Ceregene, Inc., San Diego, CA 92121, USA.
Neurobiol Aging. 2013 Jan;34(1):35-61. doi: 10.1016/j.neurobiolaging.2012.07.018. Epub 2012 Aug 24.
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.
神经营养因子作为治疗与年龄相关的神经退行性疾病的潜在疗法已经有很长时间了。然而，20 年来，大量令人失望的临床结果突显了将这些蛋白质安全有效地递送到中枢神经系统内的靶向部位所面临的困难。最近的进展表明，基因转移现在可能克服困扰神经营养因子转化的递药问题。腺相关病毒血清型 2-神经生长因子（CERE-120）的研究进展最能说明这一点，这是一种旨在将神经营养因子神经生长因子递送到帕金森病中退化的黑质纹状体神经元的病毒载体构建体。已有 80 名帕金森病患者接受了 CERE-120 的治疗（大约 7 年前），长期、靶向的神经生长因子表达得到了证实，并且没有发现严重的安全问题。一项双盲、对照的 2a 期临床试验通过 24 项预定疗效终点中的 19 项证实了 CERE-120 的临床“概念验证”，在 12 个月方案规定的时间点，有 19 项有利于 CERE-120，而在 18 个月的次要时间点，有 23 项有利于 CERE-120（p = 0.007 和 0.001）。此外，在 12 个月时，根据方案规定的几个特定的、配对的、盲法的运动和生活质量终点，以及 18 个月时的更多终点，都观察到了 CERE-120 的临床获益。由于该试验未能达到主要终点（在 12 个月时使用统一帕金森病评定量表测定的运动休止期），因此设计了一项新的多中心 1/2b 期方案，以利用 2a 期试验获得的见解来增强 CERE-120 的神经营养作用。本文综述了 CERE-120 从最初到建立“临床概念验证”及以后的发展历程。回顾了所面临的转化障碍和问题，以及应用的策略。对于那些对与年龄相关和其他神经退行性疾病相关的转化研究和开发感兴趣的研究人员来说，这些信息应该是有帮助的。
