Translating a CSF delivered AAV9-SMN for treatment of Spinal Muscular Atrophy

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DESCRIPTION (provided by applicant): The autosomal recessive disorder proximal spinal muscular atrophy (SMA) is the most common genetic cause of infant death and has an incidence of 1:6,000-10,000 live births1. The most common form is type 1 SMA or Werdnig-Hoffman Disease which results in hypotonia and progressive weakness and is typically recognized in the first few months of life2. Diagnosis of type 1 SMA occurs in the first 6 months and death usually occurs by age two. There is no treatment available to slow or halt disease progression, but our recent preclinical studies utilizing gene delivery in newborn rodent models of SMA suggest gene therapy may hold promise. SMA is an attractive disease for gene therapy because it is a single gene defect that results in low amounts of the survival motor neuron (SMN) protein (hypomorph) versus a total deficiency3. SMN is a ubiquitously expressed protein that is essential in all tissues and is not associated with toxicity when over expressed in mice4 or in humans5 with multiple copies of the gene. In addition, disease severity correlates with SMN protein levels emphasizing the potential therapeutic benefit for SMN as a treatment strategy.1 We have discovered that systemically delivered AAV96-SMN delivered early to a severe rodent model of SMA7 results in substantial rescue of the lifespan8 . This work was published in Nature Biotechnology in 20109,10 as well as similar reports 11-13. We have expanded this work in additional studies with now over 50 animals that have been treated with scAAV9-SMN and had remarkably consistent results with long survival of SMA mice. In the initial phases of treatment the evaluator is completely blinded. However, while blinding is maintained throughout the study, it is obviously difficult to maintain a true blind status with suc a dramatic effect on survival10. This sets the stage to advance to human clinical trials. However, systemic gene delivery, while it has certain advantages for the youngest patients, has limitations when advancing to the large and older patients. First, systemic gene delivery requires significant amounts of virus, and may be technically and economically challenging. Second, systemic gene delivery targets all organs, which may increase safety considerations, and in patients with neutralizing antibodies against AAV9 be less effective. We and others have recently discovered that AAV9, when delivered to the CSF results in efficient motor neuron targeting with a fraction of the virus utilized in our systemic gene delivery studies14-16. When virus is delivered to the CSF, via intraventricular injections, we and others13,17 have demonstrated that SMA mice survive significantly longer, greater than 100 days of age, which is again a remarkable finding in a mouse model that typically dies at 15 days of age (preliminary data). This formulates the basis for the proposed U01 application to advance to IND submission and human clinical trials. The specific Aims proposed for this U01 are: Aim 1: Develop pre-clinical data of CSF delivered AAV9-SMN in the 7 mouse model of SMA to support a pre-IND Aim 2: Optimize intrathecal dosing in nonhuman primates for most efficient targeting of spinal motor neurons using scAAV9.CB.GFP Aim 3: Assess toxicology and immune response following AAV9-SMN administration in mice and nonhuman primates (non-GLP) and submit a Pre-IND to the FDA. Aim 4: Formally assess toxicology, immune response, biodistribution and long-term expression in mice that will support an IND application to the FDA (GLP). Aim 5: Prepare and Submit an IND to the FDA.