PROTECTIVE EFFECT OF ENCAPSULATED CELLS PRODUCING NEUROTROPHIC FACTORCNTF IN A MONKEY MODEL OF HUNTINGTONS-DISEASE

Huntington's disease is a genetic disorder that results from degenerat ion of striatal neurons, particularly those containing GABA (gamma-ami nobutyric 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 potenti al therapeutic agent for Huntington's disease. Here we evaluate CNTF a s a neuroprotective agent in a nonhuman primate model of Huntington's disease. We gave cynomolgus monkeys intrastriatal implants of polymer- encapsulated baby hamster kidney fibroblasts that had been genetically modified to secrete human CNTF. One week later, monkeys received unil ateral injections of quinolinic acid into the previously implanted str iatum to reproduce the neuropathology seen in Huntington's disease(4,5 ). Human CNTF was found to exert a neuroprotective effect on several p opulations of striatal cells, including GABAergic, cholinergic and dia phorase-positive neurons which were all destined to die following: adm inistration of quinolinic acid. Human CNTF also prevented the retrogra de atrophy of layer V neurons in motor cortex and exerted a significan t 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, supp orting the idea that human CNTF may help to prevent the degeneration o f vulnerable striatal populations and cortical-striatal basal ganglia circuits in Huntington's disease.