Lentivirus Gene Therapy for Farber Disease in NHPs

慢病毒基因治疗 NHP 法伯病

• 批准号: 7092043
• 负责人: JEFFREY A MEDIN
• 金额: $ 12.19万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092043
• 关键词: Lentivirus; Macaca mulatta; NOD mouse; O glycosidase; SCID mouse; autologous transplantation; biotechnology; cell surface receptors; ceramide tetrahexoside; disease /disorder model; enzyme activity; enzyme deficiency; gene delivery system; gene therapy; hematopoietic tissue transplantation; inborn lysosomal enzyme disorder; inflammation; neurogenetics; nonhuman therapy evaluation; polymerase chain reaction; recombinant virus; structural genes; telemetry; therapy design /development; transfection /expression vector; virus protein

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.

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。用于校正的靶细胞通常是可访问的，并且对于许多 LSD 来说，会发生一种称为“代谢协同性”的现象。在这里，过度表达纠正性溶酶体酶的细胞会分泌这些水解酶，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，较低的效率或定向基因转移到单个位点仍然会影响系统校正。法伯病 (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。死亡常常发生在幼儿期。与许多 LSD 一样，目前对 FD 的治疗只是姑息治疗。对于某些 LSD，使用未修饰细胞的 BMT 已部分纠正，但尚未观察到对 CNS 表现的影响很小。仅对于最流行的LSD，酶替代疗法是一种选择。使用多种递送系统的基因治疗也在 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启动。尽管尚未实现临床改善，但没有报告任何毒性。之前我们展示了基因治疗可以改善 FD 的第一个概念可能性。最近，我们一直在将慢病毒（LV）用于基因增强策略。我们已经在细胞培养和小动物模型中使用 LV 测试了法布里病的成功结果；另一种LSD。然而，尽管在概念上取得了成功，并且 LSD 小动物模型的数量不断增加，但这些实验通常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 (NHP) 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 LV 介导的 LSD 校正的研究； NHP 的。