Nature 386, 395 - 399 (27 March 1997); doi:10.1038/386395a0

Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease

Dwaine F. Emerich^*, Shelley R. Winn^†, Philippe M. Hantraye^‡, Marc Peschanski^§, Er-Yun Chen^¶, Yaping Chu^¶, Patricia McDermott^*, E. Edward Baetge^* & Jeffrey H. Kordower^¶

^*CytoTherapeutics Inc., Providence, Rhode Island 02906, USA
^†Department of Surgery, Oregon Health Sciences University, Portland, Oregon 97201, USA
^‡URA CNRS 1285, Svc Hosp Frederic Joliet, 4 Place Gen Leclerc, Orsay 91406, France
^§INSERM U421, Fac De Medicine, F94010 Creteil Cedex, France
^¶Research Center for Brain Repair and Department of Neurological Sciences, Rush Presbyterian–St Luke's Medical Center, Chicago, Illinois 60612, USA
Present address: Alkermes, Inc., 64 Sidney Street, Cambridge, Massachusetts 02139, USA.

Huntington's disease is a genetic disorder that results from degeneration of striatal neurons, particularly those containing GABA (-aminobutyric acid)¹. There is no effective treatment for preventing or slowing this neuronal degeneration. Ciliary neurotrophic factor (CNTF) is a trophic factor for striatal neurons^2,3 and therefore a potential therapeutic agent for Huntington's disease. Here we evaluate CNTF as a neuroprotective agent in a non-human primate model of Huntington's disease. We gave cyno-molgus monkeys intrastriatal implants of polymer-encapsulated baby hamster kidney fibroblasts that had been genetically modified to secrete human CNTF. One week later, monkeys received unilateral injections of quinolinic acid into the previously implanted striatum to reproduce the neuropathology seen in Huntington's disease^4,5. Human CNTF was found to exert a neuroprotective effect on several populations of striatal cells, including GABAergic, cholinergic and diaphorase-positive neurons which were all destined to die following administration of quinolinic acid. Human CNTF also prevented the retrograde atrophy of layer V neurons in motor cortex and exerted a significant protective effect on the GABAergic innervation of the two important target fields of the striatal output neurons (the globus pallidus and pars reticulata of the substantia nigra). Our results show that human CNTF has a trophic influence on degenerating striatal neurons as well as on critical non-striatal regions such as the cerebral cortex, supporting the idea that human CNTF may help to prevent the degeneration of vulnerable striatal populations and cortical–striatal basal ganglia circuits in Huntington's disease.

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