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The Promise and Pitfalls of Gene Therapy for Hereditary Blindness, Muscular Dystrophy, and Peripheral Neuropathy

Friedman, Roberta PhD

doi: 10.1097/01.NT.0000390487.62275.b1
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Advances — and some of challenges — were reported in trials for Leber congenital amaurosis, limb girdle muscular dystrophy, and peripheral neuropathy.

SAN FRANCISCO — Gene therapy continues to beckon clinicians who hope to have an effect on treatment for difficult neurological conditions, with success in some instances, and continued challenge in others. In a plenary here in September at the American Neurological Association (ANA) annual meeting, investigators reported progress in treating a hereditary form of blindness, and plans for additional clinical trials in neuropathy and in muscular dystrophy.

The most promise has come from trials of a gene therapy delivered within the eye. “This has been a very exciting odyssey for us,” said Katherine A. High, MD, a hematologist who had been working on gene therapies for hemophilia when she began to collaborate with husband and wife investigators Albert M. Maguire, MD, and Jean Bennett, MD, PhD, both professors of ophthalmology at the University of Pennsylvania, and investigators at the Center for Cellular and Molecular Therapeutics of the Children's Hospital of Philadelphia. Dr. High presented the encouraging results of gene repair evident in the retina in 12 patients with Leber congenital amaurosis (LCA).

Dr. Macguire injected an adenovirus-associated vector that contains a gene called RPE65 — which encodes retinal pigmental epithelium specific 65 k-Da protein — subretinally in one affected eye of 12 patients with LCA.

At two weeks, all of the patients reported an increase in perceived “brightness” in the injected eye, Dr. High said. Pattern recognition followed; for instance, teens could recognize the numbers on their cell phones.

At six weeks and beyond, patients reported improved resolution. “The visual fields expanded,” Dr. High said, “and they mapped to where the doctor was able to inject” in the retina. A bleb was created by the subretinal injection that resolved, she said. In a video, Dr. High showed patients navigating an obstacle course using the treated eye; something they could not do using the untreated eye.

As predicted by dog data collected prior to the phase 1/2 trial, younger patients have a more robust response to the gene therapy. Both pupils will constrict to light presented to the treated eye. But a patient aged 45 didn't show this response as dramatically as younger patients, ages 8 to 35. “For a young child the gain in light sensitivity comes up close to the normal range,” Dr. High said.

Response to the gene therapy has remained stable in all 12 subjects over the period of observation, up to 35 months in the initially injected subjects. In dog experiments, the response has persisted for up to 10 years of follow up. The investigators are now preparing to inject the patients' other eyes. They also hope to treat patients as young as 3 years old. “The eventual goal is to treat [the condition] as soon as it is diagnosed,” Dr. High said.

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Immune reactions present an ongoing issue in trials of gene therapies aimed at the periphery, including muscular dystrophies. In the most successful attempts to date, Jerry R. Mendell, MD, led a double-blind randomized trial in six boys that successfully delivered a gene into a toe muscle to test the ability to repair the gene defect in limb girdle muscular dystrophy (LGMD). An immune response to the viral vector blocked gene expression in one case, not any others, Dr. Mendell emphasized, in a telephone interview.



An important finding of these published data was an increase in muscle fiber size in the other patients. Data on three of six patients were reported in 2009 in the Annals of Neurology. At the ANA meeting, Dr. Mendell described the response in an additional three patients.

Among the new findings, “patient number four had good gene expression out to six months and increased fiber size, an encouraging finding,” reported Dr. Mendell, director of the Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital in Columbus, OH.

Patient five, the most severely impaired, had good gene expression and no immune response, he said, “which speaks well for future gene therapy trials.”

Patient six had a significant immune response and no increased expression of the vector delivered alpha-sarcoglycan gene. “In this patient we found clear evidence demonstrating immunity to AAV capsid that was present prior to gene transfer.”

Dr. Mendell said, “within the first week we had significant high neutralizing antibody titers in the blood as well as T cell immunity to the AAV capsid.” He described work in non-human primates showing that pre-existing immunity to AAV capsid can be significantly reduced using plasmapheresis. “This is not planned for immediate use in clinical trial,” Dr. Mendell said in an e-mail, “but it could make a difference for certain patients or for those who have to receive re-injection of virus at a future time point.”

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Dr. Mendell, who holds professorships in neurology, pediatrics, pathology, physiology and cell biology at the Ohio State University College of Medicine, collaborates on many different approaches for MD gene repair. Potential hurdles are significant but multiple approaches to gene repair enhance the likelihood for success, he said. LGMD was targeted because the gene involved is small enough to tuck inside the AAV vector. This contrasts with the gene for Duchenne MD that is far too large to fit. Muscular dystrophy investigators are pursing alternate approaches, including using trimmed down versions of DMD genes, or bulking up failing muscles with a gene for follistatin, a glycoprotein that stimulates muscle size and strength. Dr. Mendell said this latter avenue is heading into clinical trial early in 2011 in Becker MD.

A trial in LGMD targeted for the “near future” will deliver the alpha sarcoglycan gene via the femoral artery, Dr. Mendell said. “If this can be achieved we can replace the gene in multiple muscles of the extremity or specifically targeted muscles and truly make a clinically meaningful difference for muscular dystrophy patients.”

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Other gene therapies are under investigation to help with neuropathic pain, diabetic neuropathy, and neuropathy produced by aggressive chemotherapies. Allan H. Ropper, MD, of Harvard, has tried to address the limb ischemia that results in nerve death in diabetics with the naked gene for vascular endothelial growth factor (VEGF). Schwann cells around nerves take up VEGF directly, with no vector required.

A double blind trial in diabetic neuropathy published in 2009 achieved its primary endpoints, in 39 patients suffering severe pain from the neuropathy who received injections of VEGF, and 11 others given saline instead. Results reflect better pain self-reports. Electrophysiology did not reflect changes with the therapy, however. Dr. Ropper, executive vice chair of the Department of Neurology at Brigham and Women's Hospital in Boston, also reported progress with VEGF gene therapy in neuropathy from chemotherapies.



“I would very much like to conduct a multi-center, phase 3 trial for diabetic neuropathy,” Dr. Ropper said. But, he added, “the regulatory environment is astonishing,” citing the literal truckload of documentation associated with a 50-patient trial.

David J. Fink, MD, who co-chaired the session along with Dr. Mendell, is also working to alleviate pain through gene therapy. He uses vectors crafted from herpes simplex virus that naturally infects peripheral nerves after skin innoculation. “Herpes worked it out eons ago,” remarked Dr. Fink, professor at the University of Michigan in Ann Arbor.

With funding from Diamyd Medical, phase 1 testing of a vector expressing enkephalin in patients with intractable pain is nearing completion. Dr. Fink reported that no serious adverse events have been observed, and that plans are underway to begin a phase 2 randomized, double-blind placebo controlled trial of the vector later this year.

Dr. Fink and his group have also received funding to produce a human-grade vector expressing glutamic acid decarboxylase that will be tested in patients with neuropathic pain caused by diabetes.

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Anne Louise Oaklander, MD, PhD, associate professor of neurology at Harvard who is an advisory board member of Neurology Today, pointed out that gene fixes for neuropathic pain are certainly worthy of further inquiry, but when muscular dystrophy is ultimately fatal, “you can justify a very expensive therapy.”

“They do have to deal with the immune responses,” Dr. Oaklander continued, “but they are beginning to get some idea of who gets those responses.” Progress on the retinal front partly reflects the ease of administering DNA to the retina, she added.

Also commenting on the vision research, Ari Green, MD, director of the University of California-San Francisco Neurodiagnostics Center and a neuro-ophthalmologist investigating multiple sclerosis, said, “They've done a good job of rescuing gene therapy from the bad outcomes 10 years ago.”

“Frankly, their work is extremely impressive,” Dr. Green said. “In LCA, tissue targeted gene therapy led to clinical recovery in what is in essence a neurological tissue without stimulating an undesired systemic immune response from the patient. They were fortunate that their target both underlies visual phototransduction and causes retinal degeneration, but there are similarities in the immune privilege of the retina and the brain, so this very relevant to neurologists.”

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              ©2010 American Academy of Neurology