Inserting corrective genes into the brain to fight Parkinson's disease

An international team of scientists has used gene therapy in two separate studies to renew brain cells and restore normal movements in monkeys and rats with a drug-induced form of Parkinson's disease.

The research, detailed online in the scientific publications Brain and The Journal of Neuroscience, essentially describes one strategy to halt Parkinson's disease at its onset and another strategy to treat the devastating side effects that occur when treating the disease in its later stages.

By inserting corrective genes into the brain, scientists studying small monkeys called marmosets prevented brain damage by producing therapeutic levels of a protein that helps nourish brain cells, said Ron Mandel, Ph.D., a scientist with the University of Florida's McKnight Brain Institute and Genetics Institute who was part of the research team.

The protein, called GDNF, short for g lial cell line derived neurotrophic factor, is believed to preserve brain cells and could provide protection against Parkinson's disease. But its use has been debated since trials in humans ended last year without showing clinical improvements. Amgen, the world's largest biotechnology company, conducted the trials and later halted use of the drug because of safety concerns, creating an outcry from hopeful Parkinson's patients.

But the gene therapy used in monkeys represents a different way to deliver the GDNF to the brain, causing the body to produce it naturally. It also produces more manageable levels of the protein in the brain.

“Our strategy is a neuroprotective concept and would only be amenable for early stage patients to keep a good quality of life. It would be a huge change in the way treatment is done,” said Mandel, a neuroscientist in UF's College of Medicine. “We know the GDNF protects the neurons in primates from the model that we use, so that's good. We now know we can use very low doses that are still effective, so that's good. But we need a safety net. Once we turn it on, it's on for life. So we have to control it, and we're working on this as we speak. But it's not ready for clinical trials.”

About a half million Americans struggle with Parkinson's disease, including former Attorney General Janet Reno, former heavyweight boxing champion Muhammad Ali and film star Michael J. Fox, according to the National Institute for Neurological Disorders and Stroke. Pope John Paul II was recently hospitalized because of breathing problems that were complicated by his advancing Parkinson's disease.

“The use of GDNF as an approach against Parkinson's disease has truly had some ups and downs,” said J. William Langston, M.D., scientific director and chief executive officer of The Parkinson's Institute in Sunnyvale, Calif., who recently chaired a panel probing GDNF experimentation for the Michael J. Fox Foundation for Parkinson's Research. “This is additional experimental evidence that suggests that it can be a promising approach to this disease using in vivo gene therapy, which is very applicable to humans. It even presents theoretical reasons that might solve some of the safety issues that have been raised about GDNF. But many things remain that we still don't understand.”

The recent findings in laboratory animals were a joint effort of Lund University in Lund, Sweden, the University of Cambridge in the United Kingdom, and the McKnight Brain Institute and the Genetics Institute of the University of Florida. Scientists included internationally renowned Parkinson's expert Anders Björklund of Lund, a pioneer of the experimental treatment involving the transplantation of fetal cells into the brains of Parkinson's patients, and his colleague Deniz Kirik, a neurobiologist.

“This work with GDNF in combination with other regenerative medicine approaches, including stem cells, promises to have a place for both protection and repair in Parkinson's disease,” said Dennis Steindler, Ph.D., director of the McKnight Brain Institute and a professor of neuroscience. “It is important to appropriately introduce the GDNF into the Parkinson's disease setting, where that introduction can provide insight into how to protect neural cells. This is showing us a new way to approach the problem.”

Parkinson's disease is caused by the death of brain cells that produce a vital chemical known as dopamine, which carries messages that tell the body how and when to move. In tests with 31 monkeys, including a control group, scientists inserted copies of a gene to produce GDNF into a region in the front part of the brain called the striatum. They then induced Parkinson-like conditions by introducing a drug to destroy the dopamine-producing cells. Seventeen weeks after that, not only did the GDNF-treated monkeys show improvement in performing tasks, analysis of brain tissue showed the animals' dopamine systems were actually spared by the treatment.

“The simplest question we're asking is, ‘Does any particular combination of proteins prevent or accelerate degeneration of the neurons?'” said Nicholas Muzyczka, Ph.D., an eminent scholar and professor of molecular genetics and microbiology at UF's College of Medicine who participated in the research. “For some time Dr. Mandel has been working on the idea of introducing a vector into brain that would express GDNF. What they've found is that if you get low-level expression, you can prevent cell death in a part of the brain called the substantia nigra. That's been shown before in rodent models, but it's encouraging to see data that it works in higher animals like monkeys.”

Meanwhile, in separate experiments with rats, researchers used gene therapy to completely reverse abnormal movements called dyskinesias in some of the animals, suggesting a new way to combat the flailing movements produced by a widely used drug treatment for Parkinson's disease. Levodopa, considered the gold standard of current treatment, enables the brain to replenish its dwindling supply of dopamine, sidetracking the destructive course of Parkinson's disease. But eventually the treatment can backfire.

“Levodopa generally works great for several years, but then it actually starts creating movement problems,” Mandel said. “Our idea is that instead of taking pills that create detrimental fluctuations of L-dopa levels, a continuous, therapeutic dose would be better for you.

As for efforts to reverse impaired movements in rats, scientists used 33 animals with severe dopamine depletion and transferred a gene to provide a source of L-dopa production into the animals' striata. Before receiving the treatment, all animals had limited use in their left paws. After treatment, the animals receiving the therapeutic enzyme mixture show complete recovery in their paws. Researchers say not only did the rats recover substantial degrees of function in their impaired forelimbs, continuous levels of L-dopa were being produced in their brains, blocking side effects.