Treating the CNS and Somatic Diseases of MPS IIIB by Systemic Gene Delivery

该项目的目标是向FDA提交IND申请，批准通过静脉注射（IV） rAAVG载体来纠正粘多糖病（MPS） IIIB患者的基因缺陷的i /ll期基因治疗临床试验。rAAV9基因治疗程序的设计考虑到患者提供人类NaGlu （MPS IIIB中缺失的酶）基因，因此这项研究可以很容易地转化为人类的实验治疗。本项目基于rAAVG载体具有穿越血脑屏障的能力，并且静脉注射rAAVQ载体会导致基因在中枢神经系统（CNS）以及外周广泛表达和纠正溶酶体储存的假设。事实上，我们最近的初步研究表明，单次IV rAAVQ载体注射对小鼠MPS IIIB的中枢神经系统和躯体疾病有显著的功能纠正。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，有很大的潜力改善患有这种毁灭性疾病的儿童的生活质量。该方法将在小鼠中进一步优化，并在犬MPS IIIB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小鼠中进行的初步临床前基因治疗研究。目标#1将是确定临床应用的最佳（较低）剂量，这可能进一步缓解基因从小鼠传递到人类的翻译挑战，载体生产的可扩展性和载体的潜在风险。AIM #2将使用MPS IIIB狗来测试建议的方案，使用最佳剂量，因为在大小和生理上与临床环境相似。AIM #3将评估拟议的IV rAAV9给药的毒理学、安全性和生物分布，并采取向FDA提交IND申请的最后一步，以期在MPS IIIB患者中进行i /ll期rAAVQ基因治疗临床试验。

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.