Neurodegenerative Disease Huntington’s Disease
Neural Transplantation for the Treatment of Huntington’s Disease Roger A Barker1
and Rachel A Swain2
1. Reader in Clinical Neuroscience and Honorary Consultant in Neurology, Addenbrooke’s Hospital; 2. Research Assistant, Cambridge Centre for Brain Repair, University of Cambridge
Abstract
Neural transplantation studies where foetal striatal tissue is grafted into the striatum of patients with Huntington’s disease have taken place at several sites worldwide in recent years, following success in rodent models of the disease. Studies have for the most part been safe but have had various degrees of effectiveness. This article looks at the successes and failures of these studies and considers what has been learnt in terms of safety, techniques and methodology. While knowledge of the optimal protocol is advancing, there are still many aspects that need refining, such as immunosuppression and grafting technique. Although advances in this field are hampered by the need for more complete knowledge of the disease itself, the future of neural transplantation has a great deal of potential.
Keywords Huntington’s disease, neural transplantation, striatum
Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors of this review were involved in the The European Network for Striatal Transplantation in Huntington’s Disease (NEST-UK) study by Rosser et al. (for more information see reference 11), with patients receiving long-term follow-up at the Cambridge Centre for Brain Repair from Roger Barker. The authors’ work has been supported by the Medical Research Council and a Biomedical Research Centre award to the University of Cambridge and Addenbrooke’s Hospital. Received: 17 August 2010 Accepted: 22 October 2010 Citation: European Neurological Review, 2010;5(2):41–5 Correspondence: Roger A Barker, Cambridge Centre for Brain Repair, Cambridge, CB2 0PY, UK. E:
rab46@cam.ac.uk
Huntington’s disease (HD) is a progressive neurodegenerative disorder that is inherited and characterised by involuntary movements, psychiatric and cognitive symptoms and signs. It is caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. Patients with 36 or more CAG repeats in this gene develop HD; this abnormal expansion results in the production of mutant huntingtin, which has a toxic gain-of-function leading to the formation of intracellular protein aggregates followed by neuronal dysfunction and death. This occurs at many sites in the central nervous system, but with an early predilection for the striatum and cerebral cortex. The condition is currently incurable and patients typically succumb to the disorder about 20 years after disease onset.1
This fatal outcome,
coupled with the absence of any disease-modifying therapies and focal pathology, at least at disease onset, has made this disorder a target for neural transplantation, with the main target being the striatum. Prior to clinical trials, transplantation of appropriately aged foetal striatal tissue had shown safety and efficacy in rodent and primate models of HD,2–4
albeit in non-transgenic models of disease.
This led to a number of small open-label trials, which are the subject of this article (see Table 1 for a brief summary).
Results of Huntington’s Disease Trials Kopyov et al., Los Angeles5
One of the earliest trials transplanted three moderately advanced patients bilaterally with one-year follow-up using a non-core assessment programme for intracerebral transplantation in HD (CAPIT-HD) protocol. While the authors reported no motor improvement post-grafting, magnetic resonance images (MRIs)
© TOUCH BRIEFINGS 2010 Bachoud-Lévi et al., Creteil9,10
This group carried out first unilateral and then, one year later, contralateral transplants in five patients with HD. Patients have been followed up according to the CAPIT-HD protocol for six years, with some post-mortem data after 10 years. The authors have compared this data with a cohort of 22 non-grafted patients.
Three of the five patients showed clinical improvement, a fourth showed an initial improvement that was lost suddenly after the second graft (due to the development of a putaminal cyst) and a fifth
41
showed evidence of graft survival on average 45 weeks after transplantation.6
Post-mortem studies on two of the patients have now been reported. The two patients died 74 and 79 months after transplantation7
and received transplants along six and eight different tracts through the striatal complex, respectively. At autopsy, 13 of the 14 grafts were identified, with little evidence of integration of the grafted tissue into the host brain. In some cases, aberrant growth of some tissue elements within the transplant was seen. The authors gave several explanations for this, including the possible requirement for a primitive or foetal-like environment for graft maturation and integration, which is therefore compromised in the degenerating HD brain. The authors reported no signs of HD pathology in the grafts.
A third patient had an autopsy 121 months after the intracerebral transplantation. This revealed multiple cysts. The authors attributed this to the presence of a sural nerve cograft, since overgrowth was not observed in any other autopsy study.8
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108