By David N. Leff
Thanks to medical science and better nutrition, among other factors of modern life, more and more people in the West's industrialized nations are living beyond the age of 100. But well below this magic number of longevity, far more elderly members of modern society - people in their 50s to 80s - are suffering the slings and arrows of outrageous neurodegenerative diseases.
Two such maladies, Alzheimer's disease (AD) and Parkinson's disease (PD), are prime research targets for therapies to cure, curb, and perhaps prevent, these infirmities of aging brains. Alzheimer's degrades cognition; Parkinson's, bodily movements and coordination.
Second only to AD, the most frequent neurodegenerative disease in the U.S. is PD. It affects at least half a million Americans, and costs society $20 billion a year. In the 70-plus age bracket, 1.5 to 2.5 percent have the disorder.
Just what goes wrong in the AD brain is less clear than the proximate cause of PD. It's the gradual loss of neurons that supply the central nervous system with dopamine, a key neurotransmitter. Dopamine signaling in the brain affects locomotion, neuroendocrine secretion, cognition, feeding and reward-related behaviors.
Its lack in PD brings on the tremors, rigidity, droopy posture, altered gait and mask-like facial features of the disorder. To counter or delay these hallmarks of advancing PD, patients are prescribed oral levodopa, a precursor drug that converts to dopamine in the brain. But this daily fix, usually effective at first, wanes and dwindles in efficacy with time.
Gene Therapy Once, Not Daily Pills For Life
Now, a pioneer neuroscientist and molecular biologist, Richard Palmiter, at the University of Washington, in Seattle, has teamed up with scientists at Cell Genesys Inc., of Foster City, Calif., to replace L-dopa pills with a one-shot gene that expresses dopamine in the brain, indefinitely and effectively. "So far," Palmiter told BioWorld Today, "we have mice surviving on their own, without any further L-dopa treatments, for over a year - half a rodent's normal life span - with no side effects that we can detect."
Palmiter, an investigator at the Howard Hughes Medical Institute, is senior author of a paper in the January 1999 issue of the journal Neuron. It bears the title, "Viral gene delivery selectively restores feeding and prevents lethality of dopamine-deficient mice."
Those genetically engineered rodents can't make tyrosine hydroxylase, a key enzyme for dopamine synthesis. Their sluggish locomotion resembles the restricted bodily movements of advanced PD patients. Moreover, without daily levodopa shots, the animals refuse enough food and water to survive, and die of inanition within three days.
Cell Genesys constructed a gene-therapy package consisting of an adeno-associated virus vector carrying the tyrosine hydroxylase gene, and one other essential DNA sequence. When injected directly into the striatum, a brain area implicated in PD, this construct began expressing therapeutic levels of levodopa.
To measure the transgenic animals' movement deficits, compared with wild-type mice, Palmiter recounted, "The simplest thing is just put them in a cage crisscrossed by light beams, then count the beams broken by mouse locomotion, and calculate how far they travel. Our dopamine-deficient mice, left to their own devices, will travel 10 percent or less than a normal mouse.
"Remarkably," he said, "every time we give them levodopa, as if they were PD patients, their activity not only comes back to normal, it actually exceeds normal. They become maybe five to 10 times more active than wild-type mice. Then, as the levodopa is metabolized, they revert to their immobile state. We have to inject them daily to keep them alive, and while they're active they do their feeding."
In those mice, locomotion is a less precise marker of PD behavior than aphagia - the inability, or unwillingness, to eat and drink.
"That aphagia is what has intrigued us the most," Palmiter said, "mainly because most people haven't appreciated the fact that dopamine is important for hunger, and perhaps other motivated behaviors. My understanding is that human PD patients do not have a motivational feeding deficit. If anything, their problem is getting their forks to their mouths, rather than the motivation to be hungry."
Pinpointing Dopamine's Behavior In Brain
Palmiter said that, in PD, "it's a subset of the entire range of dopaminergic neurons that are degenerating. In patients, only some dopaminergic systems are affected, whereas in our mice we've eliminated levodopa from all neurons that make dopamine. Exactly why these mice don't eat is the subject of a grant that we're writing right now.
"What interests us most," he said, "is what part of the brain requires dopamine for feeding. So we want to use smaller and smaller volumes of the virus vector that we inject, to find the smallest region we can transduce that still rescues feeding behavior. In the process of doing that, I think, we'll find areas of the brain that rescue other behaviors, perhaps locomotion, without rescuing feeding. The most striking finding in our experiments was eliminating the need for daily L-dopa treatment in the mice receiving the gene therapy. This represents a remarkable rescue of an otherwise-lethal mutation in these genetically modified mice."
As for clinical application of his gene-therapy approach, Palmiter said, "My take on it is that this paper demonstrates (a) the virus is efficacious; (b) it's safe; and (c) it lasts a long time. The problem is that what you'd really like for people with PD is to catch the disease early and prevent the neurons from dying. But you'd need a different gene for treating PD in humans. [Brain-derived neurotrophic factor] is one the community is hot on, right now. But there are others. If you find the right gene," he concluded, "I believe that this therapeutic approach is ideal." n