Category Archives: Gene Medicine

According to the World Health Organization, more than 360 million people worldwide live with disabling hearing loss, and for many, devices such as hearing aids and cochlear implants allow them to maintain a normal life style. But what if a cochlear device could offer a biological solution that would enhance a patients experience?

For the first time, researchers at the University of New South Wales in Australia have used cochlear implants to regenerate auditory nerves through gene therapy, a process where therapeutic DNA is inserted into cells to treat a disease.

Cochlear implants work by converting sounds into electrical signals that are sent directly to the auditory nerve, bypassing the outer and middle ear. The process allows for significantly improved hearing, including the ability to maintain a phone conversation, but the sounds they provide for patients are monotone and robotic.

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 Gary Housley, Director of the Translational Neuroscience Facility at UNSW Medicine.

In 1993 multiple labs discovered that mammals ears would have the ability to regenerate cells if triggered according to the National Organization for Hearing Research Foundation, but until now there hadnt been a safe or efficient way to deliver the necessary proteins to the cochlear area.

We think its possible that in the future this gene delivery would only add a few minutes to the implant procedure, says the papers first author, Jeremy Pinyon, whose PhD is based on this work. The surgeon who installs the device would inject the DNA solution into the cochlea and then fire electrical impulses to trigger the DNA transfer once the implant is inserted.

Gene therapy research has provided hope for a number of genetic disorders and diseases, including cancer, HIV and multiple sclerosis.

"Our work has implications far beyond hearing disorders, says co-author Associate Professor Matthias Klugmann, from the UNSW Translational Neuroscience Facility research team. Gene therapy has been suggested as a treatment concept even for devastating neurological conditions and our technology provides a novel platform for safe and efficient gene transfer into tissues as delicate as the brain.

The research was recently published in the journal Science Translational Medicine.

Professor Housley discusses the new gene delivery technique in the UNSW video below.

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Cochlear implant enhances patient experience through gene therapy

NIMROD Gene Tripp descended into a world of green moss, green grass and evergreen pines on Medicine Tree Hill on a recent April morning.

Two old roads ran side by side up the westslope overgrowth. One especially caught Tripps fancy, and he called to his companions above to come and take a look.

You know they used that other one to go up and work on the pipeline and stuff, said Tripp, who lives in the river valley above and owns much of the land over and beyond the hill. But there was no reason for this one to be here. Especially these ruts.

No reason unless it was a rare remnant of the original military wagon road cut over this forgotten hill. That track quickly became known as the Mullan Road, carved 624 miles through the Northern Plains and Rockies from Walla Walla, Wash., to Fort Benton in two swoops from 1859 to 1862.

The ruts in which Tripp stood were shin deep, with all the right attributes of wooden wagon wheels chain-locked to scoot down the hillside. They say tens of thousands of people flocked to Montana and its new gold fields in the 1860s, many of them on the Mullan Road. By happy (for some) coincidence, Congress had just sprung for $230,000 to build the road to move military troops and supplies into the Pacific Northwest before and during the early Civil War years.

There had to be a few wagons going up and down this thing to do what it did here, Tripp noted.

It might be a stretch but not much of one to call this a section of the road that built Montana. When Lt. John Mullan finished it in 1862, there was no such thing as a Montana in these parts. The tracks Tripp and his guests were tracing were in Washington Territory. A few months short of two years later theyd been annexed into the new Idaho, then Montana territories.

***

From the sky, the mile-long finger known as Medicine Tree Hill seems to beckon travelers upstream. Down in the valley it all but begs you not to notice it.

Interstate 90 and the current channel of the Clark Fork River have to bend to get around its steep north slope 30 miles east of Missoula. Attention tends to wander to the north side, where a waterfall and thermal hot spring make for interesting summer splashing, not to mention extralegal roadside parking.

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Medicine Tree mystery: Along Mullan Road near Nimrod, hill scoured for sacred site

NEW DELHI: In a major setback to improving tuberculosis (TB) diagnosis and treatment in the country, researchers have found that the new gene Xpert gene test being promoted by government and top health agencies of the world does not give accurate results. In fact, one out of every three sputum sample put to test using this technology gave false sensitivity to TB drug (Rifampicin) in study carried at the All India Institute of Medical Sciences (AIIMS) when they were originally drug-resistant.

Dr Sarman Singh, professor and head of the clinical microbiology and molecular medicine division at AIIMS, said GeneXpert has been a revolutionary diagnostic method in Africa but in India it can miss as many as one-third of Rifampicin-resistance cases. "The Indian strains have a peculiar gene sequence which is not recognized by the probes GeneXpert has. Hence, if such systems are used routinely, this would give a false impression that India has very low rifampicin resistance thus making the programme mangers complacent," Dr Singh added.

There are four tests approved by WHO: LED Microscope, Liquid Culture and two molecular tests - Gene Xpert and Line Probe Assay. Gene Xpert, one of the advanced tests for TB diagnosis, is available at AIIMS for a patient suffering from drug resistant TB but it is not available in all hospitals due to its high cost. But central TB division of Ministry of Health, Government of India is installing GeneExpert in all the referral TB laboratories.

Dr Singh said the national TB control program managers must evaluate the performance of Xpert MTB/RIF test before rolling it out in the Drug resistant-TB control program in view of the findings, which has been published in latest issue of the Journal of Clinical Microbiology. The AIIMS study, researchers said, was done in a double-blinded manner. "After getting the RIF mono-resistance Line Probe Assay (LPA) results, one of us asked the persons in charge for Xpert MTB/RIF to run these samples in Xpert using the newer version of cartridges as per manufacturer instruction. Comparative analysis showed only 64.4% RIF mono-resistant TB cases were correctly diagnosed by Xpert. The remaining 35.6% were detected falsely RIF susceptible," said an AIIMS researcher.

In an earlier report published in PLOS Medicine journal, researchers pointed out that Xpert MTB/RIF has a number of limitations including limited shelf-life of the diagnostic cartridges, operating temperature and humidity restrictions, requirement for electricity supply, the need for annual servicing and calibration of each machine.

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Much-hyped new tuberculosis test gives inaccurate results

The electrodes in a cochlear implant can be used to direct gene therapy and regrow neurons.

Growth factor: The cochlear nerve regenerates after gene therapy (top) versus the untreated cochlea from the same animal (bottom).

Researchers have demonstrated a new way to restore lost hearing: with a cochlear implant that helps the auditory nerve regenerate by delivering gene therapy.

The researchers behind the work are investigating whether electrode-triggered gene therapy could improve other machine-body connectionsfor example, the deep-brain stimulation probes that are used to treat Parkinsons disease, or retinal prosthetics.

More than 300,000 people worldwide have cochlear implants. The devices are implanted in patients who are profoundly deaf, having lost most or all of the ears hair cells, which detect sound waves through mechanical vibrations, and convert those vibrations into electrical signals that are picked up by neurons in the auditory nerve and passed along to the brain. Cochlear implants use up to 22 platinum electrodes to stimulate the auditory nerve; the devices make a tremendous difference for people but they restore only a fraction of normal hearing.

Cochlear implants are very effective for picking up speech, but they struggle to reproduce pitch, spectral range, and dynamics, says Gary Housley, a neuroscientist at the University of New South Wales in Sydney, Australia, who led development of the new implant.

Cyborg cavy: An Xray image shows the cochlear implant in the left ear of a guinea pig.

When the ears hair cells degrade and die, the associated neurons also degrade and shrink back into the cochlea. So theres a physical gap between these atrophied neurons and the electrodes in the cochlear implant. Improving the interface between nerves and electrodes should make it possible to use weaker electrical stimulation, opening up the possibility of stimulating multiple parts of the auditory nerve at once, using more electrodes, and improving the overall quality of sound.

Peptides called neurotrophins can encourage regeneration of the neurons in the auditory nerve. Housley used a common process, called electroporation, to cause pores to open up in cells, allowing DNA to get inside. It usually requires high voltages, and it hasnt found much clinical use, but Housley wanted to see whether the small, distributed electrodes of the cochlear implant could be used to achieve the effect.

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Cochlear Implant Also Uses Gene Therapy to Improve Hearing

By Steven Reinberg HealthDay Reporter

WEDNESDAY, April 23, 2014 (HealthDay News) -- Australian researchers say that gene therapy may one day improve the hearing of people with cochlear implants, allowing them to appreciate music and hear in noisy environments.

In experiments with deaf guinea pigs, senior study author Gary Housley and colleagues found that inserting genes in the area of the cochlear implant and passing an electric charge through the implant stimulated the growth of cochlear cells.

"Our study found a [new] way to provide safe localized delivery of a gene to the cochlea, using the cochlear implant device itself. The gene acts as a nerve growth factor, which stimulates repair of the cochlear nerve," said Housley, a professor and director of the Translational Neuroscience Facility at the University of New South Wales, in Sydney.

The cochlear implant is surgically placed in the cochlea, in the inner ear. The implant works by using a line of small electrodes within the cochlea to selectively stimulate cochlear nerve fibers at different positions and enhancing different sounds, or frequencies, Housley explained.

"In the cochlea of a person with good hearing, sound vibrations are encoded by sensory cells, called 'hair cells,' which stimulate the cochlear nerve fibers," he said. "With hearing loss, the hair cells are lost, and without them the cochlear nerve fibers die and retract into the bone within the core of the cochlea."

This makes the job of the cochlear implant difficult as the amount of electrical current needed to stimulate the nerves is quite high, Housley added.

The gene therapy, which makes the cells close to the electrode produce the nerve growth factor, causes the nerve fibers to grow out to those cells -- and therefore to the electrodes, he explained. This means that much less current is needed, so more selective groups of nerve fibers can be stimulated.

"In the future, people with cochlear implants may get this gene therapy at the time of their implant, and the computer system -- which is part of the cochlea implant that converts sound to electrical pulses along the array of electrodes -- should be able to provide a better sound perception," Housley said.

Scientists note, however, that research with animals often fails to provide similar results in humans.

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Gene Therapy May Enhance Cochlear Implants, Animal Study Finds

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

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

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

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

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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