Lentivirus Gene Therapy for Farber Disease in NHPs

描述(由申请人提供)：溶酶体储存障碍(LSD)是基因治疗的极佳目标。矫正的目标细胞通常是可以接触到的，对于许多LSD来说，会发生一种称为“代谢协同性”的现象。在这里，过度表达校正溶酶体酶的细胞分泌这些水解酶，这些水解酶可以被未修饰的旁观者细胞功能性地利用。因此，效率较低或直接将基因转移到单个位置仍会影响系统校正。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表现为衰弱的表现，包括疼痛的肉芽肿和明显的神经后果。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，只是姑息治疗。对于一些腰椎间盘突出症，使用未经修饰的细胞的骨髓移植已经部分矫正，尽管对中枢神经系统的表现几乎没有影响。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。没有毒副作用的报道，尽管临床上的改善也没有实现。在此之前，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。我们已经在细胞培养和Fabry病的小动物模型中测试了使用LV的成功结果；另一种LSD。然而，尽管在概念上取得了成功，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启动了对非人类灵长类动物(NHP)的基因治疗研究，以更好地预测患者的结果，并确定需要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临床相关的模型中全面测试LV介导的LSD校正的研究；

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.