By David N. Leff
A few years ago, neuroscientists were asking a reasonable question: If fetal brain-tissue transplantation helped Parkinson's disease patients, why not Huntington's? (See BioWorld Today, June 12, 1998.)
Now, all at once, the answer to that rhetorical query is busting out on both sides of the Atlantic. Neurosurgeon Thomas Freeman told BioWorld Today, "Four pieces of Huntington data have all come out within a four-week period." He ticked them off on four fingers: "One is our autopsy study in PNAS [Proceedings of the National Academy of Sciences]. Two is Marc Peschanski's clinical data in France. Three is the clinical data we reported Nov. 6, 2000, to the 30th annual meeting of the Society for Neuroscience in New Orleans. And four is the HD trial just getting under way by Steven Dunnett at the University of Cardiff, in Wales, UK."
Freeman, who directs the Center for Aging and Brain Repair at the University of South Florida, in Tampa, is senior author of a paper in today's PNAS, dated Dec. 5, 2000. Its title: "Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology."
Beginning in 1997, he and his co-authors implanted human fetal brain cells into the striatal brain regions of seven adult patients with moderate-to-advanced Huntington's disease (HD). "It was our hope," Freeman said, "that the transplants would be able to restore lost neuronal connections in their diseased brains, and thereby slow the disease progression."
The seven patients, with genetically confirmed HD, received transplants into both sides of the brain of striatal neurons derived from nine-week-old embryonic donors. "The primary loss of neurons in this disorder," Freeman explained, "occurs within a region of the brain called the striatum. Later in the disease there is more extensive loss throughout the brain."
The striatal cells the co-authors implanted produce the neurotransmitter GABA - gamma-aminobutyric acid. Its signals in the brain dampen excitation, for which reason GABA-based medication is used to treat clinical anxiety and epilepsy. Valium (diazepam) is one of several psychoactive drugs that rely on GABA receptors. In HD, these therapies are only palliative; the disease progresses inexorably and fatally.
Sudden Death Permits Brain Graft Analysis
Just 18 months after transplantation, one of Freeman's seven patients, a 54-year-old man, died suddenly of a massive heart attack - unrelated to his underlying HD surgery. The Florida team collaborated on the subject's brain autopsy with neuroscientist Ole Isacson, at Harvard-affiliated McLean Hospital's Neuroregeneration Laboratory in Belmont, Mass. Isacson is a co-author of the PNAS paper.
"The salient findings there," Freeman noted, "were that we had graft survival that reproduced regions of typical striatal tissue, which we had transplanted. We saw reinnervation and connectivity of the graft with the brain. What's more, the graft survived for a year and a half without immunosuppression of the patient.
"Probably most importantly," he added, "when we looked with a probe for the abnormal Huntington gene, which is expressed pathologically throughout an HD patient's brain, it was not expressed in this patient's graft. So the disease process did not adversely affect graft survival."
As Freeman reported to the Society for Neuroscience meeting, "one of the remaining six trial patients could not be evaluated because of blood clots developed over the surface of her brain, due to a fall six weeks after surgery. In the other five patients, who have come to one-year follow-up, we've got a 20 percent improvement in the HD global rating score over a one-year period. This compares with deterioration before surgery at a rate of 15 or 20 percent - which is what you would expect." The improvement occurred gradually over a six-month period.
'Similar' Franco-American Results Confirm Efficacy
Freeman compared his findings with those just reported by French neuroscientist Marc Peschanski in The Lancet dated Dec. 2, 2000, and titled: "Motor and cognitive improvements in patients with Huntington's disease after neural transplantation." He and his co-authors are at INSERM (National Institute of Health and Medical Research) in the Paris suburb of Creteil.
That paper "explored whether grafts of human fetal striatal tissue could survive and have detectable effects in five patients with mild-to-moderate HD," Freeman said, adding that Peschanski's findings "showed increased metabolic activity in various subnuclei of the striatum in three of five patients, suggesting the grafts were functional." Accordingly, he said, "motor and cognitive functions were improved and maintained within the normal range, and functional benefits were seen in daily-life activities in these three patients, but not in the other two."
Freeman sees in these two similar clinical experiments several implications, of particular interest to the biotechnology community:
"The evidence of efficacy in two separate diseases gives hope for these neural transplant techniques in other diseases in the future as well," he said. "When stem cells are differentiated into neurons, the very first neuronal type created is a GABAergic neuron - the type of striatal neuron that is lost in HD - the type we tried to transplant. So from a biotech point of view, one of the easiest uses of stem cells may well be for transplantation purposes in HD."
With neural transplants, Freeman noted, "we now have survival of numerous immunologically unrelated brain grafts in patients without immunosuppression. So any human-derived cell line - without paying much attention to its immunologic aspects- is likely to survive in the brains of patients. Therefore, from a biotech point of view, one cell line would be useful for patients around the world, as opposed to cell or organ transplantation in the periphery, where they have to be immunologically matched or require high-dose life-long immunosuppression of unmatched grafts. So stem cell transplantation - or biotechnologically derived cell lines in the brain - are likely to be viable economically, because you don't need to make a single cell line for every single patient."
Freeman's take-home message: "Now that we have preliminary evidence of efficacy, it would be much more reasonable to start long-term studies of HD patients much earlier in the disease process."