Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2002 Dec;73(6):678–685. doi: 10.1136/jnnp.73.6.678

Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475

A Rosser 1, R Barker 1, T Harrower 1, C Watts 1, M Farrington 1, A Ho 1, R Burnstein 1, D Menon 1, J Gillard 1, J Pickard 1, S Dunnett 1
PMCID: PMC1757375  PMID: 12438470

Abstract

Objectives: Huntington's disease (HD) is an inherited autosomal dominant condition in which there is a CAG repeat expansion in the huntingtin gene of 36 or more. Patients display progressive motor, cognitive, and behavioural deterioration associated with progressive cell loss and atrophy in the striatum. Currently there are no disease modifying treatments and current symptomatic treatments are only partially effective in the early to moderate stages. Neural transplantation is effective in animal models of HD and offers a potential strategy for brain repair in patients. The authors report a safety study of unilateral transplantation of human fetal striatal tissue into the striatum of four patients with HD.

Subjects and methods: Stereotaxic placements of cell suspensions of human fetal ganglionic eminence were made unilaterally into the striatum of four patients with early to moderate HD. All patients received immunotherapy with cyclosporin A, azathioprine, and prednisolone for at least six months postoperatively. Patients were assessed for safety of the procedure using magnetic resonance imaging (MRI), regular recording of serum biochemistry and haematology to monitor immunotherapy, and clinical assessment according to the Core Assessment Protocol For Intrastriatal Transplantation in HD (CAPIT-HD).

Results: During the six month post-transplantation period, the only adverse events related to the procedure were associated with the immunotherapy. MRI demonstrated tissue at the site of implantation, but there was no sign of tissue overgrowth. Furthermore, there was no evidence that the procedure accelerated the course of the disease.

Conclusions: Unilateral transplantation of human fetal striatal tissue in patients with HD is safe and feasible. Assessment of efficacy will require longer follow up in a larger number of patients.

Full Text

The Full Text of this article is available as a PDF (258.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aronin N., Kim M., Laforet G., DiFiglia M. Are there multiple pathways in the pathogenesis of Huntington's disease? Philos Trans R Soc Lond B Biol Sci. 1999 Jun 29;354(1386):995–1003. doi: 10.1098/rstb.1999.0451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bachoud-Lévi A. C., Rémy P., Nguyen J. P., Brugières P., Lefaucheur J. P., Bourdet C., Baudic S., Gaura V., Maison P., Haddad B. Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet. 2000 Dec 9;356(9246):1975–1979. doi: 10.1016/s0140-6736(00)03310-9. [DOI] [PubMed] [Google Scholar]
  3. Bachoud-Lévi A., Bourdet C., Brugières P., Nguyen J. P., Grandmougin T., Haddad B., Jény R., Bartolomeo P., Boissé M. F., Barba G. D. Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington's disease. Exp Neurol. 2000 Jan;161(1):194–202. doi: 10.1006/exnr.1999.7239. [DOI] [PubMed] [Google Scholar]
  4. Brasted P. J., Watts C., Torres E. M., Robbins T. W., Dunnett S. B. Behavioural recovery following striatal transplantation: effects of postoperative training and P-zone volume. Exp Brain Res. 1999 Oct;128(4):535–538. doi: 10.1007/s002210050877. [DOI] [PubMed] [Google Scholar]
  5. Dekkers W., Boer G. Sham neurosurgery in patients with Parkinson's disease: is it morally acceptable? J Med Ethics. 2001 Jun;27(3):151–156. doi: 10.1136/jme.27.3.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dunnett S. B., Björklund A., Lindvall O. Cell therapy in Parkinson's disease - stop or go? Nat Rev Neurosci. 2001 May;2(5):365–369. doi: 10.1038/35072572. [DOI] [PubMed] [Google Scholar]
  7. Folkerth R. D., Durso R. Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts. Neurology. 1996 May;46(5):1219–1225. doi: 10.1212/wnl.46.5.1219. [DOI] [PubMed] [Google Scholar]
  8. Freed C. R., Greene P. E., Breeze R. E., Tsai W. Y., DuMouchel W., Kao R., Dillon S., Winfield H., Culver S., Trojanowski J. Q. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 2001 Mar 8;344(10):710–719. doi: 10.1056/NEJM200103083441002. [DOI] [PubMed] [Google Scholar]
  9. Freeman T. B., Cicchetti F., Hauser R. A., Deacon T. W., Li X. J., Hersch S. M., Nauert G. M., Sanberg P. R., Kordower J. H., Saporta S. Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13877–13882. doi: 10.1073/pnas.97.25.13877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Freeman T. B., Hauser R. A., Sanberg P. R., Saporta S. Neural transplantation for the treatment of Huntington's disease. Prog Brain Res. 2000;127:405–411. doi: 10.1016/s0079-6123(00)27019-2. [DOI] [PubMed] [Google Scholar]
  11. Grasbon-Frodl E. M., Nakao N., Lindvall O., Brundin P. Phenotypic development of the human embryonic striatal primordium: a study of cultured and grafted neurons from the lateral and medial ganglionic eminences. Neuroscience. 1996 Jul;73(1):171–183. doi: 10.1016/0306-4522(96)00008-5. [DOI] [PubMed] [Google Scholar]
  12. Gutekunst C. A., Norflus F., Hersch S. M. Recent advances in Huntington's disease. Curr Opin Neurol. 2000 Aug;13(4):445–450. doi: 10.1097/00019052-200008000-00013. [DOI] [PubMed] [Google Scholar]
  13. Hauser R. A., Furtado S., Cimino C. R., Delgado H., Eichler S., Schwartz S., Scott D., Nauert G. M., Soety E., Sossi V. Bilateral human fetal striatal transplantation in Huntington's disease. Neurology. 2002 Mar 12;58(5):687–695. doi: 10.1212/wnl.58.5.687. [DOI] [PubMed] [Google Scholar]
  14. Ho L. W., Carmichael J., Swartz J., Wyttenbach A., Rankin J., Rubinsztein D. C. The molecular biology of Huntington's disease. Psychol Med. 2001 Jan;31(1):3–14. doi: 10.1017/s0033291799002871. [DOI] [PubMed] [Google Scholar]
  15. Hurelbrink C. B., Armstrong R. J., Barker R. A., Dunnett S. B., Rosser A. E. Hibernated human fetal striatal tissue: successful transplantation in a rat model of Huntington's disease. Cell Transplant. 2000 Nov-Dec;9(6):743–749. doi: 10.1177/096368970000900601. [DOI] [PubMed] [Google Scholar]
  16. Kendall A. L., Hantraye P., Palfi S. Striatal tissue transplantation in non-human primates. Prog Brain Res. 2000;127:381–404. doi: 10.1016/s0079-6123(00)27018-0. [DOI] [PubMed] [Google Scholar]
  17. Kendall A. L., Rayment F. D., Torres E. M., Baker H. F., Ridley R. M., Dunnett S. B. Functional integration of striatal allografts in a primate model of Huntington's disease. Nat Med. 1998 Jun;4(6):727–729. doi: 10.1038/nm0698-727. [DOI] [PubMed] [Google Scholar]
  18. Kieburtz K. Antiglutamate therapies in Huntington's disease. J Neural Transm Suppl. 1999;55:97–102. doi: 10.1007/978-3-7091-6369-6_9. [DOI] [PubMed] [Google Scholar]
  19. Kopyov O. V., Jacques S., Lieberman A., Duma C. M., Eagle K. S. Safety of intrastriatal neurotransplantation for Huntington's disease patients. Exp Neurol. 1998 Jan;149(1):97–108. doi: 10.1006/exnr.1997.6685. [DOI] [PubMed] [Google Scholar]
  20. Kordower J. H., Freeman T. B., Snow B. J., Vingerhoets F. J., Mufson E. J., Sanberg P. R., Hauser R. A., Smith D. A., Nauert G. M., Perl D. P. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med. 1995 Apr 27;332(17):1118–1124. doi: 10.1056/NEJM199504273321702. [DOI] [PubMed] [Google Scholar]
  21. Langston J. W., Widner H., Goetz C. G., Brooks D., Fahn S., Freeman T., Watts R. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord. 1992;7(1):2–13. doi: 10.1002/mds.870070103. [DOI] [PubMed] [Google Scholar]
  22. Lawrence A. D., Hodges J. R., Rosser A. E., Kershaw A., ffrench-Constant C., Rubinsztein D. C., Robbins T. W., Sahakian B. J. Evidence for specific cognitive deficits in preclinical Huntington's disease. Brain. 1998 Jul;121(Pt 7):1329–1341. doi: 10.1093/brain/121.7.1329. [DOI] [PubMed] [Google Scholar]
  23. Li X. J. The early cellular pathology of Huntington's disease. Mol Neurobiol. 1999 Oct-Dec;20(2-3):111–124. doi: 10.1007/BF02742437. [DOI] [PubMed] [Google Scholar]
  24. Lindvall O. Neural transplantation: a hope for patients with Parkinson's disease. Neuroreport. 1997 Sep 29;8(14):iii–x. doi: 10.1097/00001756-199709290-00036. [DOI] [PubMed] [Google Scholar]
  25. Lindvall O., Widner H., Rehncrona S., Brundin P., Odin P., Gustavii B., Frackowiak R., Leenders K. L., Sawle G., Rothwell J. C. Transplantation of fetal dopamine neurons in Parkinson's disease: one-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol. 1992 Feb;31(2):155–165. doi: 10.1002/ana.410310206. [DOI] [PubMed] [Google Scholar]
  26. Lunkes A., Trottier Y., Mandel J. L. Pathological mechanisms in Huntington's disease and other polyglutamine expansion diseases. Essays Biochem. 1998;33:149–163. doi: 10.1042/bse0330149. [DOI] [PubMed] [Google Scholar]
  27. Macklin R. The ethical problems with sham surgery in clinical research. N Engl J Med. 1999 Sep 23;341(13):992–996. doi: 10.1056/NEJM199909233411312. [DOI] [PubMed] [Google Scholar]
  28. Palfi S., Condé F., Riche D., Brouillet E., Dautry C., Mittoux V., Chibois A., Peschanski M., Hantraye P. Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease. Nat Med. 1998 Aug;4(8):963–966. doi: 10.1038/nm0898-963. [DOI] [PubMed] [Google Scholar]
  29. Peschanski M., Cesaro P., Hantraye P. Rationale for intrastriatal grafting of striatal neuroblasts in patients with Huntington's disease. Neuroscience. 1995 Sep;68(2):273–285. doi: 10.1016/0306-4522(95)00162-c. [DOI] [PubMed] [Google Scholar]
  30. Peschanski M., Defer G., N'Guyen J. P., Ricolfi F., Monfort J. C., Remy P., Geny C., Samson Y., Hantraye P., Jeny R. Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain. 1994 Jun;117(Pt 3):487–499. doi: 10.1093/brain/117.3.487. [DOI] [PubMed] [Google Scholar]
  31. Peschanski M. Le traitement de maladies neurod¿eg¿en¿eratives. Pathol Biol (Paris) 2000 May;48(4):447–448. [PubMed] [Google Scholar]
  32. Quinn N., Brown R., Craufurd D., Goldman S., Hodges J., Kieburtz K., Lindvall O., MacMillan J., Roos R. Core Assessment Program for Intracerebral Transplantation in Huntington's Disease (CAPIT-HD). Mov Disord. 1996 Mar;11(2):143–150. doi: 10.1002/mds.870110205. [DOI] [PubMed] [Google Scholar]
  33. Ross B. D., Hoang T. Q., Blüml S., Dubowitz D., Kopyov O. V., Jacques D. B., Lin A., Seymour K., Tan J. In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR Biomed. 1999 Jun;12(4):221–236. doi: 10.1002/(sici)1099-1492(199906)12:4<221::aid-nbm582>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  34. Ulrisch R., Jacques S., Kopyov O. Neural transplantation. J Neurosurg. 2000 Jul;93(1):163–164. doi: 10.3171/jns.2000.93.1.0163. [DOI] [PubMed] [Google Scholar]
  35. Vonsattel J. P., Myers R. H., Stevens T. J., Ferrante R. J., Bird E. D., Richardson E. P., Jr Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985 Nov;44(6):559–577. doi: 10.1097/00005072-198511000-00003. [DOI] [PubMed] [Google Scholar]
  36. Wictorin K. Anatomy and connectivity of intrastriatal striatal transplants. Prog Neurobiol. 1992 Jun;38(6):611–639. doi: 10.1016/0301-0082(92)90044-f. [DOI] [PubMed] [Google Scholar]
  37. Widner H., Tetrud J., Rehncrona S., Snow B., Brundin P., Gustavii B., Björklund A., Lindvall O., Langston J. W. 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 Nov 26;327(22):1556–1563. doi: 10.1056/NEJM199211263272203. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES