Aebischer P, Schluep M, Déglon N, Joseph J M, Hirt L, Heyd B, Goddard M, Hammang J P, Zurn A D, Kato A C, Regli F, Baetge E E
Gene Therapy Center and Division of Surgical Research, Centre Hospitalier Universitaire Vaudois, Lausanne University Medical School, Switzerland.
Nat Med. 1996 Jun;2(6):696-9. doi: 10.1038/nm0696-696.
Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.
神经元生长因子有望在各种神经系统疾病中提供治疗益处。作为确保生长因子充分递送至中枢神经系统并将与全身给药方法相关的重大不良副作用降至最低的一种手段，我们开发了一种使用封装的基因修饰异种细胞进行蛋白质递送的离体基因治疗方法。睫状神经营养因子（CNTF）在各种啮齿动物模型中已显示出可减少运动神经元细胞死亡，类似于在肌萎缩侧索硬化症（ALS）中所见的情况。由于存在严重的副作用，最初针对ALS患者进行的CNTF全身给药试验已停止，因此无法确定该分子的潜在疗效。为了将CNTF直接递送至神经系统，我们进行了一项I期研究，在该研究中，六名ALS患者植入了聚合物胶囊，其中含有基因工程改造的幼仓鼠肾细胞，这些细胞在体外每天释放约0.5微克人CNTF。释放CNTF的植入物通过手术放置在腰段鞘内空间。移植后至少17周内在患者脑脊液（CSF）中检测到纳克水平的CNTF，而在植入前则检测不到。鞘内递送CNTF与全身递送中观察到的限制性副作用无关。这些结果表明，神经营养因子可以通过离体基因治疗方法在人的脑脊液中持续递送，为神经系统疾病的治疗开辟了新途径。
