Dr. Michael G. Kaplitt, co-founder of Neurologix, helped design the study in which the GAD gene was infused directly into the brains of Parkinson's disease patients.

Imagine that for years you’ve lived with a body that is in constant, uncontrollable, motion: your hands tremble, your head bobs, you walk in short, shuffling steps, and muscles all over your body spasm so strongly it’s painful. Everyday activities, like going to the bathroom, are incredibly difficult and time consuming. You may look at others who walk, talk, and go to the bathroom with an ease that is impossible for you to imagine and think, that’s “them,” not me.

This description is close to what life is like for many of the estimated 7 to 10 million people worldwide who have Parkinson’s disease. But a recent study may offer hope that a change for the better could very well arrive in their near future. Neurologix, Inc., a biotech company based in Fort Lee, New Jersey, successfully used cutting edge gene therapy to improve tremors, rigidity and other motor control problems in a group of Parkinson’s disease patients, and with minimal side effects. If the therapy makes it to the market, it will be the first of its kind to do so.

For the uninitiated, gene therapy is a procedure in which a group of cells within the body are upgraded with one or more new genes to modify their behavior. The targeted cells are literally reprogrammed to exhibit new behaviors and abilities. A modified virus, called a vector, is used to safely infiltrate the targeted cells and inject them with the new genes. The viruses are mutated in a way to prevent their replicating out of control or causing any harm to the patient.

In the treatment being tested by Neurologix, gene therapy is used to modify neurons within the substantia nigra, an area in the back of the brain responsible for motor control. The gene therapy is aimed at increasing the expression of the GAD gene within the targeted neurons. GAD is used within neurons to make GABA, an inhibitory neurotransmitter which is decreased in the Parkinsonian substantia nigra, resulting in overactive neuron firing. In theory, with increased GAD production, GABA production will also increase, putting a “break” on the overactive neurons in Parkinson’s patients.

Injecting a virus into a specific part of the brain is no small feat. To inject the GAD gene, the experimental half of the patients (22) had, under local anesthesia, holes drilled into their skulls into which catheters were inserted. They then went to a recovery room where the GAD gene was injected into the catheter. The remaining control patients (23) underwent sham “surgeries” in which researchers imitated the sounds of the procedure and pretended to drill a hole in the skull and insert a catheter. Six months following surgery, the motor skills of both patient groups were assessed. The placebo group showed an improvement of 11 percent. The group that received GAD improved their motor scores by 23 percent with all but two showing improvement.

The current study was the second trial that Neurologix has subjected their GAD gene therapy to. Phase 1 took place in 2007 and included 22 patients. The study showed similar improvements but did not include a control group. Now that the therapy has passed phase 2 Neurologix is trying to raise the $30 to $40 million it will cost to conduct a phase 3 trial which requires 1,000 to 3,000 test subjects. After phase 3 is completed it is then up to the FDA to decide whether or not the therapy is safe enough to be sold.

The millions of people across the world with Parkinson’s disease and their families will be watching closely.

Neurons in the substantia nigra become impaired or die in people with Parkinson's disease. A new gene therapy, aimed at returning function to substantia nigra neurons, shows promising results.

If it does make it to market, Neurologix’s GAD gene will be a significant advancement in the treatment of Parkinson’s disease. At present the best treatment for Parkinson’s disease is levodopa. You might recall levodopa—also called L-dopa—bringing comatose patients to life in the movie “Awakenings” based on the book by Oliver Sacks. Like the GAD gene therapy, giving patients levodopa does not help prevent or reverse the actual disease but improves quality of life by alleviating symptoms. Unfortunately, as we saw in “Awakenings,” levodopa must be taken continually and its effectiveness typically wears off over time.

The Promise of Gene Therapy

To give cells back that which they have lost—as in returning Parkinsonian substantia nigra neurons to normal levels of dopamine or GABA production—is the ultimate hope in gene therapy. You permanently correct the cell itself rather than continually feeding it what it lacks. Making gene therapy ever more attractive is our increasing ability to identify the abnormal genes associated with inherited disease like Alzheimer’s disease, manic-depression, intestinal cancer, heart disease, diabetes, and many others.

But the road for gene therapy has been a rocky one. A four-year old girl with a severe combined immunodeficiency (SCID)—known to most as “bubble boy disease” from the famous story of David Vetter who was forced to live in a sterile bubble—became the first person to receive gene therapy in 1990. She got better, but whether or not it was due to the therapy or something else has since been a matter of debate. Much effort since then has been aimed at developing safe and effective gene therapies, but the fact is no gene therapy has yet been approved by the FDA.

Gene therapy is further complicated by the fact that diseases are, well, complicated. The advances in genetics that so enticingly point us to potential targets for gene therapy also reveal that many common disorders such as arthritis, diabetes, Alzheimer’s disease, and heart disease are brought on by the combined effects of multiple genes.

But a string of successes in the past few years clearly shows that gene therapy is marching forward:  in 2008, vision was restored to patients with blindness brought on by a defective gene; in 2009, 8 of 10 patients were cured of a form of bubble boy disease; in 2010, a man was cured of a kind of blood disease called beta-thalassaemia. Each of these success stories were the result of targeting single genes. The wait may be longer for gene therapies to tackle the more complicated, multi-gene diseases, but its evident that some diseases are amenable to a single gene approach. I think we can expect exciting results in the near future. Research is currently underway to develop gene therapies for Huntington’s disease, blood disorders, various forms of cancer, Sickle cell anemia, cystic fibrosis and deafness.

To be clear, both the GAD gene and levodopa treat the symptoms, not the underlying causes of Parkinson’s disease. Until we know exactly why the neurons of the substantia nigra become impaired we won’t be able to develop a cure. For now we’ll have to be okay with that. And if Neurologix one day soon delivers a gene that improves quality of life for millions of the world’s people with Parkinson’s disease, I think they’ll be okay with that too.

[image credits: wearingoff.org, New York Presbyterian/Weill Cornell Medical College via The Dana Foundation]

Peter Murray was born in Boston in 1973. He earned a PhD in neuroscience at the University of Maryland, Baltimore studying gene expression in the neocortex. Following his dissertation work he spent three years as a post-doctoral fellow at the same university studying brain mechanisms of pain and motor control. He completed a collection of short stories in 2010 and has been writing for Singularity Hub since March 2011.