In Vivo ADA Gene Delivery for the Treatment of SCID

描述（由申请人提供）：腺苷脱氨酶（ADA）缺乏导致20%的人类严重联合免疫缺陷（SCID）。目前治疗ada缺乏性SCID的方法具有临床益处，但每种方法都有局限性。因此，开发新的治疗方法对这种形式的SCID很重要，这些进展可能对其他原发性免疫缺陷、血细胞疾病和代谢紊乱有治疗应用。ADA缺乏性SCID的独特病理生理机制，以及通过ADA异位表达对免疫缺陷进行反式纠正的潜力，可能会开发出一种新的治疗方法。我们已经在小鼠ADA基因敲除小鼠模型中确定，单次静脉注射携带正常人类ADA cDNA的慢病毒载体可导致ADA基因的系统性传递和ADA酶的表达，从而恢复免疫力并显著延长生存期。该提案的中心假设是：体内系统递送正常的ADA基因将在临床上有利于纠正ADA缺陷SCID的生化和免疫异常，提供与外源性酶替代疗法相似或更高的疗效，但作为单一治疗，而不是作为慢性治疗方案。为了评估这一假设，我们将：2. ADA基因敲除小鼠体内基因传递优化；2 .评估ADA基因在体内传递的作用机制；将大型动物载体剂量学、药代动力学、生物分布和毒理学定义为临床前研究。本提案的总体目标是优化ADA系统基因递送的功效，更好地了解治疗效果的机制，并在大型动物模型中进行初步的临床前研究。与公共卫生的相关性：原发性免疫缺乏症是严重的、危及生命的疾病，患者往往在生命的头几年发生严重的、危及生命的感染。目前对这些疾病的治疗有显著的疗效，但仍然不是最佳的。因此，必须继续开发新的和改进的方法来治疗原发性免疫缺乏性疾病，这是本项目的主要目标，具有显著的疗效，但仍然是次优的。

DESCRIPTION (provided by applicant): Deficiency of adenosine deaminase (ADA) is responsible for 20% of human severe combined immune deficiency (SCID). Current therapies for ADA-deficient SCID have clinical benefits, but each approach has limitations. Thus, development of novel therapeutic approaches are important for this form of SCID and these advances may have therapeutic applications for other primary immune deficiencies, blood cell diseases and metabolic disorders. The unique pathophysiology of ADA-deficient SCID, with the potential for trans-correction of the immune deficiency by ectopic expression of ADA, may allow a novel therapy to be developed. We have determined in a murine ADA gene knock-out mouse model that a single I.V. administration of a lentiviral vector carrying a normal human ADA cDNA leads to systemic ADA gene delivery and ADA enzyme expression that restores immunity and significantly prolongs survival. The central hypothesis of this proposal is that: In vivo systemic delivery of a normal ADA gene will be clinically beneficial for correcting the biochemical and immunologic abnormalities of ADA-deficient SCID, providing efficacy similar to or greater than that of exogenous enzyme replacement therapy, but as a single treatment, rather than as a chronic regimen. To assess this hypothesis, we will 1. optimize in vivo gene delivery by IV vector administration in ADA gene knock-out mice, 2. evaluate the mechanisms of the effect from in vivo ADA gene delivery, and 3. define large animal vector dosimetry, pharmacokinetics, bio-distribution and toxicology as pre-clinical studies. The overall goals of this Proposal are to optimize the efficacy of systemic ADA gene delivery, to gain better understanding of the mechanisms of the therapeutic effects and to perform initial pre- clinical studies in a large animal model. Relevance to public health: Primary immune deficiency diseases are serious, life-threatening disorders with patients often developing severe, life-threatening infections in the first years of life. Current therapies for these diseases have significant efficacy, but remain sub-optimal. Therefore, it is imperative to continue to develop new and improved methods to treat primary immune deficiency diseases and that is the primary goal of this project have significant efficacy, but remain sub-optimal.