Correspondence
Fetal-Tissue Transplantation for Parkinson's Disease
N Engl J Med 1993; 329:1498-1500November 11, 1993
- Article
To the Editor:
In their reports of the transplantation of fetal tissue in advanced Parkinson's disease (Nov. 26, 1992, issue), Spencer et al.1 and Freed et al.2 did not compare their results with those for adrenal transplantation. A detailed comparison cannot be made without a randomized, prospective trial, but patients receiving fetal transplants and those in the United Parkinson Foundation Registry on adrenal medullary transplantation3 had similar levels of function at base line, and both groups were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS).
Adrenal transplantation was associated with more frequent and severe morbidity and longer hospital stays (mean, 42.75 days vs. approximately 72 hours) than fetal-tissue transplantation. The mortality rate at one year was 6.5 percent after adrenal surgery. In survivors, however, the pattern and extent of improvement after adrenal surgery was quite close to that described in the recent reports of fetal-tissue transplantation. The lengths of “on” periods increased and functional improvements, primarily in the “off” periods, occurred with adrenal surgery and persisted for some measures after two years. Quantitatively, the adrenal registry data also fit quite closely those reported by Freed et al.,2 although the data must be extracted from the graphs since numerical data were not provided in the article. After adrenal transplantation, patients had a mean improvement of 6 points in both the UPDRS Activities of Daily Living scores and the Motor scores during on periods at one year, as compared with respective changes of 6 and 4 points after fetal-tissue transplantation. In the former group, we considered these changes modest. After adrenal transplantation, the dose of levodopa could not be reduced, whereas it could after fetal-tissue transplantation. Thus, the data suggest that fetal-tissue transplantation is safe, and its efficacy basically equals or exceeds that of adrenal transplantation.
3 ReferencesChristopher G. Goetz, M.D.
Richard D. Penn, M.D.
Harold L. Klawans, M.D.
Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 606121
Spencer DD ,Robbins RJ ,Naftolin F , et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N Engl J Med 1992;327:1541-1548
Full Text | Web of Science | Medline2
Freed CR ,Breeze RE ,Rosenberg NL , et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 1992;327:1549-1555
Full Text | Web of Science | Medline3
Goetz CG ,Stebbins GT III ,Klawans HL , et al. United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up. Neurology 1991;41:1719-1722
Web of Science | Medline
To the Editor:
What is remarkable and disturbing about the Sounding Board by Garry et al. (Nov. 26, 1992, issue)1 on alternatives to the use of fetal tissue from elective abortion in transplantation research is the lack of any discussion of the objections to the use of such tissue for research. My concern is that this could well be the first step toward the commercial use of fetal tissue for tissue and organ donation -- a change that could eventually lead to situations in which conception takes place expressly to produce a fetus for eventual abortion for use in tissue or organ donation, perhaps for pay, perhaps for a source of histocompatible tissue. Many may well find this morally abhorrent, even those of us who do not necessarily favor a very restrictive abortion policy. Any proposal to use electively aborted fetal tissue for any purpose should include guidelines on how to avoid this sort of abuse.
1 ReferencesJohn E. Van Gilder, M.D.
Zanesville Cardiology, Zanesville, OH 437011
Garry DJ ,Caplan AL ,Vawter DE ,Kearney W . Are there really alternatives to the use of fetal tissue from elective abortions in transplantation research? N Engl J Med 1992;327:1592-1595
Full Text | Web of Science | Medline
To the Editor:
Garry et al. discussed alternatives to the use of fetal tissue from elective abortions in transplantation research. They did not consider the use of tissues from ectopic pregnancies, spontaneous abortions, or stillbirths to be a practical alternative. They were more optimistic about the use of extraembryonic tissues. They stated, “Although placental tissue cannot provide fetal islet or neuronal cells, it can be used to develop certain cell lines that might conceivably be engineered genetically to produce insulin or neurotransmitters such as dopamine.” If placental tissue could be altered to produce insulin, one advantage might be the large volume of trophoblastic tissue available for transplantation.
Genetically modified trophoblastic tissue may become available, but unmodified trophoblastic tissue may be able to supply the substances needed for many conditions. For the treatment of Gaucher's disease, Figueroa et al.1 discussed a less expensive regimen of alglucerase, a modified form of the enzyme beta-glucocerebrosidase, “the world's most expensive drug.” Since alglucerase is extracted from human placental tissue,2 transplanted placental tissue might supply this enzyme. Patients with other storage diseases and other deficiencies may also be candidates for placental-tissue transplantation. For patients who have symptomatic deficiencies of antithrombin III, protein C, protein S, and other proteins associated with hypercoagulability, transplanted placental tissue might provide a consistent supply of several anticoagulants3.
Apart from familiar steroid hormones and protein gonadotropic hormones, the placenta also produces hypothalamic-like control substances, atrial natriuretic peptide, enkephalins, dynorphin, growth hormone variant, growth factors, prostanoids, leukotrienes, parathyroid hormone-related protein, calbindin, osteopontin, 1,25-dihydroxyvitamin D, dozens of molecules not fully analyzed, and still others yet to be discovered4. Wasmoen5 has said, “In many ways, the characterization of placental proteins is still in its infancy.”
5 ReferencesChristopher H.K. Fung, M.D.
James W. Lo, M.D.
Mercy Hospital and Medical Center, Chicago, IL 606161
Figueroa ML ,Rosenbloom BE ,Kay AC , et al. A less costly regimen of alglucerase to treat Gaucher's disease. N Engl J Med 1992;327:1632-1636
Full Text | Web of Science | Medline2
Barton NW ,Furbish FS ,Murray GJ ,Garfield M ,Brady RO . Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci U S A 1990;87:1913-1916
CrossRef | Web of Science | Medline3
Uszynski M . Tissue anticoagulants in the human placenta: preliminary study with a heparin-like anticoagulant and review of the literature. Gynecol Obstet Invest 1991;32:129-133
CrossRef | Web of Science | Medline4
Siler-Khodr TM. Endocrine and paracrine function of the human placenta. In: Polin RA, Fox WW, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders, 1992:74-85.
5
Wasmoen TL. Placental proteins. In: Polin RA, Fox WW, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders, 1992:87-95.
Author/Editor Response
The authors reply:
To the Editor: We agree with Goetz et al. that a randomized, prospective trial of fetal and adrenal transplants for Parkinson's disease is the definitive way of deciding comparative efficacy and is more acceptable to patients and the public than a sham surgical procedure. However, the attendant morbidity of the adrenal procedure and dubious cell survival may preclude large clinical trials. In the studies of fetal-tissue transplantation published so far, different evaluation and reporting standards may have obscured other interesting comparisons. Although Goetz et al. appear correct regarding the magnitude of change reported by Freed et al.,1 we would add that our control subjects also showed similar degrees of improvement at one year (mean scores of 9.6 and 7.5 on the same UPDRS Activities of Daily Living and Motor scales). Our three transplant recipients had even more of an improvement (mean scores of 16.3 and 9.5, respectively) while receiving reduced doses of medication. With more objective measures of motor-task performance, our controls did not show improvement, but the transplant recipients did. We noted elsewhere2 that our patients who received fetal-tissue transplants had considerably more improvement 18 months after surgery than patients who had undergone adrenal transplantation3. We chose 18 months as the minimal period of follow-up on which to report because most of the earlier improvement in the adrenal recipients had been lost by that time3. Since comparisons of the extent of improvement are also being used to support the use of various tissue-preparation techniques and implantation sites,1,4 it is worth noting that our transplant recipients were rated as being more severely impaired (the UPDRS total score during the best on period) before surgery than the two transplant recipients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine who were described by Widner et al. (Nov. 26, 1992, issue),4 but as showing as much improvement (improvements in the UPDRS score of 20, 35, and 24 in our patients vs. 53 and 21 in theirs, and similar increases in the only comparable measure of motor-task performance, the supination-pronation test). The adoption of tightly controlled outcome measures and identical reporting methods for long-term follow-up will facilitate the comparisons necessary to arrive at standard techniques for selecting fetal-tissue age, volume, and storage; immunosuppression; duration of illness; specificity of disease; and appropriate drug treatments for larger controlled, multicenter studies to judge whether these treatments will be safe and clinically useful.
4 ReferencesDennis D. Spencer, M.D.
Kenneth L. Marek, M.D.
D. Eugene Redmond, Jr., M.D.
Yale University School of Medicine, New Haven, CT 06510-80681
Freed CR ,Breeze RE ,Rosenberg NL , et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 1992;327:1549-1555
Full Text | Web of Science | Medline2
Redmond DE Jr, Robbins RJ, Naftolin F, et al. Cellular replacement of dopamine deficit in Parkinson's disease using human fetal mesencephalic tissue: preliminary results in four patients. In: Waxman SG, ed. Molecular and cellular approaches to the treatment of neurological disease. Research publications: Association for Research in Nervous and Mental Disease. Vol. 71. New York: Raven Press, 1993:325-59.
3
Olanow CW ,Koller W ,Goetz CG , et al. Autologous transplantation of adrenal medulla in Parkinson's disease: 18-month results. Arch Neurol 1990;47:1286-1289
Web of Science | Medline4
Widner H ,Tetrud J ,Rehncrona S , et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992;327:1556-1563
Full Text | Web of Science | Medline
Author/Editor Response
As Goetz et al. note, autografts of adrenal medulla to the brain of patients with Parkinson's disease produce only modest clinical benefit and have unacceptable morbidity and mortality. Only 19 percent of patients had sustained improvement two years after surgery. Since 18 percent of patients died during this time, half as a consequence of surgery, the risk-benefit ratio was unsatisfactory1. By contrast, we have provided evidence that patients with fetal-dopamine-cell implants may have improvements that last at least four years (our Patient 1), perhaps as a consequence of the continued outgrowth of nerve fibers from the transplant into host brain.
The improvement in our patients has ranged from slight to very substantial. After surgery, some patients appear clinically normal in their best on state. Nearly all patients require reduced doses of levodopa. Modifications in technique may enhance results. Preliminary findings show that immunosuppression with cyclosporine and prednisone compromises the effect of transplantation. If further study bears this out, eliminating these drugs will reduce long-term morbidity and cost. We have pioneered the widespread distribution of fetal tissue in the caudate and putamen and have shown that simultaneous bilateral implantation into the putamen can be safely performed. Improving graft survival and providing tissue more highly enriched in dopamine cells will probably lead to a better clinical outcome.
Still uncertain is the amount of fetal tissue needed for optimal benefit. Tissue from a single fetus was used in six of our seven patients. Widner et al. used tissue from six to eight embryos. The extent of improvement in the off state in their two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was 1 point on the Hoehn-Yahr scale (4 to 3), about the same as the average response in our group of seven patients (from 3.71 to 2.5, P<0.01). We have seen improvement beginning 6 to 12 weeks after surgery, as predicted from primate studies,2 whereas improvement in their patients was delayed for 6 months to 1 year. It is possible that they put too much tissue into the brain, creating a lesion effect as described in animals3. Their results may represent a combination of a negative lesion effect and a positive effect of dopamine-fiber outgrowth, with a balance shifting in favor of the dopamine effect only at one year.
Studies in animals have provided the rich base needed for the rational design of experiments with fetal-tissue transplantation in humans. With the demonstration that such procedures can be undertaken safely in humans, we can now perfect this therapy in expanded clinical trials.
3 ReferencesCurt R. Freed, M.D.
Robert E. Breeze, M.D.
Neil L. Rosenberg, M.D.
University of Colorado School of Medicine, Denver, CO 802621
Goetz CG ,Stebbins GT III ,Klawans HL , et al. United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up. Neurology 1991;41:1719-1722
Web of Science | Medline2
Bankiewicz KS ,Plunkett RJ ,Jacobowitz DM , et al. The effect of fetal mesencephalon implants on primate MPTP-induced parkinsonism: histochemical and behavioral studies. J Neurosurg 1990;72:231-244
CrossRef | Web of Science | Medline3
Lu SY ,Giordano M ,Norman AB ,Shipley MT ,Sandberg PR . Behavioral effects of neural transplants into the intact striatum. Pharmacol Biochem Behav 1990;37:135-148
CrossRef | Web of Science | Medline
Author/Editor Response
The concern expressed by Dr. Van Gilder regarding the need for guidelines for the use of fetal tissue from elective abortions in research and transplantation is important. However, the goal of our paper was a critical review of the feasibility of using fetal tissue from other sources for the purposes of transplantation. The decision by the National Institutes of Health to allocate millions of dollars for grants aimed at investigating the feasibility of procuring and banking tissue obtained from sources other than elective abortions seems to us to be inconsistent with the requirements of research on fetal-tissue transplantation1.
Since the publication of our article, President Clinton has rescinded the executive ban on funding research using tissue from electively aborted fetuses for transplantation. This decision makes the issue raised by Dr. Van Gilder especially timely.
It is important to note that the National Organ Transplant Act was amended by Congress in 1988 to prohibit the buying and selling of fetal tissue. More stringent guidelines have been proposed legislatively through bills in the U.S. House (H.R. 2507) and Senate (S. 1523). We have suggested additional guidelines for using human fetal tissue in basic-science research and clinical transplantation2-4.
The research described by Drs. Fung and Lo involving the transplantation of extraembryonic tissue confirms the optimism we expressed in our article about the prospects for advances in this area.
4 ReferencesDaniel J. Garry, M.D., Ph.D.
Arthur L. Caplan, Ph.D.
University of Minnesota, Minneapolis, MN 554551
Thompson L . Fetal transplants show promise. Science 1992;257:868, 870-868, 870
Web of Science2
Vawter DE, Kearney W, Gervais KG, Caplan AL, Garry D, Tauer C. The use of human fetal tissue: scientific, ethical, and policy concerns. Minneapolis: University of Minnesota, 1990.
3
Vawter DE ,Caplan AL . Strange brew: the politics and ethics of fetal tissue transplant research in the United States. Lab Clin Med 1992;120:30-34
Medline4
Kearney W ,Vawter DE ,Gervais KG . Fetal tissue research and the misread compromise. Hastings Cent Rep 1991;21:7-12
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Adam N. Mamelak, Faye A. Eggerding, Daniel S. Oh, Erika Wilson, Richard L. Davis, Richard Spitzer, Jefferey A. Hay, William L. Caton. (1998) Fatal cyst formation after fetal mesencephalic allograft transplant for Parkinson's disease. Journal of Neurosurgery 89:4, 592-598
CrossRef
