The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease

Roger A Barker, Sarah L Mason, Timothy P Harrower, Rachel A Swain, Aileen K Ho, Barbara J Sahakian, Raj Mathur, Sohier Elneil, Steven Thornton, Carrie Hurrelbrink, Richard J Armstrong, Pam Tyers, Emma Smith, Adrian Carpenter, Paola Piccini, Yen F Tai, David J Brooks, Nicola Pavese, Colin Watts, John D Pickard, Anne E Rosser, Stephen B Dunnett, NEST-UK collaboration, S A Simpson, J Moore, P J Morrison, T F G Esmonde, N Chada, D Craufurd, J Snowdon, J Thompson, P Harper, R Glew, R Harper, Roger A Barker, Sarah L Mason, Timothy P Harrower, Rachel A Swain, Aileen K Ho, Barbara J Sahakian, Raj Mathur, Sohier Elneil, Steven Thornton, Carrie Hurrelbrink, Richard J Armstrong, Pam Tyers, Emma Smith, Adrian Carpenter, Paola Piccini, Yen F Tai, David J Brooks, Nicola Pavese, Colin Watts, John D Pickard, Anne E Rosser, Stephen B Dunnett, NEST-UK collaboration, S A Simpson, J Moore, P J Morrison, T F G Esmonde, N Chada, D Craufurd, J Snowdon, J Thompson, P Harper, R Glew, R Harper

Abstract

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Keywords: Huntington's.

Figures

Figure 1
Figure 1
Annual Unified Huntington's Disease Rating Scale total motor scores from 3 years prior to and up to 10 years following the time of the first transplant surgery in the five patients with grafts, and in the 12 reference control patients synchronised with the stage at which they would have received transplants if the programme had been able to continue. *The first four transplant cases (TP1-4) received serial transplant surgeries on the two sides at times T1 and T2 separated by approximately 2 years, whereas TP5 received a single bilateral surgery at T1. The bold line indicates the best fit linear regression applied to the five transplant cases (solid) and separately to the 12 controls (dashed). Note that the separation between the two lines is fully attributable to the one transplant case TP4, whose Unified Huntington's Disease Rating Scale scores were significantly higher than any other case in the cohort, whereas the slope of the two regression lines, indicating rate of disease progression in the two groups, do not differ.
Figure 2
Figure 2
Mean striatal 11C-raclopride binding potential of subjects 1–4 compared with a group of the non-grafted Huntington’s disease controls (n=7). T1=first implantation (right-sided); T2=second implantation (left-sided); BP, binding potential; R, Right; L, left. Error bars indicates SDs.

References

    1. Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011;10:83–98
    1. Cattaneo E, Rigamonti D, Goffredo D, et al. Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci 2001;24:182–8
    1. Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011;10:31–42
    1. Leegwater-Kim J, Cha JH. The paradigm of Huntington's disease: therapeutic opportunities in neurodegeneration. Neuro Rx 2004;1:128–38
    1. Foroud T, Gray J, Ivashina J, et al. Differences in duration of Huntington's disease based on age at onset. J Neurol Neurosurg Psychiatry 1999;66:52–6
    1. Bachoud-Levi AC, Remy P, Nguyen JP, et al. Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet 2000;356:1975–9
    1. Bachoud-Levi AC, Gaura V, Brugieres P, et al. Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study. Lancet Neurol 2006;5:303–9
    1. Reuter I, Tai YF, Pavese N, et al. Long-term clinical and positron emission tomography outcome of fetal striatal transplantation in Huntington's disease. J Neurol Neurosurg Psychiatry 2008;79:948–51
    1. Furtado S, Sossi V, Hauser RA, et al. Positron emission tomography after fetal transplantation in Huntington's disease. Ann Neurol 2005;58:331–7
    1. Gaura V, Bachoud-Levi AC, Ribeiro MJ, et al. Striatal neural grafting improves cortical metabolism in Huntington's disease patients. Brain 2004;127(Pt 1):65–72
    1. Cicchetti F, Saporta S, Hauser RA, et al. Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration. Proc Natl Acad Sci U S A 2009;106:12483–8
    1. Hauser RA, Furtado S, Cimino CR, et al. Bilateral human fetal striatal transplantation in Huntington's disease. Neurology 2002;58:687–95
    1. Freeman TB, Cicchetti F, Bachoud-Levi AC, et al. Technical factors that influence neural transplant safety in Huntington's disease. Exp Neurol 2011;227:1–9
    1. Wijeyekoon R, Barker RA. The Current Status of Neural Grafting in the Treatment of Huntington's Disease. A Review. Front Integr Neurosci 2011;5:78.
    1. Rosser AE, Barker RA, Harrower T, et al. Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475. J Neurol Neurosurg Psychiatry 2002;73:678–85
    1. Directive 2004/23/EC of 31 March 2004, On setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissue and cells. Official J Eur Union 2004;L102:48–58
    1. Rosser AE, Barker RA, Armstrong RJ, et al. Staging and preparation of human fetal striatal tissue for neural transplantation in Huntington's disease. Cell Transplant 2003;12:679–86
    1. Peschanski M, Cesaro P, Hantraye P. Rationale for intrastriatal grafting of striatal neuroblasts in patients with Huntington's disease. Neuroscience 1995;68:273–85
    1. Peschanski M, Cesaro P, Hantraye P. What is needed versus what would be interesting to know before undertaking neural transplantation in patients with Huntington's disease. Neuroscience 1996;71:899–900
    1. Torres EM, Fricker RA, Hume SP, et al. Assessment of striatal graft viability in the rat in vivo using a small diameter PET scanner. Neuroreport 1995;6:2017–21
    1. Watts C, Dunnett SB. Towards a protocol for the preparation and delivery of striatal tissue for clinical trials of transplantation in Huntington's disease. Cell Transplant 2000;9:223–34
    1. Langston JW, Widner H, Goetz CG, et al. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13
    1. Farrington M, Wreghitt TG, Lever AM, et al. Neural transplantation in Huntington's disease: the NEST-UK donor tissue microbiological screening program and review of the literature. Cell Transplant 2006;15:279–94
    1. Watts C, Donovan T, Gillard JH, et al. Evaluation of an MRI-based protocol for cell implantation in four patients with Huntington's disease. Cell Transplant 2003;12:697–704
    1. Quinn M, Mukhida K, Sadi D, et al. Adjunctive use of the non-ionic surfactant Poloxamer 188 improves fetal dopaminergic cell survival and reinnervation in a neural transplantation strategy for Parkinson's disease. Eur J Neurosci 2008;27:43–52
    1. Huntington Study Group Unified Huntington's sisease rating scale: reliability and consistency. Mov Disord 1996;11:136–42
    1. Michell AW, Goodman AO, Silva AH, et al. Hand tapping: a simple, reproducible, objective marker of motor dysfunction in Huntington's disease. J Neurol 2008;255:1145–52
    1. Sahakian BJ, Owen AM. Computerized assessment in neuropsychiatry using CANTAB: discussion paper. J R Soc Med 1992;85:399–402
    1. Pavese N, Andrews TC, Brooks DJ, et al. Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study. Brain 2003;126(Pt 5):1127–35
    1. Dunnett SB, Nathwani F, Björklund A. The integration and function of striatal grafts. Prog Brain Res 2000;127:345–80
    1. Watts C, McNamara IR, Dunnett SB. Volume and differentiation of striatal grafts in rats: relationship to the number of cells implanted. Cell Transplant 2000;9:65–72
    1. Gallina P, Paganini M, Lombardini L, et al. Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation. Exp Neurol 2010;222:30–41
    1. Keene CD, Chang RC, Leverenz JB, et al. A patient with Huntington's disease and long-surviving fetal neural transplants that developed mass lesions. Acta Neuropathol 2009;117:329–38
    1. Folkerth RD, Durso R. Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts. Neurology 1996;46:1219–15
    1. Boer GJ, Widner H. Clinical neurotransplantation: core assessment protocol rather than sham surgery as control. Brain Res Bull 2002;58:547–53
    1. Ho AK, Sahakian BJ, Brown RG, et al. Profile of cognitive progression in early Huntington's disease. Neurology 2003;61:1702–6
    1. Lawrence AD, Sahakian BJ, Hodges JR, et al. Executive and mnemonic functions in early Huntington's disease. Brain 1996;119(Pt 5):1633–45

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere