Daily Archives: April 24, 2014

PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Glenna Picton picton@bcm.edu 713-798-4710 Baylor College of Medicine

HOUSTON (April 24, 2014) A team of international scientists led by Baylor College of Medicine has discovered a novel gene (CLP1) associated with a neurological disorder affecting both the peripheral and central nervous systems. Together with scientists in Vienna they show that disturbance of a very basic biological process, tRNA biogenesis, can result in cell death of neural progenitor cells. This leads to abnormal brain development and a small head circumference as well as dysfunction of peripheral nerves.

The study published today in the current issue of the journal Cell.

"This is the first human disorder associated with the gene CLP1," said Dr. Ender Karaca, post-doctoral associate in the department of molecular and human genetics at Baylor.

The gene find is significant because CLP1 has a role in RNA processing and has important implications for genomic approaches to Mendelian disease and for our understanding of human biology and brain development, Karaca said.

Karaca's work with families of this rare disorder began many years ago during his residency training as a clinical geneticist in Turkey.

A chance meeting with Dr. James R. Lupski, the Cullen Professor and Vice Chair of Molecular and Human Genetics and professor of pediatrics at Baylor, at a medical meeting in Istanbul, Turkey would lead to Karaca's recruitment as a trainee in Lupski's lab where the research took off and eventually the team unveiled new clues about the genetic malfunction that may be causing the disorder in these families.

Lupski leads the Center for Mendelian Genomics at Baylor, a joint program with the Johns Hopkins University School of Medicine that is funded by the National Human Genome Research Institute. The Center is focused on advancing research of the cause of rare, single-gene diseases usually called Mendelian disorders.

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International collaboration unravels novel mechanism for neurological disorder

A new study out of Australia has promising potential for patients across the globe who use cochlear implants. Photo by Flickr user ryanjpoole

A new study outlines how gene therapy could reverse hearing loss and deafness. This may be music to the ears of the roughly 300,000 patients across the globe that depend on cochlear implants to hear.

Australian researchers published their findings Wednesday in the journal Science Translational Medicine. By stimulating gene cells, which were injected into the ear canal with electrical impulses, chemically deafened guinea pigs were able to regrow auditory nerve cells.

The scientists used guinea pigs as test subjects because of the similarities between the ear canals of humans and guinea pigs. While the researchers noted just how effective cochlear implants have been to date in helping those with profound hearing loss, they also noted their limitations. They hope to overcome those limitations through their research.

People with cochlear implants do well with understanding speech, but their perception of pitch can be poor, so they often miss out on the joy of music, said the studys senior author Gary Housley, a professor of neuroscience at the University of South Wales.

The cochlea is a tiny seashell-shaped organ located in the inner ear. It is filled with groups of microscopic hair cells that move in response to vibrations, and then convert those vibrations into electrical impulses that are carried to the brain and interpreted as sound. In some peoples ears, either because of genetics, old age, poisoning or loud noises, those tiny hair cells are damaged or lost and scientists havent found a way found to regrow them yet. In certain patients who experience profound hearing loss, a cochlear implant with electrodes can help stimulate whatever nerve cells are left.

With this study, Housley and his colleagues encouraged the production of neurotrophins, small proteins that stimulate the growth and maintenance of the hair-like nerve cells. They injected small rings of DNA, called plasmids, into the inner ear of the guinea pigs. Then, they exposed the animals cochleas to electrical currents that mimicked the electrical impulses provided to human cochleas through cochlear implants. By doing so, the membranes of the guinea pigs cells became more permeable to the injected DNA. The result triggered the production of neurotrophins and thus, the regrowth of nerve cells. The researchers are hoping that, in human subjects, they can achieve similar results.

While the researchers were ecstatic over the results, some of their enthusiasm was tempered because in some guinea pigs, results began to taper after three to six weeks. They hope to continue studying the application of gene therapy going forward.

The development of electrode array gene delivery may not only improve the hearing of cochlear implant recipients but also find broader therapeutic applications, Housely said. [Gene therapy] could be used to treat a range of neurological disorders, from Parkinsons disease to psychiatric disorders.

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Gene therapy shows promise to help people regrow auditory nerve cells

PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Bonnie Prescott bprescot@bidmc.harvard.edu 617-667-7306 Beth Israel Deaconess Medical Center

BOSTON Ever since it was first identified more than 15 years ago, the PTEN gene has been known to play an integral role in preventing the onset and progression of numerous cancers. Consequently, when PTEN is either lost or mutated, malignant cells can grow unchecked and cancer can develop.

Now a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) helps explain more precisely how PTEN exerts its anti-cancer effects and how its loss or alteration can set cells on a cancerous course. The new study, which reveals that PTEN loss and PTEN mutations are not synonymous, not only provides key insights into basic tumor biology but also offers a potential new direction in the pursuit of new cancer therapies.

The findings are reported online in the April 24 issue of the journal Cell.

"By characterizing the ways that two specific PTEN mutations regulate the tumor suppressor function of the normal PTEN protein, our findings suggest that different PTEN mutations contribute to tumorigenesis by regulating different aspects of PTEN biology," explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. "It has been suggested that cancer patients harboring mutations in PTEN had poorer outcomes than cancer patients with PTEN loss. Now, using mouse modeling, we are able to demonstrate that this is indeed the case. Because PTEN mutations are extremely frequent in various types of tumors, this discovery could help pave the way for a new level of personalized cancer treatment."

The PTEN gene encodes a protein, which acts as a phosphatase, an enzyme that removes phosphates from other substrates. Several of the proteins that PTEN acts upon, both lipids and proteins, are known to promote cancer when bound to a phosphate. Consequently, when PTEN removes their phosphates, it is acting as a tumor suppressor to prevent cancer. When PTEN is mutated, it loses this suppressive ability, and the cancer-promoting proteins are left intact and uninhibited. This new study unexpectedly shows that the PTEN mutant protein is not only functionally impaired (losing its enzymatic function) it additionally acquires the ability to affect the function of the normal PTEN proteins, thereby gaining a "pro-tumorigenic" function.

"We sought to compare PTEN loss with PTEN mutations," explains first author Antonella Papa, PhD, an investigator in the Pandolfi laboratory. "We wanted to know, would outcomes differ in cases when PTEN was not expressed compared with cases when PTEN was expressed, but encoded a mutation within its sequence? It turned out the answer was yes."

The scientific team created several genetically modified strains of mice to mimic the PTEN mutations found in human cancer patients. "All mice [and humans] have two copies of the PTEN gene," Papa explains. "The genetically modified mice in our study had one copy of the PTEN gene that contained a cancer-associated mutation [either PTENC124S or PTENG129E] and one normal copy of PTEN. Other mice in the study had only one copy of the normal PTEN gene, and the second copy was removed."

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Surprising new insights into the PTEN tumor suppressor gene

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Newswise BOSTON Ever since it was first identified more than 15 years ago, the PTEN gene has been known to play an integral role in preventing the onset and progression of numerous cancers. Consequently, when PTEN is either lost or mutated, malignant cells can grow unchecked and cancer can develop.

Now a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) helps explain more precisely how PTEN exerts its anti-cancer effects and how its loss or alteration can set cells on a cancerous course. The new study, which reveals that PTEN loss and PTEN mutations are not synonymous, not only provides key insights into basic tumor biology but also offers a potential new direction in the pursuit of new cancer therapies.

The findings are reported online in the April 24 issue of the journal Cell.

By characterizing the ways that two specific PTEN mutations regulate the tumor suppressor function of the normal PTEN protein, our findings suggest that different PTEN mutations contribute to tumorigenesis by regulating different aspects of PTEN biology, explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. It has been suggested that cancer patients harboring mutations in PTEN had poorer outcomes than cancer patients with PTEN loss. Now, using mouse modeling, we are able to demonstrate that this is indeed the case. Because PTEN mutations are extremely frequent in various types of tumors, this discovery could help pave the way for a new level of personalized cancer treatment.

The PTEN gene encodes a protein, which acts as a phosphatase, an enzyme that removes phosphates from other substrates. Several of the proteins that PTEN acts upon, both lipids and proteins, are known to promote cancer when bound to a phosphate. Consequently, when PTEN removes their phosphates, it is acting as a tumor suppressor to prevent cancer. When PTEN is mutated, it loses this suppressive ability, and the cancer-promoting proteins are left intact and uninhibited. This new study unexpectedly shows that the PTEN mutant protein is not only functionally impaired (losing its enzymatic function) it additionally acquires the ability to affect the function of the normal PTEN proteins, thereby gaining a pro-tumorigenic function.

We sought to compare PTEN loss with PTEN mutations, explains first author Antonella Papa, PhD, an investigator in the Pandolfi laboratory. We wanted to know, would outcomes differ in cases when PTEN was not expressed compared with cases when PTEN was expressed, but encoded a mutation within its sequence? It turned out the answer was yes.

The scientific team created several genetically modified strains of mice to mimic the PTEN mutations found in human cancer patients. All mice [and humans] have two copies of the PTEN gene, Papa explains. The genetically modified mice in our study had one copy of the PTEN gene that contained a cancer-associated mutation [either PTENC124S or PTENG129E] and one normal copy of PTEN. Other mice in the study had only one copy of the normal PTEN gene, and the second copy was removed.

The researchers found that the mice with a single mutated copy of PTEN were more tumor-prone than the mice with a deleted copy of PTEN. They also discovered that the mutated protein that was produced by PTENC124S or PTENG129E was binding to and inhibiting the PTEN protein made from the normal copy of the PTEN gene.

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Surprising New Insights Into PTEN Tumor Suppressor Gene

The performance of cochlear implants has been improved with the use of gene therapy, suggesting a new avenue for developing better hearing aids

A computer-tomography scan shows a deaf guinea pig's skull and cochlear implant. Credit:UNSW Australia Biological Resources Imaging Laboratory and National Imaging Facility of Australia

Gene therapy delivered to the inner ear can help shrivelled auditory nerves to regrow and in turn, improve bionic ear technology, researchers report today inScience Translational Medicine. 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.

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.

Listening to sounds is an intricate process, and a cochlear implant cannot simulate such complexity, says Edward Overstreet, an engineer at Oticon, a hearing technology company in Somerset, New Jersey. So it is not clear that simply sharpening the electrodes signal will help a user to hear sounds in a more natural way. We would probably need a leap in cochlear-implant electrode array technology to make this meaningful in terms of patient outcomes, he says.

If the method works well in humans, the authors say, it might help profoundly deaf people enjoy music and follow conversations in restaurants. And it might also enhance a newer type of hearing technology: hybrid electro-acoustic implants, which are designed to help people who have only partial hearing loss. The gene therapy might work to keep residual hearing intact and allow the implants to replace only what is missing, creating a blend of natural and electric hearing.

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Bionic Ears Boosted by Gene Therapy and Regrown Nerves

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 isn't ready for human testing, but it's 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.

Cochlear implants substitute for the missing hair cells, sending electrical impulses to directly activate auditory nerves in the brain. They've been implanted in more than 300,000 people. While highly successful, they don't 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 Australia's 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.

That made the membranes of nearby cells temporarily permeable, so the gene could slip inside. Those cells began producing the growth factor, which in turn stimulated regrowth of the nerve fibers - closing some of the space between the nerves and the cochlear implant, the team reported in the journal Science Translational Medicine.

The animals still needed a cochlear implant to detect sound - but those given the gene therapy had twice the improvement, they concluded.

Senior author Gary Housley estimated small studies in people could begin in two or three years.

Excerpt from:
Gene therapy may boost power of cochlear implants, study says

Image Caption: This shows regenerated auditory nerves after gene therapy (top) compared with no treatment (below). Credit: UNSW Translational Neuroscience Facility

[ Watch The Video: Bionic Ear Delivers DNA To Regrow Auditory Nerve Cells ]

University of New South Wales

Researchers at UNSW Australia have for the first time used electrical pulses delivered from a cochlear implant to deliver gene therapy, thereby successfully regrowing auditory nerves.

The research also heralds a possible new way of treating a range of neurological disorders, including Parkinsons disease, and psychiatric conditions such as depression through this novel way of delivering gene therapy.

The research is published today (Thursday 24 April) in the prestigious journal Science Translational Medicine.

People with cochlear implants do well with understanding speech, but their perception of pitch can be poor, so they often miss out on the joy of music, says UNSW Professor Gary Housley, who is the senior author of the research paper.

Ultimately, we hope that after further research, people who depend on cochlear implant devices will be able to enjoy a broader dynamic and tonal range of sound, which is particularly important for our sense of the auditory world around us and for music appreciation, says Professor Housley, who is also the Director of the Translational Neuroscience Facility at UNSW Medicine.

The research, which has the support of Cochlear Limited through an Australian Research Council Linkage Project grant, has been five years in development.

[ Watch The Video: Regenerated Auditory Nerves ]

Read more:
Existing Cochlear Technology Used To Re-grow Auditory Nerves