Research into potential treatments for Huntington's disease continues worldwide. A recent meeting of the International Society for Neurotransplantation, held in San Diego, CA, examined the most promising avenues of research: gene therapy and neurotransplantation. At this meeting, Dr. Oleg Kopyov of the Neurosciences Institute at the Good Samaritan Hospital, Los Angeles, presented the results of the first trials of transplantation for Huntington's disease patients. The first ten Huntington's patients to receive transplants have now recovered from their surgery for over three months, allowing a more detailed analysis of the transplants' effects. In response to requests for an update on transplantation results, we have prepared a preliminary overview of the data obtained from these follow-up evaluations. Analyses of graft survival and patient outcomes have been submitted for publication in peer-reviewed journals.
While the patients included in the transplantation group were similar in the number of CAG repeats, they varied widely in terms of duration of disease and age, ranging from 24 to 61 years of age at the time of transplantation. The grafts' conditions have been assessed with MR spectroscopy, a method that allows the biochemical content of living neural tissue to be analyzed. MR spectroscopy of the transplant has revealed a biochemical profile that resembles that of developing neural tissue. MR images exhibit regions of heightened signal intensity that is consistent with transplant growth at 5 months following surgery. This growth is confined within the striatum, conforming to the boundaries of striatal tissue.
The patients' motor, behavioral, and functional status were assessed prior to and following transplantation with the Unified Huntington's Disease Rating Scale (UHDRS). According to the UHDRS protocol, patients are evaluated on a series of criteria, and receive a score from 0 (normal) to 4 (incapacitated) for each. Examples of the parameters tested are as follows: Motor UHDRS includes chorea and rigidity in various regions of the body, balance, eye movement, and ability to walk; behavioral UHDRS include frequency and severity of depression, irritability, and disruptive/inappropriate behavior; functional UHDRS includes the patient's ability to perform such tasks as regular or volunteer employment, preparing a meal, navigating in a familiar neighborhood, or moving from one chair to another.
All ten patients have been tested with the UHDRS three months following surgery, while two patients have received a nine month followup assessment and one has been tested one year following surgery. The most uniform results were seen in the area of motor UHDRS, while functional and behavioral UHDRS changes were more varied. Some improvement of motor capacity was observed three months following surgery, which was maintained or increased six and nine months following surgery. Patients showed great variability on functional and behavioral status before as well as following surgery. While there was a slight improvement on behavioral scores three months following surgery, the two patients with longer followup times did not seem to maintain the same level of improvement.
Five of the HD patients have also undergone neuropsychological evaluations six months following their surgery. As with the behavioral and functional subtests of UHDRS, the neuropsychological tests revealed a great deal of variability between the subjects. Statistical analysis of patients' pre- and postoperative scores revealed no significant differences following transplantation, although a test of visual recall did demonstrate a trend toward improvement, with p<0.075. (Standard statistical criteria require p<0.05 for a trend to be considered significant.) As more patients reach this stage of transplantation followup, the variability in scores may be decreased, allowing a determination of whether visual recall is indeed significantly improved.
Finally, the HD patient outcomes were summarized qualitatively, taking into account not only the UHDRS scores, but patients' general abilities to perform activities of daily living as well as their sense of well-being. In this subjective summary, four of the ten patients demonstrated good improvement, meaning that they either improved on their UHDRS scores by over 50%, or they experienced improvements that led to a dramatic change in lifestyle (e.g., recovering the ability to walk unaided). Two of the patients demonstrated moderate improvement, with 30-50% improvements on UHDRS scores, and three of the patients demonstrated only mild improvement of 20-30% on UHDRS scores. One patient was found to have had a cerebral hemorrhage that was removed; that patient has demonstrated no improvement at the three month post-operative followup.
Of the four patients with strong improvement in their HD symptoms, three have only received a three month followup. While their improvement is promising, the possibility remains that it will not persist over time. The mechanisms for such an early improvement are unclear and unprecedented, as no change is usually observed in recipients of neurotransplants for Parkinson's disease for six to nine months following surgery. This delay is considered to reflect the time required for transplanted neurons to mature, extend processes, and establish contact with the host brain. Some potential mechanisms for the improvement observed three months after transplantation in HD patients include: a placebo effect, an unrecognized effect of the mechanical disruption caused to the striatum during surgery, or an effect of soluble factors within the transplanted fetal tissue which diffuse and influence the surviving host tissue. The latter effect may be exerted by supportive neurotrophic proteins within the transplant, or by enzymes and/or neurotransmitters which replenish a depleted supply within the host tissue. This possibility is supported by studies which have shown that transplanted cells contained within a permeable membrane - so that factors within the grafted tissue can cross to the host environment but no connections can be established between graft and host - can improve behavioral symptoms in a primate model of Parkinson's disease. Basic research is underway to determine which of these possible mechanisms may be acting in the transplants for Huntington's disease.
The improvement observed in patient motor capacity following neurotransplantation provides evidence that fetal striatal transplantation can improve the symptoms of HD. While the procedure has potential for treatment of HD in future cases, it has not improved all HD symptoms. The four patients demonstrating strong improvement do demonstrate cognitive and functional improvement as well, however, little is known as to what factors may have led to such strong outcomes in these patients. Prediction of which patients will experience similarly good results is difficult at this time. The ten cases analyzed at this point do demonstrate that fetal transplants do not appear to have negative effects and that they have the potential to significantly improve the lives of HD patients. Extensive further investigation and followup at longer timepoints following the transplantation is required to confirm that the ameliorative effects of the transplantation do not fade. Until the long-term effects of neurotransplantation for Huntington's disease are analyzed in a large pool of patients, the procedure must be considered to be highly experimental.
Converted to HTML by Renette Davis with permission from Carole Hilton, The Neurosciences Institute, Good Samaritan Hospital.
For further information on the transplantation program at Good Samaritan, contact Carole at chilton@GoodSam.Org
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Created: Feb. 28, 1997
Last updated: Dec. 1, 2010