Lentivirus Gene Therapy for Farber Disease in NHPs

溶酶体贮积症（LSD）是基因治疗的极好目标。校正的目标细胞是 对于许多LSD来说，发生了一种称为“代谢协同性”的现象。这里的细胞 其分泌这些水解酶，这些水解酶可被功能性地利用 被未修饰的旁观者细胞杀死因此，低效率或定向基因转移到单个位点仍然可以影响 系统性矫正法伯病（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 后果死亡往往发生在幼儿期。目前对FD的治疗，像许多LSD一样， 姑息治疗对于一些LSD，使用未修饰细胞的BMT已经部分纠正，尽管对LSD的影响很小。 观察到CMS表现。对于最常见的LSD，酶替代疗法是 一个选择使用各种传递系统的基因治疗也已经在体外和体内进行了测试 LSD的模型。还启动了一些针对LSD的临床基因治疗方案。没有 尽管还没有实现临床改善，但报告了毒性。以前我们 第一次证明了基因治疗可以改善FD的概念可能性。最近，我们 使慢病毒（LV）适应基因扩增策略。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LSD。然而，尽管这一概念 尽管LSD的小动物模型越来越多，但这些实验仍然是成功的。 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UHN中， 其中需要更多的研究或方案开发。因此，这项拟议的研究将是第一个 在临床相关性更高的模型中，充分测试LV介导的LSD校正; NHP。

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.