By David N. Leff
If it works in Parkinson's disease, why not in Huntington's?
That's the question that neurosurgeons on both sides of the Atlantic are beginning to answer. The "it" refers to human fetal brain tissue transplanted into the brains of patients — so far, only those with Parkinson's disease. (See BioWorld Today, May 4, 1998, p. 1.)
Huntington's disease (HD) also is called Huntington's chorea, a Latin term for irregular, involuntary, dance-like movements of limbs and face. The spasmodic symptoms are accompanied by progressive dementia. The slow degeneration of cerebral neurons governing these motor and cognitive brain functions is linked to the relentless expansion of CAG [cytosine-adenine-guanine] triplet codons in the genomes of HD sufferers. Normal individuals have 11 to 34 copies of the CAG repeat in their genomes; HD patients, upwards of 37. (See BioWorld Today, June 4, 1998, p. 1.)
The British collaborative HD project has named the Cambridge University Center for Brain Repair as the U.K.-wide surgical center for impending clinical trials of the fetal tissue approach to HD therapy.
"We aim to start transplants within the next 18 to 24 months," Cambridge research neuroscientist Lisa Kendall told BioWorld Today, adding, "We have patients already being worked up."
Kendall is lead author of a paper in this month's Nature Medicine, dated June 1998, and titled, "Functional integration of striatal allografts in a primate model of Huntington's disease." It reports experiments designed to restore motor function to marmoset monkeys made to mimic HD-like motor dysfunction. Marmosets are small New World primates (Callithrix jacchus) that weigh in at 350 to 400 grams (1.6 to 1.8 pounds).
"Although rats are the animal model of choice in in vivo neurological testing," Kendall pointed out, "there has been no demonstration that allograft [same-species] techniques that work well in rats translate effectively to the much larger, differentiated striatum of primates."
Primate Studies Successful
She and her co-authors began four years ago by injecting a neurotoxin called quinolinic acid into the putamen regions of 12 marmosets — but on only one hemisphere of their brains — to simulate the motor lesions in HD patients' brains. Four weeks later, six of the 12 animals received several follow-up injections of embryonic-monkey striatal tissues directed to the same site on the putamen — the brain area that manages motor behavior in the body.
"Creating this unilateral model," Kendall explained, "meant that each animal could act as its own control. So they always had a good side and a bad side."
In their cages, the team then placed a clear plastic set of ten steps — five going up, and five down. Each step held a primate gourmet delicacy, consisting of a bread morsel soaked in sugar syrup. This "staircase" was designed to measure a monkey's motor skills while reaching, grasping and retrieving the sweet treats.
Within two to three months after transplant surgery, the six grafted monkeys "showed a significant alleviation of the reaching deficit," the Nature Medicine paper reported. "Their ability to grasp and retrieve pieces of food was less clumsy, and the speed to clear the staircase with their affected hand increased to almost normal levels."
A year later, during which this near-normal performance held up, post-mortem examination revealed severe cell loss and atrophy of the putamen in all monkeys. However, the six transplantees "had surviving graft tissue, and in each case the multiple deposits had merged to form one large graft," the paper reported.
"What you're looking at in a human HD brain," Kendall observed, "is the degeneration commencing in the basal ganglia, but predominantly in an area called the caudate and the putamen. Obviously, the motor symptoms from the putamen are only one part of the main disease for the patient.
"So we're now looking at the cognitive aspects," she continued, " concentrating on the caudate structure.
"This is slightly different," Kendall pointed out, "because in order to get an animal model that's applicable, we must use a bilateral lesion." That is, lesioning the caudate in both hemispheres.
Early Trials In Humans Promising
She and her co-authors are giving their new cohort of re-smartened-up marmosets, and control animals, "a lot of the same cognitive tests that are being used in assessing HD patients themselves. We're trying to see if replacement of caudate neurons by transplantation will actually restore much more complex functions, such as cognition, in the monkeys," Kendall concluded. "We hope to have some data within the next 12 months."
At Good Samaritan Hospital, in Los Angeles, neurosurgeon Oleg Kopyov and his colleagues have described emplacing fetal striatal tissue into the brains of three patients with "moderately advanced, nondemented Huntington's disease."
One year later, as reported in the journal Experimental Neurology for January 1998, "magnetic resonance imaging [MRI] of all three patients revealed that the grafts survived and grew within the striatum. ..."
Neurologist Abraham Lieberman is medical director of the National Parkinson's Foundation, in Miami. He also is a consultant to the Good Samaritan HD program, and a co-author of Kopyov's paper in Experimental Neurology.
"By now," Lieberman told BioWorld Today, "the number of patients treated is about 20. They range in age from 21 to the mid-40s. With a disease like Huntington's, you are not going to see an impact that people in the field will believe, until you've gone about five years and patients are not getting worse."
Lieberman continued, "Have we seen any improvements? In terms of motor scores, which have their inherent limitations, there's an improvement in motor function. There also is improvement in certain cognitive functions for the group as a whole. And we've not seen anyone get worse."
European trials of fetal-tissue transplants in HD patients have just started in France, but are still reportedly at the pre-publication safety stage, Kendall informed BioWorld Today. *