Can Human Fetal Striatal Neuroblasts Halt or Only Briefly Improve Huntington’s Disease?
Can Human Fetal Striatal Neuroblasts Halt or Only Briefly Improve Huntington’s Disease?
Abstracts & Commentary
Sources: Bachoud-Lévi AC, et al. Lancet 2000;356:1975-1979; Freeman BF, et al. Proc Natl Acad Sci U S A 2000;97:13877-13882.
Can human fetal striatal neuroblasts halt or only briefly improve Huntington’s disease (HD)? The answer to this question appears to be yes for the first few years, but length of time and/or complications have not yet been thoroughly tested.
Bachoud-Levi and colleagues at INSERM in France describe an open-label pilot study consisting of injecting normal human fetal striatal neuroblasts into the striatum of clinically impaired patients with HD.
Animal testing has been successful in such injections, and no inflammatory reactions after the implanting of functionally normal striatal neuroblasts have been identified. Indeed, their immediate effects ameliorated excitotoxins or metabolic toxins at the point where the injected cells were placed in the striatum. Following these favorable reactions in animals, Bachoud-Levi et al selected 10 relatively healthy controls with HD to serve as a clinical baseline. At the same time, they also selected and treated by striatal neuroblasts five HD patients who were moderately impaired from the disease. The first injected tissue was taken from normal human fetuses 7.5-9 weeks old and was transferred in small blocks into the right HD striatum. Twelve months after the first successful injections, fetal striatal neuroblasts were inserted into the left striatum. Immunosuppressive therapy was applied from the start until 12 months after the second injection. Because of Bachoud-Levi et al’s firm intention for accuracy, they spent one and a half years evaluating baseline behavioral assessments using psychological and neurophysiological test intervals before the first injections. As a result, they were continued up until 24 months after the first implantation. Both electrophysiological and PET plus MRI were used as diagnostic tools. Twenty-two untreated, similarly affected HD patients were also followed by similar neuropsychological and psychological tests. Most of these (with 1 exception) doubled their neuropsychological defects and their mean chorea intensity.
The five patients who were grafted had suffered baseline HD symptoms for 2-7 years prior to the graft. After the graft, three of the five showed either an increase or stable striatal metabolism 24 months following the first injection. Their functional improvements included cycling, various rigorous home tasks, and odd jobs. One resumed working. Family members considered that both thinking and physical efforts improved in the treated HD patients. Patients 1 and 2 recovered evoked bilateral N20 waves but another patient lost one. The other two patients resumed their previously steady deterioration and showed a greater metabolic decay in both the images of their striata and their worsening clinical behavior. Unfortunately, Bachoud-Levi et al state that the three "improved" HD patients began to slow down motor function as the three years approached their limit. On the whole, however, attention and executive capacity remained and their total improved scores have now lasted for three years. One of the three patients improved after the first one-sided implant, but started to regress slowly five months after the second when a cyst appeared in the left, second-injected putamen. As a pilot study, Bachoud-Levi et al concluded that all together, these somewhat encouraging results may lead to a large-scale multicentered study in a measurably larger cohort.
Freeman and colleagues from The University of South Florida, as well as several other academic institutions, similarly injected normal fetal striatal tissue into the degenerating striatum of seven patients with HD. One of these patients, a 54-year-old man, had received a total of 10 such cell implants into both sides of his striatum 18 months before he suddenly died from chronic heart disease. Autopsy disclosed three transplants in the right putamen and two in the left putamen. The implants were calculated as providing 9.8% of the total remaining left putamen and 7.6% on the right. All grafts were interpreted as being functional by neuronal markers, namely the normal huntingtin protein that possesses less than 35-37 CAG repeats. Normal cell protein-associated immunostained cells appeared in both graft tissues, with minimal abnormal huntingtin identified in the transplants. The findings indicate that human fetal tissue, which arises from striatal primordia, can withstand functional transplantation into an abnormal putamen for at least 18 months. Inflammation was not found in the post-mortem samples and a number of natural markers that imply functional pre-mortem activity were identified.
In addition, both Bachoud-Levi et al and Freeman et al reported additional clinical effects of fetal transplants into patients with HD. These both appear in abstract form in the AAN Program book for 2000 on page A 153 and theie contents are referred to in the next paragraph.
Guara and colleagues report PET/MRI values in the five patients described previously by Bachoud-Levi et al. Patient 1 was clinically improved and CMR glu increased in both striata one year after fetal neuroblasts implantation. Patients 2 and 3 showed right striatal CMR glu increases from + 0 to 22% one year after the right graft but only -11 to 4% on the left. Patient 4 at first improved but then declined and patient 5 had no benefit from the graft.
Hauser and colleagues report on pilot evaluation of human fetal striatal transplantation in HD. They indicated that they transplanted seven patients with staged fetal striatal grafts ranging from 2-8 implants per side. All patients received cyclosporine for two weeks before and six months after the surgery. Five patients had undergone at least nine months after transplantation. Two of the nine developed subdural hematomas (SDH) following implantation and necessitated drainage. Despite evacuation, one of the two failed to return to cognitive baseline. One patient’s condition worsened from bilateral SDH, but four patients who reached one year after implantations had improved their Unified Huntington’s Disease Rating Scale means from 34.5 to 27.8. The lower basemark reflects improvement.
Commentary
These four reports from two high-quality neurological centers provide great hope for future striatal gene generation in HD. However, Bachoud-Levi et al only had a three-year follow-up and Freeman et al reported a small average of improvement over more than a year. Hints of developing larger groups of patients with human fetal transplants and still-delicate neurosurgical proceedings have been suggested. As things go presently, evidence to date indicates that sustained improvement may decline after three postsurgical years. Strong improvement has not occurred much longer than two years after the present initial implantation. Hopefully, the experimenters will become able to improve longer than three years in length with an incidence rate of successful transgenesis of at least 80%. — Fred Plum
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