Lentivirus Gene Therapy for Farber Disease in NHPs

溶酶体储存障碍(LSD)是基因治疗的极佳目标。要更正的目标单元格是 通常是可以获得的，对于许多LSD来说，会发生一种称为“代谢协作性”的现象。这里的单元格 过度表达校正溶酶体酶分泌这些水解酶，这些水解酶可以在功能上加以利用 由未经修改的旁观者细胞。因此，较低的效率或直接将基因转移到单个位置仍会产生影响 系统性修正。Farber病(FD)是一种由于酸性神经酰胺酶缺乏而导致的非常严重的LSD。fd 表现为虚弱的表现，包括疼痛的肉芽肿和明显的神经症状 后果。死亡通常发生在儿童早期。目前对FD的治疗，就像许多LSD一样，只是 治标不治本。对于一些LSD，使用未经修饰的细胞的BMT已经部分纠正了，尽管对 已观察到CMS的表现。仅对于最普遍的LSD，酶替代疗法是 一种选择。使用各种递送系统的基因治疗也已经在体外和体内进行了测试。 LSD的型号。一些针对LSD的临床基因治疗方案也已经启动。不是 虽然临床改善也没有实现，但已有毒性反应的报道。以前我们 论证了基因治疗可以改善FD的第一个概念性可能性。最近，我们一直在 适应慢病毒(LV)的基因扩增策略。我们已经使用LV测试了成功的结果 在细胞培养和法布里病的小动物模型中；另一种迷幻药。然而，尽管在概念上 成功，尽管LSD的小动物模型越来越多，但这些实验是 通常不能预测临床基因治疗的结果。因此，我们最近启动了基因治疗研究。 在非人类灵长类动物(NHP)的超高密度氮(UHN)中，更好地预测患者的结果并确定区域 其中需要更多的研究或协议开发。因此，这项拟议的研究将是第一个 在更临床相关的模型中全面测试LV介导的LSD校正；NHP的模型。

Lysosomal storage disorders (LSDs) are excellent objectives for gene therapy. Target cells for correction are often are 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 CMS 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 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-mediatedcorrection for an LSD in a more clinically relevant model; that of NHPs.