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Sending Genes into the Brain

More-invasive therapies show promise for treating Parkinson’s.

The brain has long presented a special challenge to drug developers: tightly enclosed by the blood brain barrier, it remains locked to many therapies delivered orally or intravenously.

Promise for Parkinson’s: Twelve months after receiving an experimental gene therapy for Parkinson’s disease developed by Neurologix, this patient has reduced metabolic activity (indicated in blue) in the brain area most damaged by the disease.

However, thanks to more-precise methods of targeting the brain, advances in brain imaging, and the growing popularity of implanted stimulators for treating neurological diseases, the brain is no longer off limits. This is highlighted by a number of new clinical trials involving Parkinson’s patients, in which a therapeutic gene or another treatment is delivered directly to a specific part of the brain.

“My belief is that we’re entering into an era where instrumentation in the brain will become routine, not just for Parkinson’s, but for myriad central nervous system disorders,” says Howard Federoff, a neurologist and executive dean of the School of Medicine at Georgetown University, in Washington, DC. “I anticipate that delivery technologies will drive the development of new therapeutics and the repurposing of existing treatments, where they could be delivered directly to the part of the brain where it’s needed at the appropriate dose.”

Drugs that replace the chemical messenger dopamine have been very effective in treating Parkinson’s disease, but the benefits of these medications frequently decline over time. About a third of the more than half a million Parkinson’s patients in the United States are in the later stages of the disease and resistant to medication. One option for these patients is deep brain stimulation (DBS)–a surgical procedure in which an electrode is implanted directly into the brain. While the exact mechanism underlying the benefits of DBS is unknown, scientists believe that the electrical pulses sent to the damaged part of the brain override the abnormal neural signaling that triggers tremors, rigidity, and other symptoms of Parkinson’s.

More than 40,000 people worldwide have undergone the procedure–a figure that reflects its relative safety and efficacy, as well as a growing acceptance of more-invasive treatments for neurological disease. Many academic researchers and some startup companies are now searching for new alternatives that also directly target the brain, but which involve shorter surgical time and a better prognosis. While DBS is effective in reducing the symptoms of Parkinson’s disease, it does not cure it.

One approach is to correct abnormal activity with gene therapy rather than with electricity. Neurologix, a biotechnology company based in Fort Lee, NJ, has developed a novel gene-therapy treatment that is now being tested in clinical trials. The therapeutic gene involved, called GAD, codes for an enzyme that catalyzes production of the chemical messenger GABA. (Dopamine is a chemical precursor to GABA, and the cells that produce it are lost in Parkinson’s.) “By delivering the gene, you can bypass the area affected by cell death,” said John Mordock, the company’s chief executive officer, at the Neurotechnology Industry conference in San Francisco last week. “It’s taken up into the cells, allowing them to express GABA, restoring balance to the circuit.”

As with DBS, surgeons first drill a small hole in the skull, then insert an electrode to search for a small brain area called the subthalamic nucleus, which emits a characteristic pattern of electrical activity. But the electrode is then removed, and a small catheter is inserted, and a small pump infuses the genetic material into the brain. The specialized drug-delivery device was developed by Medtronic, a medical-device company that also markets DBS systems. Mordock says that Neurologix plans to market the device and the gene-therapy treatment together.

In a small trial in which every Parkinson’s patient received the same treatment, they showed a 29 percent improvement in motor function. Researchers have begun a larger, blinded trial and expect to have preliminary results later this month.

A second approach is to use gene therapy to slow or prevent cell death in the brain area ravaged by Parkinson’s. Federoff is overseeing an academic consortium planning human tests of a gene therapy that codes for a protein called GDNF (glia-derived neurotropic factor), which enhances neuronal survival. The therapy is also delivered via a catheter in the brain, but the infusion is driven by a small pressure gradient, a technique known as convection-enhanced delivery. Federoff, who is also the founder of Canadian startup MedGenesis Therapeutix, which is commercializing the technology, says that this allows for more-targeted delivery.

In addition to convection-enhanced delivery, surgeons will use real-time neuroimaging to make sure that the gene therapy is delivered as precisely as possible. Scientists can add a labeled marker to the gene-therapy solution, which can then be seen on CT or MRI scans and used to visualize the diffusion of the molecules in the brain. Researchers have already used this technique to deliver therapies to patients with brain cancer.

In addition to cancer, Parkinson’s disease will likely be the first to be treated using these approaches: scientists know which part of the brain is most damaged and can design therapies accordingly. (Alzheimer’s disease, in contrast, has a much more diffuse effect on the brain.)

Success with Parkinson’s could pave the way for treating other disorders. “As we learn more about the biology of these disorders and develop more treatment compounds, opportunities will expand with the ability to deliver drugs locally,” says Russell Lonser, chair of the Surgical Neurology Branch of the National Institute for Neurological Disorders and Stroke, in Bethesda, MD.

Gene therapy does have its downsides compared with DBS, however. “DBS can be turned off, catheters can be removed, and patients can then be brought back to their basal state,” says Federoff. “We believe that gene delivery is lifelong.”

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