By David N. Leff
Well before the end of this second millennium - now only 17 months off - 150 patients with Parkinson's disease (PD) will enter a five-year trial of a drug that tackles PD's cause, not just its symptoms.
That disease-challenging therapeutic is a molecule called monosialoglycosphingolipid - GM1 ganglioside for short. The compound is now poised for its randomized, double-blind, placebo-controlled clinical trial.
"GM1 ganglioside is a normal constituent of nerve-cell outer membranes," explained neuroscientist Jay Schneider, a professor of neurology at Thomas Jefferson University in Philadelphia. "Because of its location in these membranes, GM1 has been found to play a role during the development and growth of neurons. It seems to influence the way nerve cells respond to various signals in their environment - including the compound's unique ability to rescue neurons that have been damaged."
A clinical example is a recently concluded unpublished study that included some 750 patients, looking at the effects of GM1 in treating acute spinal cord injury. Patients in the moderate-injury group had significant improvements in sensory and motor function, compared to those on placebo.
Schneider's laboratory focuses primarily on Parkinson's disease, where the loss of neurons that secrete the neurotransmitter dopamine occasions the hand tremor, slow, shuffling gait, rigidity, imbalance, and other hallmarks of PD.
He pointed out, "Dopamine is manufactured in a part of the brain called the substantia nigra, which sends axons - nerve fibers - to another part of the brain, the striatum. The terminal, or nerve ending, is the place on the striatum where the neurochemical dopamine is actually released, synaptically.
"Once one of these dopamine neurons was injured," Schneider recounted, "the presence of GM1 ganglioside that we administered to mice and monkeys seemed to keep at least some of these nerve cells from dying. And it also seemed to promote a sprouting or regrowth of dopamine terminals from those cells that remained. So our hope was that we'd be able to turn these very promising animal findings into something that would be able to translate into positive effects on human PD patients."
Preliminary Trial PD Cohort Did Well On GM1
Schneider reported his initial full-dress human study last year, and a prior eight-patient Phase I trial, in the journal Neurology's May 1998 issue, under the title: "Parkinson's disease: Improved function with GM1 ganglioside treatment in a randomized placebo-controlled study." That Phase II trial enrolled 45 patients with mild to moderate PD. They received injections of GM1 or placebo for 16 weeks.
Encouraged by the improvement in lifestyle symptoms and motor functions observed in the GM1 ganglioside cohort, but not in controls, Schneider concluded that Neurology report by suggesting: "A larger multicenter trial is warranted to confirm the clinical benefit of GM1 in PD. ... to determine whether there are any effects of GM1 treatment on disease progression, and to verify the long-term safety of ganglioside use."
That recommendation gave rise to a $2.4 million grant from NIH's National Institute of Neurological Disorders and Stroke to fund the university's 150-patient study. "We are actively looking for PD patients," Schneider told BioWorld Today, "who would like to participate in this exciting new trial. We'd be happy to consider any patient with mild to moderate PD, who is interested in being part of a research project such as this. Interested persons [can phone Thomas Jefferson University at 1-800-533-3669]."
"A number of PD people - maybe 25 or so - " Schneider added, "have already inquired about being in this study, and have submitted information to us. We will soon begin going through their data, and starting the formal recruitment process. We figure the study will certainly get under way early in the fall. But it's a little bit tough sometimes to get these things rolling, as August comes around. Everybody seems to be on vacation."
An Italian research-based company, Fidia SpA, of Abano Terme, which manufactures high-purity GM1 in quantity, will supply the drug for the study.
Besides expanding the previous 45-patient database, the impending 150-patient trial will add some new features. "For one," Schneider related, "we would like to confirm in this larger study those initial results that we obtained in those patients. But additionally we would like to see if we can get some evidence for the biological mechanism that might be underlying that kind of clinical improvement."
Counting Neurons Via Photon Emission
"So in this study," he pointed out, "we're going to be doing functional brain scanning with single-photon-emission tomography - the SPECT scan - through a collaboration with a research team at the University of Pennsylvania, also here in Philadelphia. We will be getting baseline SPECT scans on all the patients who participate in this trial, so we can visualize - and more important, quantify - the number of dopamine terminals that they have prior to the start of the study, and at its conclusion.
"And then," Schneider continued, "we want to compare patients with a control cohort that didn't get GM1, over approximately a two-year period. We want to see if the GM1 patients really do have a different rate of symptom progression, compared to non-ganglioside-treated subjects.
"An important point here," he concluded, "is that this trial represents somewhat of a departure from the way we've been conditioned to study and treat PD, which was primarily to come up with agents that can better mask the symptoms. I think that the future of PD clinical research, whether it turns out to be a GM1 ganglioside, or some analogue of it, or another kind of agent, will be to develop compounds that actually have disease-modifying properties; that will either rescue nerve cells that have already been damaged in the disease process, or protect nerve cells from becoming damaged in the first place. I think that is probably the most viable approach to treating Parkinson's disease."