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Regrown nerves boost bionic ears

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UNSW Australia Biological Resources Imaging Laboratory and National Imaging Facility of Australia

A computer-tomography scan shows a deaf guinea pig's skull and cochlear implant.

Gene therapy delivered to the inner ear can help shrivelled auditory nerves to regrow and in turn, improve bionic ear technology, researchers report today in Science Translational Medicine1. The work, conducted in guinea pigs, suggests a possible avenue for developing a new generation of hearing prosthetics that more closely mimics the richness and acuity of natural hearing.

Sound travels from its source to ears, and eventually to the brain, through a chain of biological translations that convert air vibrations to nerve impulses. When hearing loss occurs, its usually because crucial links near the end of this chain between the ears cochlear cells and the auditory nerve are destroyed. Cochlear implants are designed to bridge this missing link in people with profound deafness by implanting an array of tiny electrodes that stimulate the auditory nerve.

Although cochlear implants often work well in quiet situations, people who have them still struggle to understand music or follow conversations amid background noise. After long-term hearing loss, the ends of the auditory nerve bundles are often frayed and withered, so the electrode array implanted in the cochlea must blast a broad, strong signal to try to make a connection, instead of stimulating a more precise array of neurons corresponding to particular frequencies. The result is an aural smearing that obliterates fine resolution of sound, akin to forcing a piano player to wear snow mittens or a portrait artist to use finger paints.

To try to repair auditory nerve endings and help cochlear implants to send a sharper signal to the brain, researchers turned to gene therapy. Their method took advantage of the electrical impulses delivered by the cochlear-implant hardware, rather than viruses often used to carry genetic material, to temporarily turn inner-ear cells porous. This allowed DNA to slip in, says lead author Jeremy Pinyon, an auditory scientist at the University of New South Wales in Sydney, Australia.

UNSW Australia Translational Neuroscience Facility, Jeremy Pinyon and Gary Housley

Gene therapy stimulated cochlear nerve growth (top) in deaf guinea pigs, compared to measurements taken before treatment (below).

Pinyon and his colleagues were able to deliver a gene encoding neurotrophin, a protein that stimulates nerve growth, to the inner-ear cells of deaf guinea pigs. After injecting the cells with a solution of DNA, they sent a handful of 20-volt pulses through the cochlear-implant electrode arrays. The cells started producing neurotrophin, and the auditory nerve began to regenerate and reach out for the cochlea once again. The researchers found that the treated animals could use their implants with a sharper, more refined signal, although they did not compare the deaf guinea pigs to those with normal hearing. The work was partially funded by Cochlear, a cochlear-implant maker based in Sydney.

Regenerating nerves and cells in the inner ear to boost cochlear implant performance has long been a goal of auditory scientists. This clever approach is the most promising to date, says Gerald Loeb, a neural prosthetics researcher at the University of Southern California in Los Angeles, who helped to develop the original cochlear implant. Although clinical applications are still far in the future, the ability to deliver genes to specific areas in the cochlea will probably reduce regulatory obstacles, he says. But it is unclear why cochlear implants help some patients much more than others, so whether this gene therapy translates into actual clinical benefit is still unclear.

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Regrown nerves boost bionic ears

Researchers add gene therapy to cochlear implants in deaf animals

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Australian researchers are trying a novel way to boost the power of cochlear implants: They used the technology to beam gene therapy into the ears of deaf animals and found the combination improved hearing.

WASHINGTON Australian researchers are trying a novel way to boost the power of cochlear implants: They used the technology to beam gene therapy into the ears of deaf animals and found the combination improved hearing.

The approach reported Wednesday isnt ready for human testing, but its part of growing research into ways to let users of cochlear implants experience richer, more normal sound.

Normally, microscopic hair cells in a part of the inner ear called the cochlea detect vibrations and convert them to electrical impulses that the brain recognizes as sound. Hearing loss typically occurs as those hair cells are lost, whether from aging, exposure to loud noises or other factors.

READ MORE: 6 Canadian game-changing ideas for global health care

Cochlear implants substitute for the missing hair cells, sending electrical impulses to directly activate auditory nerves in the brain. Theyve been implanted in more than 300,000 people. While highly successful, they dont restore hearing to normal, missing out on musical tone, for instance.

The idea behind the project: Perhaps a closer connection between the implant and the auditory nerves would improve hearing. Those nerves bush-like endings can regrow if exposed to nerve-nourishing proteins called neurotrophins. Usually, the hair cells would provide those.

Researchers at Australias University of New South Wales figured out a new way to deliver one of those growth factors.

They injected a growth factor-producing gene into the ears of deafened guinea pigs, animals commonly used as a model for human hearing. Then they adapted an electrode from a cochlear implant to beam in a few stronger-than-normal electrical pulses.

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Researchers add gene therapy to cochlear implants in deaf animals

Broad Institute Gets Patent on Revolutionary Gene-Editing Method

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The Harvard-MIT genomic science institute stays mute on how it will assert control over the tools expected to speed cures and change gene therapy.

One of the most important genetic technologies developed in recent years is now patented, and researchers are wondering what they will and wont be allowed to do with the powerful method for editing the genome.

On Tuesday, the Broad Institute of MIT and Harvard announced that it had been granted a patent covering the components and methodology for CRISPRa new way of making precise, targeted changes to the genome of a cell or an organism. CRISPR could revolutionize biomedical research by giving scientists a more efficient way of re-creating disease-related mutations in lab animals and cultured cells; it may also yield an unprecedented way of treating disease (see Genome Surgery).

The patent, issued just six months after its application was filed, covers a modified version of the CRISPR-Cas9 system found naturally in bacteria, which microbes use to defend themselves against viruses. The patent also covers methods for designing and using CRISPRs molecular components.

The inventor listed on the patent is Feng Zhang, an MIT researcher and core faculty member of the Broad. Zhang was an MIT Technology Review Innovator Under 35 in 2013.

The patent describes how the tools could be used to treat diseases, and lists many specific conditions from epilepsy, to Huntingtons, to autism, and macular degeneration. One of the most exciting possibilities for CRISPR is its potential to treat genetic disorders by directly correcting mutations on a patients chromosomes. That would enable doctors to treat diseases that cannot be addressed by more traditional methods, a goal already set by a startup cofounded by Zhang called Editas Medicine (see New Genome-Editing Method Could Make Gene Therapy More Precise and Effective).

Another founder of Editas, Jennifer Doudna, and her institute, the University of California, have a pending patent application for CRISPR technology. How that west coast application will be affected is not yet clear. Its also unclear what impact the Broads claims on the technology will have on its commercial use and on basic research.

Chelsea Loughran, an intellectual property litigation lawyer who has been following CRISPR over the last year, says that lots of people are already using CRISPR and its not clear if it will now become harder for them to do that. All of that is in the hands of MIT and the Broad, she says.

While MIT, Harvard, and the Broad all jointly own the CRISPR patents announced yesterday, the Broads technology licensing office is managing decisions about who will get licenses to use the technology, says Lita Nelsen, director of the MIT Technology Licensing Office. (Licenses areformal permissions to use a patented technology, often in exchange for money.)

A spokesperson for the Broad says that specific details around licensing arent available at this time, but the Broad does intend to make this technology broadly available to scientists.

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Broad Institute Gets Patent on Revolutionary Gene-Editing Method

Scientist for gene therapy regulation

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While highlighting the need to define ethical principles to guide research studies with human subjects, K. Kasturirangan, member (science), Planning Commission, Government of India, sounded a word of caution on gene therapy, and called for regulation and legislation to prevent misuse.

Over the years, we are witnessing that the trend of medical science is to shift away from treating the evident symptoms or organ failures in diagnosis and treatment at the molecular level. This revolution, this ability to intervene at the genetic level, has the potential to permanently change the human gene pool, and has also triggered moral debates, he said, delivering the address at the 19 convocation of Sri Ramachandra University on Thursday.

He called for careful regulation, legislation and social consensus to guide actions against any misuse of this capability.

With Indias plans for manned space missions, he said, a new dimension needed to be created with respect to medical education to understand the physiological and psychological effects on humans in space environment, and to adopt necessary counter measures.

Mr. Kasturirangan distributed gold medals to meritorious students. MBBS graduate D. Rajmadhangi bagged four gold medals.

Chancellor of the university V.R. Venkataachalam and vice-chancellor J.S.N. Murthy were present.

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Scientist for gene therapy regulation

Gene, immune therapy help cancer war

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Stanford University researcher Irving Weissman explains how the drug Rituxan, generically called rituximab, improves the cancer-killing effect of a new antibody that renders cancer cells vulnerable to immune attack. He spoke Monday, April 7, at the American Association for Cancer Research meeting in San Diego.

The war on cancer is getting some potent reinforcements, including a potentially broad-spectrum new weapon and genetically engineered immune cells with improved cancer-fighting abilities, speakers said at a major cancer research conference held this week in San Diego.

The American Association for Cancer Research, attended by an estimated 18,000 participants, is being held at the San Diego Convention Center through Wednesday. While it is covering the gamut of research, cancer immunotherapy is a major focus. The field began more than 100 years ago, and has lately scored impressive advances by using gene therapy to its tool kit.

The weapon is an antibody that makes a wide range of cancer cells vulnerable to immune attack. It's close to entering human clinical trials, said Irving L. Weissman, a Stanford University professor leading that project. The antibody neutralizes a chemical signal many cancers exude to decoy the immune system, Weissman said in a Monday morning plenary session.

The antibody is being tested first in acute myeloid leukemia patients, backed by $20 million from the California Institute for Regenerative Medicine, Weissman said. The institute is interested because the target cells are cancer stem cells, the cells that proliferate to spread cancer.

Moreover, research indicates the method can be used against many solid tumors that emit the signal, a protein called CD47. These include breast, ovarian, bladder, pancreatic and colon cancer.

"Every human cancer that we've seen has CD47," Weissman said.

Animal studies show that anti-CD47 antibodies inhibit growth of transplanted patient tumors, he said. And when used against non-Hodgkin's lymphoma along with an existing antibody drug called Rituxan, the result is a potent cancer-killing effect. Immune cells called macrophages actually engulf and destroy the cancer cells.

The CD47 molecule is normally present on young cells, serving as a "don't eat me" signal to immune system cells that might otherwise attack them, Weissman said. Cancer cells have chanced on mutations that cause the protein to be made in exceptionally high amounts. So even when they might be abnormal enough to merit immune system attack, they escape surveillance.

Another approach already in the clinic is to genetically engineer immune cells called T cells to be better at fighting cancer. Carl June, a University of Pennsylvania researcher behind one of the studies, said results continue to be encouraging. This approach targets another protein abnormally made by cancer cells, CD19. Novartis is testing the therapy.

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Gene, immune therapy help cancer war

AAVLife Formed To Advance Gene Therapy For Friedreich's Ataxia

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By Estel Grace Masangkay

The Friedreich's Ataxia Research Alliance (FARA) announced the birth of a new company, AAVLife, for the rapid development of a promising gene-therapy program for the treatment of cardiomyopathy in Friedreichs ataxia (FA).

The founding of AAVLife is based on the groundbreaking research of FARA-funded scientist Dr. Hlne Puccio. Dr. Puccio and her colleagues reported significant results showing that gene-replacement therapy using an adeno-associated virus to deliver the frataxin gene missing in patients with FA prevented and corrected cardiac damage in an FA mouse model.

Jennifer Farmer, FARA Executive Director, said, When we first learned of Dr. Puccio's results and saw that she was demonstrating prevention and correction of the cardiomyopathy at both the functional and cellular levels we were beyond excited because this gave us evidence that we could attack the cardiomyopathy, which takes an individual's life at an early age. While we also want to have therapies that treat the neurological aspects of the disease, the significance of the cardiac disease is often under appreciated.

FA is a rare, degenerative, life-shortening, neuro-muscular disorder that affects balance and coordination in both children and adults. As the disease progresses it affects other organs including the pancreas, skeletal muscle, and the heart. The primary cause of early death in patients with FA (usually in the early 20s to 30s) is cardiomyopathy.

Ron Bartek, FARA President and co-founder, said, The launch of AAVLife and Dr. Puccio's tremendous achievement reported in Nature Medicine represent an exciting new opportunity for the FA community that comes from our international partnership. Dr. Puccio's research was funded by public agencies in France, Europe, and the United States, and AAVLife is bringing together international expertise and resources. This partnership is essential when we are battling a rare disease like FA FARA will continue working closely with AAVLife, FA scientists, and the patient community as, together, we drive this promising therapeutic approach forward into the clinic.

FARA is a non-profit, charitable organization committed to accelerating research FA treatments. The organization has been in close collaboration with the founders of AAVLife since 2013.

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AAVLife Formed To Advance Gene Therapy For Friedreich's Ataxia

Gene therapy improves limb function following spinal cord injury

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1-Apr-2014

Contact: Anne Nicholas media@sfn.org 202-962-4086 Society for Neuroscience

Delivering a single injection of a scar-busting gene therapy to the spinal cord of rats following injury promotes the survival of nerve cells and improves hind limb function within weeks, according to a study published April 2 in The Journal of Neuroscience. The findings suggest that, with more confirming research in animals and humans, gene therapy may hold the potential to one day treat people with spinal cord injuries.

The spinal cord is the main channel through which information passes between the brain and the rest of the body. Most spinal cord injuries are caused by damage to the axons, the long extensions that brain cells use to send these messages. Once these injuries take place, scar tissue forms and prevents the damaged nerves from re-growing.

Previous animal studies show that one way to promote the growth of injured spinal nerve cells is to administer the enzyme chondroitinase ABC (ChABC), which digests scar-forming proteins, to the site of injury. However, because ChABC breaks down quickly, maintaining these beneficial effects for a long period of time requires invasive and repeated administration of the enzyme to the spinal cord. To get around this hurdle, in recent years, scientists began exploring gene therapy as a method to efficiently coax spinal cord cells to produce the enzyme.

In the current study, a group of researchers led by Elizabeth Bradbury, PhD, of King's College London used a single injection to deliver the ChABC gene therapy into the spinal cord of injured adult rats. The treatment not only led the spinal cord cells to produce and secrete ChABC in large quantities over areas spanning the injury epicenter, it helped to maintain the overall health of the damaged spinal cord and restored hind limb function in the animals within 12 weeks.

"These findings provide convincing evidence that gene therapy with chondroitinase not only encourages the sprouting of injured axons, but also imparts significant protection to nerve cells," said Mark Tuszynski, MD, PhD, who studies how nerve cells recover following injury at the University of California, San Diego, and was not involved in this study. "These are new and important findings that could lead to the development of testable therapies for spinal cord injury in people," he added.

Bradbury's team delivered the ChABC gene into the matrix of the spinal cord (the space between spinal cord cells). Twelve weeks later, the animals that received the therapy had more surviving spinal nerve cells and fibers present through and around the scar compared with animals that did not receive the treatment. ChABC gene therapy also led to the recovery of hind limb function in the animals, allowing them to navigate the rungs of a horizontal ladder.

Additional analysis revealed that ChABC gene therapy changed the way that inflammatory cells in the region respond following injury. Normally, after injury, immune cells invade the spinal cord and cause destructive and irreparable tissue damage. However, ChABC gene therapy decreased the presence of these cells and increased the presence of other immune cells called M2 macrophages that help to reduce inflammation and enhance tissue repair.

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Gene therapy improves limb function following spinal cord injury

$2.5 million Defense Department grant funds gene therapy study for Lou Gehrig's disease

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1-Apr-2014

Contact: Sandy Van sandy@prpacific.com 808-526-1708 Cedars-Sinai Medical Center

LOS ANGELES (April 1, 2014) The Cedars-Sinai Regenerative Medicine Institute has received a $2.5 million grant from the Department of Defense to conduct animal studies that, if successful, could provide the basis for a clinical trial of a gene therapy product for patients with Lou Gehrig's disease, also called amyotrophic lateral sclerosis, or ALS.

The incurable disorder attacks muscle-controlling nerve cells motor neurons in the brain, brainstem and spinal cord. As the neurons die, the ability to initiate and control muscle movement is lost. Patients experience muscle weakness that steadily leads to paralysis; the disease usually is fatal within five years of diagnosis. Several genes have been identified in familial forms of ALS, but most cases are caused by a complex combination of unknown genetic and environmental factors, experts believe.

Because ALS affects a higher-than-expected percentage of military veterans, especially those returning from overseas duties, the Defense Department invests $7.5 million annually to search for causes and treatments. The Cedars-Sinai study, led by Clive Svendsen, PhD, professor and director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center, and Genevive Gowing, PhD, a senior scientist in his laboratory, also will involve a research team at the University of Wisconsin, Madison and a Netherlands-based biotechnology company, uniQure, that has extensive experience in human gene therapy research and development.

The research will be conducted in laboratory rats bred to model a genetic form of ALS. If successful, it could have implications for patients with other types of the disease and could translate into a gene therapy clinical trial for this devastating disease.

It centers on a protein, GDNF, that promotes the survival of neurons. In theory, transporting GDNF into the spinal cord could protect neurons and slow disease progression, but attempts so far have failed, largely because the protein does not readily penetrate into the spinal cord. Regenerative Medicine Institute scientists previously showed that spinal transplantation of stem cells that were engineered to produce GDNF increased motor neuron survival, but this had no functional benefit because it did not prevent nerve cell deterioration at a critical site, the "neuromuscular junction" the point where nerve fibers connect with muscle fibers to stimulate muscle action.

Masatoshi Suzuki, PhD, DVM, assistant professor of comparative biosciences at the University of Wisconsin, Madison, who previously worked in the Svendsen Laboratory and remains a close collaborator, recently found that stem cells derived from human bone marrow and engineered to produce GDNF protected nerve cells, improved motor function and increased lifespan when transplanted into muscle groups of a rat model of ALS.

"It seems clear that GDNF has potent neuroprotective effects on motor neuron function when the protein is delivered at the level of the muscle, regardless of the delivery method. We think GDNF will be able to help maintain these connections in patients and thereby keep the motor neuron network functional," Suzuki said.

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$2.5 million Defense Department grant funds gene therapy study for Lou Gehrig's disease

Gene Therapy Expert to Join The Children's Hospital of Philadelphia

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Newswise Philadelphia, April 1, 2014 Beverly L. Davidson, Ph.D., a nationally prominent expert in gene therapy, is joining The Childrens Hospital of Philadelphia (CHOP) today.

Dr. Davidson, who investigates gene therapy for neurodegenerative diseases, arrives from the Center for Gene Therapy at the University of Iowa. She served as associate director at that Center, as well as director of the Gene Therapy Vector Core, and held the Roy J. Carver Biomedical Research Chair in Internal Medicine at the University. She also was Vice Chair of the Department of Internal Medicine and was a Professor in Internal Medicine, Neurology, and Physiology & Biophysics.

She has been named to the Arthur V. Meigs Chair in Pediatrics at CHOP and will join the hospitals Department of Pathology and Laboratory Medicine. We heartily welcome Dr. Davidson to our hospital, and are excited that she has chosen to continue her groundbreaking gene therapy research here, said Robert W. Doms, M.D., Ph.D., pathologist-in-chief at The Childrens Hospital of Philadelphia. She will greatly enhance our abilities to translate important biological discoveries into pioneering treatments for deadly diseases.

In addition, Dr. Davidson will serve as the new director of the Center for Cellular and Molecular Therapeutics at CHOP. The mission of the Center is to use pioneering research in cell and gene therapy to develop novel therapeutic approaches for hitherto untreatable illnesses. The inaugural director of the Center, Katherine A. High, M.D., said, I am thrilled that we have been able to recruit one of the premier translational investigators in the U.S. to serve as the next director of the Center. I have led the Center for the last ten years, and I eagerly look forward to the innovations of the next decade, under Dr. Davidsons leadership.

Dr. Davidson has concentrated on inherited genetic diseases that attack the central nervous system, with a particular focus on childhood-onset neurodegenerative diseases such as Batten disease and similar diseases called lysosomal storage disorders. In these disorders, the lack of an enzyme impairs lysosomes, proteins that perform crucial roles in removing unwanted by-products of cellular metabolism. Toxic waste products then accumulate in the brain and cause progressively severe brain damage.

Dr. Davidson has studied the cell biology and biochemistry of these disorders, and has developed novel methods to deliver therapeutic genes to the central nervous system. Her laboratory team has succeeded in reversing neurological deficits in small and large animal models of disease, and is working to advance this approach to treating human diseases.

In addition to lysosomal storage disorders, she has studied other inherited neurological diseases such as Huntingtons disease and spino-cerebellar ataxia. In these studies, she has delivered forms of RNA to the brains of animals to silence the activity of disease-causing genes. She also is collaborating with scientists at Massachusetts General Hospital in animal studies of Alzheimers disease.

Although much of Dr. Davidsons research has centered on delivering beneficial genes to the central nervous system, the viral vectors that she has developed are applicable to other organs and tissuesfor example, in gene therapy directed to the lungs or the liver.

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Gene Therapy Expert to Join The Children's Hospital of Philadelphia


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