Lentivirus Gene Therapy for Farber Disease in NHPs

描述（由申请人提供）：溶酶体贮积症（lsd）是基因治疗的极好目标。校正的靶细胞通常是可接近的，对于许多lsd来说，一种称为“代谢协同性”的现象发生了。在这里，过度表达纠正溶酶体酶的细胞分泌这些水解酶，这些酶可以被未修饰的旁观者细胞在功能上利用。因此，低效率或定向基因转移到单个位点仍然可以影响系统纠正。法伯病（FD）是一种非常严重的LSD，由于缺乏酸性神经酰胺酶。FD表现为虚弱的表现，包括疼痛的肉芽肿和明显的神经系统后果。死亡通常发生在儿童早期。与许多lsd一样，目前对FD的治疗也只是治标不治本。对于一些lsd，使用未经修饰的细胞进行BMT已部分纠正，尽管对中枢神经系统表现的影响很小。对于最常见的迷幻药，酶替代疗法是一种选择。使用多种传递系统的基因治疗也已在lsd的体外和体内模型中进行了测试。一些针对lsd的临床基因治疗方案也已经启动。没有毒性的报告，虽然临床改善也没有实现。先前我们首次在概念上证明了基因治疗可以改善FD的可能性。最近，我们一直在适应慢病毒（LV）的基因增强策略。我们已经在法布里病的细胞培养和小动物模型中测试了lv的成功结果；另一个迷幻药。然而，尽管这种概念上的成功，尽管lsd的小动物模型越来越多，但这些实验往往不能预测临床基因治疗的结果。因此，我们最近在UHN启动了非人类灵长类动物（NHPs）的基因治疗研究，以更好地预测患者的结果，并确定需要进行更多研究或方案开发的领域。因此，这项拟议的研究将是第一个在更具临床相关性的模型中全面测试LSD介导的校正；NHPs。

DESCRIPTION (provided by applicant): Lysosomal storage disorders (LSDs) are excellent objectives for gene therapy. Target cells for correction are often accessible and for many LSDs a phenomenon called 'metabolic cooperativity' occurs. Here cells that overexpress corrective lysosomai enzymes secrete these hydrolases, which can be functionally utilized by unmodified bystander cells. Thus lower efficiencies or directed gene transfer to single sites can still effect systemic correction. Farber disease (FD) is a very severe LSD due to a deficiency in acid ceramidase. FD presents with debilitating manifestations including painful granulomas and pronounced neurological consequences. Death often occurs in early childhood. Current treatment for FD, like for many LSDs, is only palliative. For some LSDs, BMT using unmodified cells has been partially corrective, although little impact on CNS manifestations has been observed. For only the most prevalent LSDs, enzyme replacement therapy is an option. Gene therapy using a variety of delivery systems has also been tested in vitro and in vivo models of LSDs. A few clinical gene therapy protocols addressing LSDs have also been initiated. No toxicities were reported although clinical improvements have also not been realized. Previously we demonstrated the first conceptual possibility that gene therapy could ameliorate FD. Lately, we have been adapting lentiviruses (LV) for gene augmentation strategies. We have tested successful outcomes using LVs in cell culture and in small animal models for Fabry disease; another LSD. Yet despite this conceptual success, and notwithstanding the growing number of small animal models of LSDs, these experiments are not often predictive of clinical gene therapy outcomes. Thus we have recently initiated gene therapy studies here at the UHN in non-human primates (NHPs) to better predict outcomes in patients and to identify areas wherein more research or protocol development is warranted. This proposed study would thus be the first to fully test LV-mediated correction for an LSD in a more clinically relevant model; that of NHPs.