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Thread: fetal stem cell transplants

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    Senior Member giambjj's Avatar
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    See Max's topic entitled "Treatment Setback for Parkinson's Patients" for the news article based on this Nature news comment on a study published in the Annals of Neurology.

    Other previously posted topics on the subject include:
    Neural Jun 20, 2003 - Transplantation for Parkinson's Disease: the Challenge
    Apr 17, 2002 - Fetal Cell Transplant Shows Promise for Parkinson's
    Apr 24, 2002 - Research benefitting Parkinsons

    This Nature commentary is quite negative and quoted a statement from the lead author (Warren Olanow from Mt. Sinai School of Medicine) saying "Unless we resolve this, it will have a tremendous negative impact on stem-cell research". The lead paragraph of the commentary said "the average condition of the 23 patients who received the treatment did not improve significantly compared with a group of 11 who did not have it".

    I think that it is very important that we take a look at the original paper rather than take the word of the commentators, given that use of fetal transplants is very controversial.

    The abstract of the Olanow, et al. study is listed below. Basically, they randomized 34 patients to a one-donor fetal nigral neuronal transplant, a four-donor transplant, or placebo. This is a placebo controlled trial with a small number of patients. They score the patients on the Unified Parkinson's Disease Rating Scale, comparing the difference of scores before and at 24 months after the procedure. Patients in the placebo group deteriorated by 9.4±4.25 points, while those that received a one-donor transplant deteriorated by 3.5±4.23 and those that received a four-donor transplant improved by 0.72±4.05. The patients that received the four donor transplant were significantly better than those that received placebo. When the investigators stratified the patients by severity of disease, they found that patients with less severe disease improved more from the transplant. However, 56% of the transplanted patients developed dyskinesias (abnormal movements). The authors did not recommend this treatment based on these results.

    It is true that if you combine the one-donor and the four-donor groups, there was no overall difference between transplanted and placebo group (p=0.244). However, if one compared the four-donor transplants and placebo, the results were nearly significant (p=0.096). Finally, if they stratified the patients by severity of disease, it showed a highly significant treatment effect of p=0.006.

    In my opinion, this study commits a scientific faux pas by concluding that the treatment is ineffective when their data, based on relatively few patients divided into too many groups, showed a strong trend for significant effects particularly in higher doses and in less severe cases. Instead of concluding that the treatment was ineffective, they should perhaps have concluded that the study was inconclusive but showed that the next clinical trial should be carried out in patients with less severe Parkinson's disease and that they should use the four-donor transplant instead of one-donor transplant. The high incidence of dyskinesias, however, is worrisome.

    References

    A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease
    C. Warren Olanow, MD 1 *, Christopher G. Goetz, MD 2, Jeffrey H. Kordower, PhD 2, A. Jon Stoessl, MD 3, Vesna Sossi, PhD 3, Mitchell F. Brin, MD 1, Kathleen M. Shannon, MD 2, G. Michael Nauert, MD 4, Daniel P. Perl, MD 5, James Godbold, PhD 6, Thomas B. Freeman, MD 4
    1Department of Neurology, Mount Sinai School of Medicine, New York, NY
    2Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, IL
    3Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
    4Department of Neurosurgery, University of South Florida, Tampa, FL
    5Department of Pathology, Mount Sinai School of Medicine, New York, NY
    6Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY
    email: C. Warren Olanow (warren.olanow@mssm.edu)

    *Correspondence to C. Warren Olanow, Department of Neurology, Box 1137, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029
    For a list of contributors to this study, see the Appendix on page 413.

    Funded by:
    National Institutes of Health; Grant Number: NS32842
    Bendheim Parkinson's Disease Center
    Bachman Strauss Dystonia and Parkinson Foundation

    Abstract
    Thirty-four patients with advanced Parkinson's disease participated in a prospective 24-month double-blind, placebo-controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinson's Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one-donor groups deteriorated by 9.4 ± 4.25 and 3.5 ± 4.23 points, respectively, whereas those in the four-donor group improved by 0.72 ± 4.05 points. Pairwise comparisons were not significant, although the four-donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty-six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication (off-medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.Ann Neurol 2003;54:403-414

    [This message was edited by Wise Young on 09-02-03 at 03:02 AM.]

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