Neuroprotective Gene Therapy for Huntington's Disease, Using Polymer-Encapsulated Cells Engineered to Secrete Human Ciliary Neurotrophic Factor: Results of a Phase I Study

Abstract

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

The Neuroprotective Agent CNTF Decreases Neuronal Metabolites in the Rat Striatum: An in Vivo Multimodal Magnetic Resonance Imaging Study

“…Encapsulated cells are known to produce CNTF less efficiently due to their low survival rate after implantation. 18 This may explain the limited beneficial effects observed in a phase I clinical trial for HD patients, 3 although this strategy was very efficient in primates. 19 Considering the strong evidence for CNTF neuroprotective effects in the striatum, our results show that decreased tNAA and Glu levels may occur independently of neuronal dysfunction, and may instead be associated with significant neuroprotective effects.…”

Imaging in cell-based therapy for neurodegenerative diseases

“…Simultaneously, ex vivo gene transfer techniques using encapsulated genetically engineered cells have been used to test the neuroprotective properties of ciliary neuroptrophic factor (CNTF) in HD patients. In this context, intraventricular implantation of CNTFproducing capsules in HD patients for one year proved to be a safe procedure, with no noticeable adverse events [82]. This encouraging phase I trial will be followed soon by a phase II protocol.…”

Advances in Gene Therapy for Movement Disorders

“…Retrieved capsules contained variable numbers of surviving cells, and CNTF release was low in more than half the cases, which emphasizes the need for improving the technique. 101 No follow-up information has been published on the clinical application of this approach in movement disorders.…”