATE:

11-Nov-2014

Contact: Scott LaFee slafee@ucsd.edu 619-543-6163 University of California - San Diego @UCSanDiego

With the help of mouse models, induced pluripotent stem cells (iPSCs) and the "tooth fairy," researchers at the University of California, San Diego School of Medicine have implicated a new gene in idiopathic or non-syndromic autism. The gene is associated with Rett syndrome, a syndromic form of autism, suggesting that different types of autism spectrum disorder (ASD) may share similar molecular pathways.

The findings are published in the Nov. 11, 2014 online issue of Molecular Psychiatry.

"I see this research as an example of what can be done for cases of non-syndromic autism, which lack a definitive group of identifying symptoms or characteristics," said principal investigator Alysson Muotri, PhD, associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine. "One can take advantage of genomics to map all mutant genes in the patient and then use their own iPSCs to measure the impact of these mutations in relevant cell types. Moreover, the study of brain cells derived from these iPSCs can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental/neurological disorders."

But to effectively exploit iPSCs as a diagnostic tool, Muotri said researchers "need to compare neurons derived from hundreds or thousands of other autistic individuals." Enter the "Tooth Fairy Project," in which parents are encouraged TO register for a "Fairy Tooth Kit," which involves sending researchers like Muotri a discarded baby tooth from their autistic child. Scientists extract dental pulp cells from the tooth and differentiate them into iPSC-derived neurons for study.

"There is an interesting story behind every single tooth that arrives in the lab," said Muotri.

The latest findings, in fact, are the result of Muotri's first tooth fairy donor. He and colleagues identified a de novo or new disruption in one of the two copies of the TRPC6 gene in iPSC-derived neurons of a non-syndromic autistic child. They confirmed with mouse models that mutations in TRPC6 resulted in altered neuronal development, morphology and function. They also noted that the damaging effects of reduced TRPC6 could be rectified with a treatment of hyperforin, a TRPC6-specific agonist that acts by stimulating the functional TRPC6 in neurons, suggesting a potential drug therapy for some ASD patients.

The researchers also found that MeCP2 levels affect TRPC6 expression. Mutations in the gene MeCP2, which encodes for a protein vital to the normal function of nerve cells, cause Rett syndrome, revealing common pathways among ASD.

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Multiple models reveal new genetic links in autism

New York, Nov 11 (IANS): Effecting changes to a single gene called FosB could help control both addiction and depression, says a new research.

Researchers have also developed a DNA regulatory technique that modifies the environment around this gene to control gene expression and behavioural consequences.

Using mouse models, the researchers introduced synthetic-transcription factors into a brain region called the nucleus accumbens near the gene FosB.

They found that changes to this single gene brought on by the transcription factors made the study mice more resilient to stress and less likely to become addicted to cocaine.

Transcription factors act by epigenetic mechanisms: chemically modifying either the DNA itself, or the histone proteins packaged around DNA.

"Because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease," said lead researcher Eric Nestler from Icahn School of Medicine at Mount Sinai.

To directly address this issue, the researchers developed an innovative method to control epigenetic regulation of FosB.

Heller introduced synthetic transcription factors called Zinc Finger Proteins (ZFPs), designed to target only a single gene out of 20,000, by incorporating them into a virus and injecting that virus into the reward-related brain region.

Upon binding to that one gene, the FosB-ZFPs modified histones in the vicinity of the FosB gene, in order to either activate (turn on) or repress (turn off) expression.

The study appeared online in the journal Nature Neuroscience.

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Tinkering with a gene could control addiction, depression

Playing a computer game or letting your mind go to its happy place might one day ease a migraine, administer drugs or prevent epileptic seizures, according to Swiss bioengineers who pulled off a strange mind-over-gene trick.

The researchers took advantage of a technique that engineers genes to switch into action in response to light input. But instead of just flipping on a light, they got brain waves to trip the switch.

Neither element by itself is all that novel these days. Synthetic biology and cybernetics have brought us the ability to insert DNA that responds to light into the regulatory programming of a gene. Electroencephalogram (EEG) receivers, which detect voltage changes from brain cells, have been linked to computers to control movement of prosthetic limbs or to play computer games. Hooking that up in tandem was the trick.

A brain is essentially nothing else but electricity the nerve cells firing electricity around as our brain thinks, said bioengineer Martin Fussenegger of the Swiss Federal Institute of Technology, lead investigator of the study published online Tuesday in Nature Communications. So we have electricity, which can then be linked to the light, and the light can then be linked to gene expression. If we daisy-chain these features, it allows us to control transgenes by the power of our thoughts.

The gene they used isnt as important as the concept itself at least not yet. They chose one that triggered production of a protein thats easy to see and measure, to figure out if their synthetic signalingpathway would work. Still, these were human brain waves controlling the inner workings of cells derived from human kidney stem cells -- albeit injected in a mouse.

The human volunteers needed little training beyond learning to play Minecraft, or taking relaxing breaths and thinking pleasant thoughts, Fussenegger said. Once they learned to associate such mental states with the light rigged to the mouse, they readily tinkered with the rodents genetic biochemistry.

Scientists aren't really after this kind of purposeful mind control of genetic activity - after all, it's a lot easier to just push a button to turn on implanted light-sensitive DNA.

What we intend to do is to capture pathological brain wave patterns, Fussenegger said.

That way, Fussenegger said, the brain waves could automatically trigger genes involved in pain mitigation, or perhaps genes engineered to administer medicine for those who are "locked in" by degenerative brain diseases.

A proof of concept is always a crucial step in science, but its also a baby step. Even if this strange bit of sci-fi wi-fi leads in the right direction, there are some foreseeable chasms to bridge en route to a world in which we think our way to health.

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Sci-fi meets wi-fi in a mind over gene experiment

PUBLIC RELEASE DATE:

11-Nov-2014

Contact: Kathryn Ryan kryan@liebertpub.com 914-740-2100 Mary Ann Liebert, Inc./Genetic Engineering News @LiebertOnline

New Rochelle, NY, November 11, 2014--Zelig Eshhar, PhD, The Weizmann Institute of Science and Sourasky Medical Center, and Carl H. June, MD, PhD, Perelman School of Medicine, University of Pennsylvania, are co-recipients of the Pioneer Award, recognized for lentiviral gene therapy clinical trials and for their leadership and contributions in engineering T-cells capable of targeting tumors with antibody-like specificity through the development of chimeric antigen receptors (CARs). Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers, is commemorating its 25th anniversary by bestowing this honor on the leading Pioneers in the field of cell and gene therapy selected by a blue ribbon panel* and publishing a Pioneer Perspective by the award recipients. The Perspectives by Dr. Eshhar and Dr. June are available free on the Human Gene Therapy website at http://www.liebertpub.com/hgt until December 11, 2014.

In his Pioneer Perspective entitled "From the Mouse Cage to Human Therapy: A Personal Perspective of the Emergence of T-bodies/Chimeric Antigen Receptor T Cells" Professor Eshhar chronicles his team's groundbreaking contributions to the development of the CAR T-cell immunotherapeutic approach to treating cancer. He describes the method's conceptual development including initial proof-of-concept, and the years of experimentation in mouse models of cancer. They first tested the CAR T-cells on tumors transplanted into mice then progressed to spontaneously developing cancers in immune-competent mice, which Dr. Eshhar describes as "a more suitable model that faithfully mimics cancer patients." He recounts successful antitumor effects in mice with CAR modified T-cells injected directly into tumors, with effects seen at the injection site and at sites of metastasis, and even the potential of the CAR T-cells to prevent tumor development.

Dr. Carl H. June has led one of the clinical groups that has taken the CAR therapeutic strategy from the laboratory to the patients' bedside, pioneering the use of CD19-specific CAR T-cells to treat patients with leukemia. In his Pioneer Perspective, "Toward Synthetic Biology with Engineered T Cells: A Long Journey Just Begun" Dr. June looks back on his long, multi-faceted career and describes how he combined his knowledge and research on immunology, cancer, and HIV to develop successful T-cell based immunotherapies. Among the lessons Dr. June has embraced throughout his career are to follow one's passions. He also says that "accidents can be good: embrace the unexpected results and follow up on these as they are often times more scientifically interesting than predictable responses from less imaginative experiments."

"These two extraordinary scientists made seminal contributions at key steps of the journey from bench to bedside for CAR T-cells," says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

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*The blue ribbon panel of leaders in cell and gene therapy, led by Chair Mary Collins, PhD, MRC Centre for Medical Molecular Virology, University College London selected the Pioneer Award recipients. The Award Selection Committee selected scientists that had devoted much of their careers to cell and gene therapy research and had made a seminal contribution to the field--defined as a basic science or clinical advance that greatly influenced progress in translational research.

About the Journal

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Zelig Eshhar and Carl H. June honored for research on T cell engineering for cancer immunotherapy

PUBLIC RELEASE DATE:

10-Nov-2014

Contact: Elizabeth Dowling newsmedia@mssm.edu 212-241-9200 The Mount Sinai Hospital / Mount Sinai School of Medicine @mountsinainyc

Regulation of a single, specific gene in a brain region related to drug addiction and depression is sufficient to reduce drug and stress responses, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published October 27 online in the journal Nature Neuroscience.

The Mount Sinai study focuses on epigenetics, the study of changes in the action of human genes caused, not by changes in DNA code we inherit from our parents, but instead by molecules that regulate when, where and to what degree our genetic material is activated.

Previous research has found links between epigenetic regulation and the diseases of drug addiction and depression, in both human patients and animal models. Such regulation derives, in part, from the function of transcription factors, specialized proteins that bind to specific DNA sequences and either encourage or shut down the expression of a given gene.

Using mouse models of human depression, stress and addiction, the current research team introduced synthetic- transcription factors into a brain region called the nucleus accumbens at a single gene called FosB, which has been linked by past studies to both addiction and depression. They found that changes to this single gene brought on by the transcription factors made the study mice more resilient to stress and less likely to become addicted to cocaine.

Found in every cell of the body, DNA contains genes and the instructions needed for an organism to develop and survive. To carry out these functions, DNA sequences are converted into messages that "tell" cells which proteins to make, dictating the specific function of a given cell. While all cells contain the DNA that codes for every gene, most genes are not activated at all times. The expression of a given gene depends on the action of transcription factors, proteins that regulate the structure of DNA within the cell, allowing some genes to be active and others to be repressed. Transcription factors act by epigenetic mechanisms: chemically modifying either the DNA itself, or the histone proteins packaged around DNA that change shape given the right signal to make stretches of DNA available to the protein building machinery.

"Earlier work in our laboratory found that several transcription factors and downstream epigenetic modifications are altered by exposure to drugs or to stress and that these changes, in turn, control gene expression," says Eric J. Nestler, MD, PhD, Nash Family Professor, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, who led the study. "But because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease."

To directly address this issue, Elizabeth A Heller, PhD, lead author on the paper, developed an innovative method to control epigenetic regulation of FosB. Dr. Heller introduced synthetic transcription factors called Zinc Finger Proteins (ZFPs), designed to target only a single gene out of 20,000, by incorporating them into a virus and injecting that virus into the reward-related brain region. Study results indicate that upon binding to that one gene, the FosB-ZFPs modified histones in the vicinity of the FosB gene, in order to either activate (turn on) or repress (turn off) expression.

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Changes in a single gene's action can control addiction and depression-related behaviors

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Newswise PHILADELPHIA Oncology researchers studying gene mutations in the childhood cancer neuroblastoma are refining their diagnostic tools to predict which patients are more likely to respond to drugs called ALK inhibitors that target such mutations. Removing some of the guesswork in diagnosis and treatment, the researchers say, may lead to more successful outcomes for children with this often-deadly cancer.

Some mutations are more important than others, said Yal P. Moss, MD, a pediatric oncologist at The Childrens Hospital of Philadelphia, and a co-leader of the new study published online today in the journal Cancer Cell. By integrating biochemistry into our clinical strategies, we can better match a patients specific ALK-mutation profile with an optimum treatment. Moss is also an assistant professor of Pediatrics in the Perelman School of Medicine, University of Pennsylvania.

Understanding the specific mutations that trigger signals in cell receptors to stimulate cell growth will help us identify biomarkers for specific subtypes of neuroblastoma, said study co-leader Mark A. Lemmon, PhD, professor and chair of Biochemistry and Biophysics at Penn. Lemmons research focuses on cell receptors in cancer.

Moss, Lemmon and their computational collaborator Ravi Radhakrishnan, PhD, an associate professor in the department of Bioengineering at Penn, say their new findings will provide crucial data for a pivotal phase 3 study for patients with ALK-driven high-risk neuroblastoma. This trial will be conducted through the Childrens Oncology Group (COG), a cooperative research organization encompassing over 250 pediatric cancer programs in North America. The COG is supported by the National Cancer Institute.

A solid tumor of the peripheral nervous system, often appearing in the chest or abdomen, neuroblastoma is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children, with cure rates lagging behind those for other pediatric cancers.

The current study concentrates on various mutations in ALK, the anaplastic lymphoma kinase gene. Moss led a team that first discovered in 2008 that an ALK mutation caused a hereditary form of neuroblastoma, and also identified ALK mutations implicated in some non-hereditary neuroblastoma.

Moss was subsequently able to expedite a phase 1 pediatric trial for neuroblastoma and other ALK-dependent childhood cancers using an existing drug called crizotinib, a molecule that inhibits the ALK protein when it is switched on by some ALK gene mutations. Crizotinib had a stronger anticancer effect against some ALK mutations than in others. In later collaboration with Lemmon, the investigators analyzed the biochemistry of how the two most common ALK mutations responded to crizotinib. The results strongly suggested that higher doses of the drug would be necessary for children with one mutation compared to the otherand that this knowledge could help oncologists define the correct dosage before an initial treatment.

Neuroblastoma is complex, with many subtypes of the disease. The current study explored the full spectrum of neuroblastoma, analyzing DNA from a COG tumor bank drawn from nearly 1,600 patients. The team discovered ALK mutations in 8 percent of the tumors, with a higher rate among tumors from older patients and those with high-risk neuroblastoma. The researchers also investigated which ALK mutations were more sensitive to crizotinib in cell cultures.

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Classification of Gene Mutations in a Children's Cancer May Point to Improved Treatments

11:00 09 November 2014

Paul Wright

Professor Lucy Walker was one of three professors involved in the discovery. Picture: Polly Hancock

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Researchers at the Royal Free hospital have made a significant discovery in ensuring people are able to fight infections.

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Professors at the UCL Institute of Immunity and Transplantation (IIT), based at the hospital in Pond Street, discovered a faulty copy of a single gene CTLA4 leads to the condition primary immunodeficiency (PID).

The research will mean doctors can diagnose this condition more easily, using a simple genetic test.

Patients with PID have an immune system which does not provide them with enough protection from infections.

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UCL and Royal Free researchers hail new gene discovery

By Amy Norton HealthDay Reporter

THURSDAY, Nov. 6, 2014 (HealthDay News) -- Even among people who live well into their 90s, those with a particular gene variant may survive the longest, a new study finds.

The variant is in a gene known as CETP, and researchers have known for more than a decade that people who carry it have a better shot at an exceptionally long life -- past 95 or even 100.

CETP is involved in cholesterol metabolism, and the longevity-linked variant raises blood levels of HDL cholesterol (the "good" kind) and promotes larger-than-normal HDL particles, researchers say.

The new findings show that even when you look at people who've already lived beyond age 95, those with the "favorable" CETP variant survive longer, said Dr. Sofiya Milman, an assistant professor at the Albert Einstein College of Medicine in New York City.

Milman was scheduled to present the findings Thursday at the annual meeting of the Gerontological Society of America in Washington, D.C. Data and conclusions presented at meetings are usually considered preliminary until published in a peer-reviewed medical journal.

The results build on work that began at Einstein in the late 1990s. Researchers there have been studying centenarians in and around New York City, all of Ashkenazi Jewish descent. They've found that people in this long-lived group often carry the CETP variant, and have very high HDL levels.

"They don't only live longer, they live healthier, too," Milman said.

Research has linked the CETP variant to lower-than-average rates of heart disease and stroke, as well as sharper mental function in old age, Milman noted. But she said the gene could have other, yet unknown roles in aging, too.

These latest results are based on more than 400 people from the Einstein project. They were typically 97 years old when they entered the study, and were followed anywhere from one to 11 years, Milman said.

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'Longevity Gene' One Key to Long Life, Research Suggests

A new study lends additional evidence to the likelihood that genes associated with high levels of the so-called good cholesterol appear to contribute to exceptionally long life expectancy and resistance to age-related disease.

Sofiya Milman , an assistant professor of medicine in geriatrics and endocrinology at Albert Einstein College of Medicine in New York, said her teams findings could open the way to finding drugs that target the gene and mimic its functions, thereby extending life.

These genotypes may explain the mechanisms responsible for the beneficial HDL, Milman said, saying further study of the genes could help unlock the secrets of what she called successful agers. One of the gene variants related to HDL cholesterol appeared to not only contribute to longer life, but to protect older people from age-related cognitive impairment, she said.

But Milman also cautioned that studies with larger sample sizes and more diverse populations should be conducted to validate the results.

Milmans research was one of several presentations on the science of aging offered Thursday at the annual meeting of the Gerontological Society of Americas annual scientific conference at the Walter E. Washington Convention Center. The conference, which opened Wednesday, draws about 4,000 researchers. More than 500 presentations of original research are scheduled before the conference ends Sunday.

The Einstein study focused on 300 women and 94 men who were at least 95 years old and living independently when the study began in 1998. All of the people were from the northeastern United States and all were Jews of European descent, a factor that was useful because of the relative homogeneity of their genetics.

Researchers then monitored the participants until the participants deaths, focused on their levels of HDL, which stands for high-density lipoprotein. HDL , helps the body regulate and maintain the level of cholesterol, an important component of health. Cholesterol, which is found in certain foods and created by the body itself, helps create hormones, synthesizes vitamin D, and builds and maintains cell membranes.

To transport and store cholesterol, the liver transforms it into lipoproteins. Low-density lipoproteins (LDL) carry cholesterol to the bodys cells; HDL moves through the bloodstream acting as a scavenger that returns cholesterol to the liver for excretion or recycling.

The Einstein team theorized that long life might be linked to high HDL levels and the presence of a gene variant of an enzyme known as CETP, or cholesterol ester transfer protein that transfers cholesterol between HDL particles and LDL particles circulating in the bloodstream.

The team also looked at a gene variant known as apolipoprotein 1 (APOA1), which codes for a protein that is a major component in HDL, to see whether that too might be a marker for exceptional longevity.

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Gene for HDL cholesterol linked to longer life, study finds