Trans-BBB AAV9 gene therapy targeting CNS neuropathy of MPS I

Project Summary The goal of this Phase II SBIR project is to further develop an effective gene replacement therapy product for treating Mucopolysaccharidosis (MPS) I, towards clinical application and commercialization. MPS I is a rare lysosomal storage disease (LSD) caused by autosomal recessive defects in α-L-iduronidase (IDUA). The severe form of MPS I (MPS IH, Hurler syndrome) represents the majority of known cases, with premature deaths usually before age 10 years, predominantly due to neurological impairments and cardio- respiratory failure. No effective treatment is available for neurological indications of MPS IH. Because of the global diffuse neuropathy and the blood brain barrier (BBB), MPS IH is not amenable to either recombinant enzyme replacement therapy (ERT) or bone marrow transplantation, which are the standard of care for treating somatic symptoms of MPS I. Gene replacement therapy (GRT) targeting the root cause has been demonstrated to be an ideal strategy for treating monogenic diseases. Numerous studies have demonstrated success in IV or intrathecal (IT) delivery of trans-BBB-neurotropic AAV9 targeting the root cause for treating neurogenetic diseases. Importantly, the efficacy and safety profiles of IV and IT rAAV9 delivery have been demonstrated to be highly reproducible across different neurogenetic diseases, including LSDs. For optimal therapeutic potential, we have developed a novel self-complementary (sc) AAV vector, scAAV- mCMV-∆hIDUAop, to deliver a miniaturized human IDUA cDNA with codon-optimization. The scAAV-∆hIDUAop vector was shown to significantly enhance the expression and secretion of functional IDUA protein, compared to the previous single-stranded (ss) rAAV-hIDUA construct. We further tested the scAAV-mCMV-∆hIDUAop GRT product in pre-clinical studies in MPS I mouse model using AAV9 in Phase I STTR project. With an IV injection of scAAV9-mCMV-∆hIDUAop vector in MPS IH mice, we achieved functional correction and reversal of neurological and somatic disorders of MPS I, without detectable toxicity, strongly support the therapeutic potential of the proposed scAAV9-mCMV-∆hIDUAop vector product for treating MPS I in humans. Further, our data allowed us to identify the minimal effective dose (MED). We believe that we are well-positioned to move forward towards a Phase I/II IND. In this Phase II SBIR project, we will hold the Pre-IND meeting, complete the IND-enabling toxicology studies and submit an IND application to the FDA for approval of a Phase I/II clinical trial in patients with MPS I.