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.
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.”