527. CERE-110, an AAV2-Based Vector To Deliver NGF, Provides Trophic Activity to Basal Forebrain Cholinergic Neurons in Rats and Cynomolgous Monkeys
Authors: Kathie M. Bishop, Katrin Hofer, Denise Rius, Arpesh Mehta, Shokry Lawandry, Lamar Brown, Brian Kruegel, Mehdi Gasmi, Mark Tuszynski, Raymond T. Bartus
Journal: Molecular Therapy (2004)

Numerous studies indicate that providing trophic support to degenerating basal forebrain cholinergic neurons with nerve growth factor (NGF) is a logical approach to treating mild to moderate Alzheimer's disease. However, since NGF does not effectively reach basal forebrain cholinergic neurons when delivered systemically and causes adverse effects when delivered to the cerebral ventricles, direct administration of NGF to the basal forebrain is required. CERE-110 is an adeno-associated virus (serotype 2)-based gene delivery vector being developed by Ceregene, Inc. for the delivery of NGF to the basal forebrain in Alzheimer's patients. The bioactivity of CERE-110 was tested in four separate in vivo animal models. CERE-110 was found to provide trophic support to basal forebrain cholinergic neurons in two commonly used rat models of basal forebrain cholinergic neurodegeneration: the fimbria-fornix lesion model and natural degeneration of cholinergic neurons in aged rats. In both of these models, CERE-110 application to basal forebrain cholinergic neurons resulted in both significantly increased cholinergic cell size and cell number, as compared to controls, at 2 weeks or 3 months after vector delivery. Results in the fimbria-fornix lesion model of cholinergic neuronal degeneration demonstrate that the use of an AAV vector is an effective means of delivering NGF to prevent degeneration of basal forebrain cholinergic neurons. Results in the aged rat brain demonstrate that the use of CERE-110 is an effective means of delivering NGF to reverse NBM cholinergic neuronal degeneration, as assayed by cellular atrophy and the downregulation of phenotypic markers. In addition, in young rats and young monkeys, CERE-110 application to basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NBM) elicited a trophic response, as evidenced by hypertrophic cell size, for at least 9 months in young rats and for at least 3 months in young monkeys following vector delivery. In young rats, the biological response provided by a dose of 1 x 108 vector genomes (vg)/NBM of CERE- 110 was not significantly less than the response produced by 2 x 109 vg/NBM of CERE-110 (a 20x greater dose) at any of the time points examined. In young monkeys, a dose response effect was observed, where doses of 4 x 1010 vg/NBM and 1 x 1010 vg/NBM of CERE-110 produced a significant biological response, but 1 x 109 vg/NBM of CERE-110 did not. Even when the highest doses of CERE-110 were tested, no cytotoxicity or loss of basal forebrain cholinergic neurons was observed in either rats or monkeys for up to 9 or 3 months, respectively. Overall, these four studies provide convergent evidence that CERE-110 is an effective means to deliver NGF and provide trophic support to basal forebrain cholinergic neurons, and therefore may be beneficial to Alzheimer's patients.