title: 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.
authors.affiliation: Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. jocelyne.bloch@chuv.hospvd.ch
authors.forename: J
authors.initials: J
authors.lastname: Bloch
authors.forename: A C
authors.initials: AC
authors.lastname: Bachoud-Lévi
authors.forename: N
authors.initials: N
authors.lastname: Déglon
authors.forename: J P
authors.initials: JP
authors.lastname: Lefaucheur
authors.forename: L
authors.initials: L
authors.lastname: Winkel
authors.forename: S
authors.initials: S
authors.lastname: Palfi
authors.forename: J P
authors.initials: JP
authors.lastname: Nguyen
authors.forename: C
authors.initials: C
authors.lastname: Bourdet
authors.forename: V
authors.initials: V
authors.lastname: Gaura
authors.forename: P
authors.initials: P
authors.lastname: Remy
authors.forename: P
authors.initials: P
authors.lastname: Brugières
authors.forename: M-F
authors.initials: MF
authors.lastname: Boisse
authors.forename: S
authors.initials: S
authors.lastname: Baudic
authors.forename: P
authors.initials: P
authors.lastname: Cesaro
authors.forename: P
authors.initials: P
authors.lastname: Hantraye
authors.forename: P
authors.initials: P
authors.lastname: Aebischer
authors.forename: M
authors.initials: M
authors.lastname: Peschanski
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D020934:Ciliary Neurotrophic Factor / Q000737:chemistry / Q000235:genetics; D003062:Codon; D006224:Cricetinae; D004594:Electrophysiology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000628:therapy*; D008297:Male; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors
chemical_list: D020934:Ciliary Neurotrophic Factor; D003062:Codon; D018696:Neuroprotective Agents; D011108:Polymers