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Neural transplantation for Huntington’s disease.

Where next after the recent controversial US study in Parkinson’s disease?

September 2001

The recent publication of a controversial transplant trial using embryonic dopaminergic neurons for treating patients with advanced Parkinson’s disease (PD) has caused a great deal of excitement from the world media, and has dampened the hopes of many who felt that such a transplant approach would be useful for a range of degenerative disorders of the Central Nervous System (CNS) including Huntington’s disease (HD). However in this article I wish to highlight the problems with this study and what impact it has on our current MRC sponsored transplant trial for HD based at Cambridge and a number of other UK centres.

The background to the US study

The use of embryonic dopamine cells as a possible treatment for PD was first pioneered some twenty years ago in a number of animal studies. These studies clearly showed that if the embryonic dopamine cells were harvested at the time of their normal development, then they could survive transplantation into animal models of PD, extend processes and make connections with and from the host brain, release dopamine and have a number of functional benefits to the animal on a variety of behavioural tests. It was on this background that the first clinical trials of neural transplantation took place in the late 1980s most notably in Lund, Sweden. These transplants have continued over the last eleven years with good clinical benefits in the majority of patients, assuming that an orthodox technique validated experimentally has been adopted.

This clinical improvement whilst not being seen in all areas of disease symptomatology has nevertheless correlated well with surviving grafts as evidenced using functional imaging with PET scans and in the limited number of post-mortem in patients who have died (from unrelated causes I should add) following grafting. It therefore seemed that neural transplantation for Parkinson’s disease was a safe and effective therapy although still experimental, or at least that was the case until the recent paper by Freed and colleagues. This study from Freed et al has raised new concerns about the use of this approach because of the adverse effects they reported including the development of abnormal movements in some of their grafted patients some time after grafting.

It is this aspect of the trial that has caused much excitement in the media, although in the original paper the comments relating to this were much more measured in their content. Nevertheless the development of these side effects raises fundamental questions not only as to the use of this approach in Parkinson’s disease but in HD and a range of other disorders of the CNS. However, the fact that these side effects have only been seen in this study raises questions as to whether they are more related to the approach adopted by Freed et al than neural transplantation per se.

The US trial on neural grafting in advanced Parkinson’s disease

The trial design adopted by Freed et al involved recruiting forty patients with advanced Parkinson’s disease and randomising them to either receive a fetal dopamine transplant or a sham operation. The sham operation involved taking the patient to theatre, drilling holes in the frontal part of the skull and then pretending to implant the tissue. The procedure was so effective, that the patients themselves were unaware of whether they had had a transplant or not, as assessed by questionnaires immediately after the operation. The patients were then followed clinically and after a year, those patients in the sham operated group were offered a transplant and fourteen of the twenty in this group were transplanted, whilst the other six were not as a result of the side effects that had developed in 5 of the grafted patients.

Overall nine patients noticed an improvement and five developed these abnormal movements off all medication. Two patients died during the trial, neither of which deaths was related to the transplant procedure itself, and at post mortem these patients were found to have low numbers of surviving dopamine cells as compared to other post mortem studies from patients reporting significant clinical and imaging improvement.

So why did this US trial produce such effects?

This trial adopted by Freed et al used radically different techniques to other studies, much of which has never been validated experimentally. In particular:

• this trial used less tissue than other transplant trials, including the more successful Swedish studies based at Lund.
• the tissue was stored for much longer times prior to grafting (up to a month in some cases) than in any other study which will tend to reduce its viability.
• the tissue was grafted using a novel preparation and surgical approach.
• none of the patients received immunosuppression, which may be necessary to allow good graft survival.

Whilst it is impossible to know whether the side effects seen in this trial relate to any or all of above factors, it is probable that the transplants have led to great imbalances in the amount of dopamine released within the brain which in turn has led to the development of these major side effects. It is therefore clear that whilst the trial has produced adverse effects, this is more a consequence of the technique used than transplantation of embryonic dopamine cells for Parkinson’s disease. There is certainly no evidence for dopamine overgrowth as was suggested in some media reports, as the number of transplanted cells at post mortem in those that have died was much less than those seen in other studies.

So where does this leave the field of neural grafting for Parkinson’s disease?

First of all it highlights the dangers of going into clinical trials without first validating the safety of the technique being developed, and also argues for extensive experimental studies before any clinical trials are undertaken. Furthermore whilst this trial has certainly put a dent in the use of neural tissue to repair the brain in Parkinson’s disease, it by no means derails the procedure as further studies have failed to show such adverse side effects. Indeed this study like many others has shown that a significant number of patients benefit from the procedure. However, for those seeking a quick fix with either neural stem cells or other forms of cellular replacement therapy, this study is a warning that until one has reliable and robust scientific and experimental data, the move to the clinical domain is not to be recommended.

And what does this mean for neural transplantation in HD?

The MRC sponsored trial with Cambridge as the designated surgical centre has an independent committee of leading scientists and clinicians who are overseeing the trial. The trial itself is approaching the conclusion of the phase 1 safety part of the study and the data from this will be reviewed by the above trial steering committee (TSC) who also met following the publication of the Freed et al paper. Our current MRC sponsored trial is based on a large number of experimental studies and adopts a technique similar to that used in France by *Marc Peschanski et al. This group recently published their efficacy and safety data on 5 patients with HD grafted with embryonic striatal tissue. These patients did not develop any adverse side effects from the graft and some of them actually reported benefit from the procedure. Therefore the transplant approach adopted in the current MRC supported trial has a sound basis experimentally and is similar to those other centres that have successfully grafted patients with HD (and Parkinson’s disease). It was therefore the overwhelming and unanimous view of the TSC that the MRC sponsored trial should continue given the major differences between this study and that undertaken by Freed et al. Thus whilst neural grafting remains experimental and unproven in HD, the recent US study does not undermine the validity and hopes that the transplantation of human fetal striatal tissue will help in HD. If anyone has any queries about this then do contact me.

• Roger Barker on behalf of the UK-NEST consortium.