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Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating "clinical proof-of-concept" for AAV-neurturin (CERE-120) in Parkinson's disease

Ceregene, Inc., San Diego, CA, USA.
Neurobiology of aging (Impact Factor: 4.85). 08/2012; 34(1). DOI: 10.1016/j.neurobiolaging.2012.07.018
Source: PubMed

ABSTRACT Neurotrophic factors have long shown promise as potential therapies for age-related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE-120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long-term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof-of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol-prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational research and development for age-related and other neurodegenerative diseases.

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    ABSTRACT: Background Adeno-associated virus (AAV) vectors are used to deliver potentially therapeutic genes in clinical trials in Parkinson's disease (PD). Pre-existing immunity to AAV and a local neuroinflammatory response might negatively affect the efficacy of such AAV-mediated gene delivery. Methods We pre-immunized rats with wild-type AAV-2. Three months later, we created PD-like lesions by intrastriatal injections of 6-hydroxydopamine (6-OHDA) in 50% of the animals. One month later, we injected AAV2 vector expressing enhanced green fluorescent protein (eGFP) in the striatum. Using immunohistochemistry, we assessed eGFP expression, microglia activation and CD8 T cell infiltration. We also measured AAV-2 specific neutralizing antibody titers in the serum. ResultsThe number of striatal cells transduced with AAV2 vector expressing eGFP was reduced by 71% in rats pre-immunized with wild-type AAV2 compared to non-immunized animals. We detected elevated numbers of OX6(+) activated microglia in the striatum and circulating AAV2-specific neutralizing antibodies in pre-immunized rats. We also observed that the intrastriatal 6-OHDA injection promoted CD8(+) T cell infiltration and enhanced microglia activation. Nevertheless, the 6-OHDA lesion did not alter AAV2-mediated expression of eGFP in either pre-immunized or non-immunized rats. Conclusions Our findings indicate that intracerebral AAV2-based gene therapy is compromised in rats with pre-existing immunity to AAV2. By contrast, a local neuroinflammatory response, caused by intrastriatal a 6-OHDA injection, does not affect viral vector-mediated transgene expression. Our results emphasize the importance of monitoring circulating AAV-specific neutralizing antibodies in patients undergoing intracerebral gene therapy using AAV vectors. Copyright (c) 2014 John Wiley & Sons, Ltd.
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