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

该项目的目标是通过静脉注射重组AAVG载体向FDA提交IND申请，以批准L/11期基因治疗临床试验，以纠正粘多糖病(MPS)IIIB患者的基因缺陷。RAAV9基因治疗程序的设计考虑到了患者提供人类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性治疗。该项目基于rAAVG载体具有跨越血脑屏障的能力的确认假设，静脉注射rAAVQ载体将导致中枢神经系统(CNS)和外周的广泛基因表达和溶酶体存储的纠正。事实上，我们最近的初步研究表明，一次静脉注射rAAVQ载体可以显著纠正小鼠中枢神经系统和MPS IIIB的躯体疾病。转化到临床上，这种微创基因治疗方案将对MPS IIIB患者产生直接影响，极有可能改善患有这种毁灭性疾病的儿童的生活质量。该程序将在小鼠身上进一步优化，并在MPS IIIB的犬模型中得到证实。这项建议包括三个具体目标，基于我们完善的原则证明研究和我们在MPS IIIB小鼠上的初步临床前基因治疗研究。目的1是确定临床应用的最佳(较低)剂量，这可能进一步缓解从小鼠到人的基因传递的挑战、载体生产的可扩展性以及来自载体的潜在风险。目标2将是使用MPS IIIB犬来测试所建议的方案，使用最佳剂量，因为其大小和生理与临床环境相似。目的#3将评估拟议的IVrAAV9的毒理学、安全性和生物分布，并采取最后一步向FDA提交IND申请，以期在MPS IIIB患者中进行L/11rAAVQ基因治疗的临床试验。

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.