HD Transplantation Project
Clinical trials of cells transplantation in Huntington's disease
Huntington's disease is an inherited neurodegenerative disease of the brain. People carrying a single copy of the mutant gene will, with high probability, develop the disease in middle life, and will pass it on to 50% of their children.
The disease causes a mixture of symptoms involving a movement disorder (chorea and dyskinesia), cognitive problems (a type of dementia) and behavioural problems (including rapid mood changes, eating disorders and depression).
The disease progresses over approximately 15 -20 years from diagnosis to death.
The disease is due to degeneration of particular nuclei in the forebrain (the striatum) that control movements and selection of action. This pattern of degeneration is now known to be caused by a specific mutation (an expanded trinucleotide repeat) in a gene on chromosome 4.
The gene encodes a protein (known as huntingtin), although the normal function of this protein is still completely unknown. However, now that the genetic basis of the disease has been identified, tests are now available that allow accurate diagnosis, providing the basis for guidance and more informed decision in matters such as family planning.
No effective treatment is yet available, either pharmacological or surgical.
Experimental studies in animal models of Huntington's disease (see the associated Striatal project) have shown that transplants of embryonic striatal cells can survive, repair the striatal damage, and alleviate both motor and cognitive deficits in rats.
Based on the success of these experimental studies of models of Huntington's disease in animals, and of the recent trials of neuronal grafts in Parkinson's disease, many groups of scientists and clinicians are now considering whether a similar transplantation approach can be effective for surgical treatment of the damage in patients with Huntington's disease.
European trials of clinical transplantation in Huntington's disease are being set up as a collaboration between all research and clinical groups active in this area, coordinated by the European Network for Striatal Transplantation in Huntington's Disease (NEST-HD), under the auspices of the wider NECTAR network that has co-ordinated the effective European trials of clinical transplantation in Parkinson's disease
In preparation for clinical application the following experimental studies have been undertaken and are ongoing:
· Identification of optimal sources of donor tissue and parameters for graft preparation.
· Demonstration that the cells survive, grow and differentiate appropriately in vitro.
· Demonstration that the grafts alleviate cognitive as well as motor deficits in experimental models.
· Demonstration that the tissue preparations procedures are safe and sterile.
· Determination of the optimum implantation parameters for graft tissues.
· Improved understanding of the immune responses in the brain.
· Development of consensus assessment protocols for longitudinal evaluation of transplanted patients – the Core Assessment Protocol for Intracerebral Transplantation in Huntington’s disease (CAPIT-HD)
Based on these preclinical studies, there are two European trials
of cell transplantation in progress.
The first trial to commence is coordinated by Professor Anne-Cathérine Bachoud-Lévi, Créteil, France.
The French trial has already reported on the Safety, Efficacy and 6-year Follow up.
In the UK, a multicentre trial is coordinated under the auspices of
NEST-UK, comprising 5 centres:
· Cardiff – coordination centre, fetal tissue collection programme, experimental studies, patient assessment;
· Cambridge – surgical centre, fetal tissue collection programme, experimental studies, patient assessment;
· Hammersmith hospital, London – PET imaging;
· Belfast – patient assessment;
· Manchester – patient assessment.
The NEST-UK trial commenced first operations in 2000. We reported on the safety of the procedure based on unilateral transplantation in the first four patients, this study is published in the Journal of Neurology, Neurosurgery & Psychiatry.
By December 2003, 5 patients had received bilateral operations and they are all continuing to be regularly assessed according to the CAPIT-HD protocol. A summary of trial progress can be found here.
In April 2004, the UK adopted the EU Tissue Directive “on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells”. This requires that all cells or tissues donated for human application are processed in pharmaceutical grade facilities. Although our procedures in university laboratories in Cardiff and Cambridge had already been assessed for safety and the programme approved by the local ethical committees, neither lab is compliant with the very high level of environmental control required in the new regulations. As a consequence, further transplant operations in the NEST-UK trial have been suspended pending completion of building works to upgrade the environmental monitoring and control necessary to achieve compliance and accreditation by the MHRA regulatory authority.
It is anticipated that the upgrading of facilities will be completed by end of 2006, allowing the trial to continue to completion. According to the trial protocol, we will only be in a position to report on the effectiveness of the transplant procedures when we have assessed 10 patients over a minimum of 2 years following receiving bilateral implants.
Selected recent publications
- Farrington M, Wreghitt TG, Lever AM, Dunnett SB, Rosser AE, Barker RA (2006) Neural transplantation in Huntington¹s Disease: NEST-UK donor tissue microbiological screening programme and review of the literature. Cell Transplant in press.
- Rosser AE, Barker RA, Armstrong RA, Elneil S, Jain M, Hurelbrink CB, Prentice A, Carne C, Thornton SR, Hutchinson H, Dunnett SB (2003) Staging and preparation of human fetal striatal tissue for UK study of neural transplantation in Huntington's disease. Cell Transplant 12: 679-686.
- Hurelbrink CB, Tyers P, Armstrong RJE, Dunnett SB, Barker RA, Rosser AE (2003) Long-term hibernation of human fetal striatal tissue does not adversely affect its differentiation in vitro or graft survival: implications for clinical trials in Huntington's disease. Cell Transplant 12: 687-695.
- Watts C, Donovan T, Gillard H, Antoun NM, Burnstein R, Menon DK, Carpenter TA, Fryer T, Thomas DGT, Pickard JD (2003) Evaluation of an MRI-based protocol for cell implantation in four patients with Huntington's disease. Cell Transplant 12: 697-704.
- Rosser AE, Barker RA, Guillard J, Harrower T, Watts C, Pickard J, Dunnett SB, the NEST-UK consortium (2002) Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report (ISRCTN no 36485475). J Neurol Neurosurg Psychiat 73: 678-685.
- Rosser AE, Dunnett SB (2006) Cell transplantation for Huntington's disease. Lancet Neurol 6: 284-285.
- Handley O, Naji JJ, Dunnett SB, Rosser AE (2006) Pharmaceutical, cellular and genetic therapies for Huntington's disease. Clin Sci 110: 73-88.
- Dunnett SB, Rosser AE (2004) Cell therapy in Huntington's disease. NeuroRx 1: 394-405.
- Hurelbrink CB, Armstrong RJE, Dunnett SB, Rosser AE, Barker RA (2002) Neural cells from primary human striatal xenografts migrate extensively in the adult rat CNS. Eur J Neurosci 15: 1255-1266.
- Hurelbrink CB, Armstrong RJE, Barker RA, Dunnett SB, Rosser AE (2000) Hibernated human fetal striatal tissue: successful transplantation in a rat model of Huntington's disease. Cell Transplant 9: 743-749.
- Pavese N, Andrews TC, Brooks DJ, Ho AK, Rosser AE, Barker RA, Robbins TW, Sahakian BJ, Dunnett SB, Piccini P (2003) Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study. Brain 126: 1127-1135.
- Ho AK, Brown R, Hodges JR, Ane MN, Snowden JS, Thompson J, Esmonde T, Gentry R, Moore J, Bodner T, Rosser AE, Barker RA, Dunnett SB, Pickard J, the NEST-UK consortium (2003) Profile of cognitive progression in Huntington's disease. Neurology 61: 1702-1706.
- Ho AK, Sahakian BJ, Robbins TW, Barker RA, Rosser AE, Hodges JR (2002) Verbal fluency in Huntington's disease: a longitudinal analysis of phonemic and semantic clustering and switching. Neuropsychologia 40: 1277-1284.
- Berrios GE, Wagle AC, Markova IS, Wagle SA, Ho LW, Rubinsztein DC, Whittaker J, ffrench-Constant C, Kershaw A, Rosser A, Bak T, Hodges JR (2001) Psychiatric symptoms and CAG repeats in neurologically asymptomatic Huntington's disease gene carriers. Psychiat Res 102: 217-225.