Treating the CNS and Somatic Diseases of MPS IIB Systemic Gene Delivery

描述（由申请人提供）：本项目的目的是向FDA提交IND申请，以批准通过静脉内（IV）注射rAAVG载体进行I/II期基因治疗临床试验，以纠正粘多糖样变性（MPS）IIIB患者的基因缺陷。rAAV 9基因治疗程序是为患者设计的，目的是提供人类NaGlu（MPS IIIB中缺失的酶）基因，因此该研究可以很容易地转化为人类的实验性治疗。该项目基于已证实的假设，即rAAVG载体具有穿过血脑屏障的能力，并且IV注射rAAVQ载体将导致广泛的基因表达和校正中枢神经系统（CNS）以及外周中的溶酶体储存。事实上，我们最近的初步研究表明，通过单次IV rAAVQ载体注射，小鼠中MPS IIIB的CNS和体细胞疾病得到了显著的功能矫正。转化为临床，这种微创基因治疗方案将对MPS IIIB患者产生直接影响，具有改善这种毁灭性疾病儿童生活质量的巨大潜力。该程序将在小鼠中进一步优化，并在MPS IIIB犬模型中得到证实。该提案包括三个具体目标，基于我们完善的原理验证研究和我们在MPS IIIB小鼠中的初步临床前基因治疗研究。目的#1将是确定用于临床应用的最佳（较低）剂量，这可以进一步缓解将基因递送从小鼠翻译到人类的挑战、载体生产的可扩展性和载体的潜在风险。目标#2将使用MPS IIIB犬来测试使用最佳剂量的拟定方案，因为其大小和生理学与临床环境相似。目的#3将是评估所提出的IV rAAV 9递送的毒理学、安全性和生物分布，并采取向FDA提交IND申请的最后步骤，期望在MPS IIIB患者中进行I/II期rAAVQ基因治疗临床试验。

DESCRIPTION (provided by applicant): The goal of this project is to submit an IND application to the FDA for approval of a phase l/ll gene therapy clinical trial by intravenous (IV) rAAVG vector injection to correct the gene defect in patients with Mucopolysaccharidosis (MPS) IIIB. The rAAV9 gene therapy procedure is designed with patients in mind to deliver a human NaGlu (the missing enzyme in MPS IIIB) gene, so that the research can be readily translated into an experimental therapy in humans. This project is based on the confirmed hypothesis that rAAVG vector has the ability to cross the blood-brain-barrier, and an IV injection of rAAVQ vector will lead to widespread gene expression and the correction of lysosomal storage in the central nervous system (CNS), as well as in the periphery. Indeed, our very recent preliminary studies demonstrated significant functional correction of CNS and somatic disease of MPS IIIB in mice by a single IV rAAVQ vector injection. Translated into the clinic, this minimally invasive gene therapy regimen will have direct impacts on MPS IIIB patients with great potential of improving the quality of life in children with this devastating disease. The procedure will be further optimized in mice and corroborated in a canine model of MPS IIIB. This proposal includes three specific aims, based on our well-established proof-of-principle studies and our preliminary preclinical gene therapy studies in MPS IIIB mice. AIM #1 will be to determine the optimal (lower) dose for clinical application, which may further ease the challenge in translation of gene delivery from mouse to humans, the scalability of vector production and potential risk from the vector. AIM #2 will be to use MPS IIIB dogs to test the proposed regimen using the optimal dose, because of parallels in size and physiology to the clinical environment. AIM #3 will be to assess the toxicology, safety and biodistribution of the proposed IV rAAV9 delivery, and to take the final step of submitting an IND application to the FDA in expectation of a phase l/ll rAAVQ gene therapy clinical trial in MPS IIIB patients.