Lentivirus Gene Therapy for Farber Disease in NHPs

描述（由申请方提供）：溶酶体贮积症（LSD）是基因治疗的极好目标。用于校正的靶细胞通常是可接近的，并且对于许多LSD来说，发生了称为“代谢协同性”的现象。在此，过表达校正性溶酶体酶的细胞分泌这些水解酶，其可以被未修饰的旁观者细胞功能性地利用。因此，较低的效率或定向基因转移到单个位点仍然可以影响系统校正。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表现为使人衰弱的表现，包括疼痛性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，像对许多LSD一样，只是姑息性的。对于某些LSD，使用未修饰细胞的BMT已部分纠正，尽管观察到对CNS表现的影响很小。只有最普遍的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在LSD的体外和体内模型中进行了测试。还启动了一些针对LSD的临床基因治疗方案。没有报告毒性，尽管临床改善也没有实现。以前，我们证明了基因治疗可以改善FD的第一个概念上的可能性。最近，我们一直在调整慢病毒（LV）的基因扩增策略。我们已经在细胞培养和法布里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，尽管这种概念上的成功，尽管越来越多的小动物模型的LSD，这些实验并不经常预测临床基因治疗的结果。因此，我们最近在UHN启动了非人灵长类动物（NHP）的基因治疗研究，以更好地预测患者的结局，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全面测试LV介导的校正LSD在一个更临床相关的模型; NHP。

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.