Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study

doi:10.1016/S1474-4422(06)70381-7

The Lancet Neurology

Volume 5, Issue 4, April 2006, Pages 303-309

https://doi.org/10.1016/S1474-4422(06)70381-7 Get rights and content

Summary

Background

Although we have shown in three out of five patients with Huntington's disease that motor and cognitive improvements 2 years after intracerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. We undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting.

Methods

Five patients with Huntington's disease from our pilot study were assessed annually with the unified Huntington's disease rating scale, neuropsychological tests, and MRI, for up to 6 years after neural grafting. Resting cerebral activity was recorded at 2 and 6 years.

Findings

Clinical improvement plateaued after 2 years and then faded off variably 4–6 years after surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypometabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at 2 years continued to decline in the same way as non-grafted patients.

Interpretation

Neuronal transplantation in Huntington's disease provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure and in patient selection could improve the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.

Introduction

Patients with Huntington's disease have recently benefited from intracerebral cell therapy, which aims to substitute striatal neurons lost to the disease by striatal neuroblasts and neural precursors obtained from embryos after elective abortion. Maturation of grafted cells led to recovery of brain metabolism¹ and both motor and cognitive function in three out of five patients with Huntington's disease.2, 3 Autopsy, undertaken 18 months after grafting,⁴ showed that the disease did not affect transplanted cells that lack the mutant huntingtin gene. Conversely, wild-type cells might not affect progression of degeneration in gene-carrying host cells.5, 6

Theoretical projection models suggest that the clinical effects of grafting will include an initial period of graft maturation and integration, leading to improvement, and a period of secondary decline due to the ongoing disease process in patients’ brains. The duration of clinical benefit is therefore a major parameter to be taken into account when assessing the outcome of such treatment.3, 5 The longest follow-up recorded of patients treated with these grafts is 30 months.2, 7, 8

In 2000, we presented a preliminary report of motor and cognitive improvement over 2 years in three patients with Huntington's disease after intracerebral fetal neural grafting.² Recovery of brain metabolic activity occurred in grafted striatal areas and connected regions of the cerebral cortex. However, because fetal neural grafts are not known to have protective effects on the host brain per se, we sought to describe the time course of clinical benefits and improvements in resting brain metabolism over a long period in these previously reported patients.

Section snippets

Methods

Five patients with Huntington's disease from a pilot study² were assessed annually according to previously described protocols. Briefly, patients were followed up for 2 years and then treated with bilateral grafts in two sessions 1 year apart. Small blocks of tissue retrieved from the whole ganglionic eminence of human embryos (7·5–9 weeks old) were implanted through four to five tracks in the head of the caudate nucleus, the precommissural putamen, and the post-commissural putamen. Clinical

Results

In a preliminary report, patients 4 and 5 were shown to have no long-lasting clinical benefit nor improvement in brain function after grafting.² These two patients continued to decline in the following years. By contrast, patients 1, 2, and 3 showed motor and cognitive stabilisation or improvement at 2 years, consistent with an increase in brain activity in the grafted striata and in frontal and prefrontal cortices. Their results are described in detail here. At subsequent follow-up, clinical

Discussion

The main result of this long-term follow-up analysis of patients with Huntington's disease who received fetal neural transplants is the prolonged benefit of the procedure, both clinically and in terms of brain activity. Altogether, a period of stabilisation of several years followed an initial 2 years of progressive clinical improvement. Within this general framework, however, the evolution was heterogeneous with, in particular, dystonia progressing more rapidly than other motor symptoms.

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Fast track — ArticlesEffect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Lancet

Lancet

Exp Neurol

Striatal neural grafting improves cortical metabolism in Huntington's disease patients

Brain

Fetal neural grafts for Huntington's disease: a prospective view

Mov Disord

Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology

Proc Natl Acad Sci USA

Integrating fetal neural transplants into a therapeutic strategy: the example of Huntington's disease

Brain

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

Bilateral human fetal striatal transplantation in Huntington's disease

Neurology

Fast track — Articles
Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study