Brian Kaspar

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

We have discovered that systemically delivered AAV9-SMN delivered early to a severe rodent model of SMA results in substantial rescue of the lifespan. This work was published in Nature Biotechnology in 2010 as well as similar reports. 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 survival. 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 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 studies. When virus is delivered to the CSF, via intraventricular injections, we and others 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. This formulates the basis for the proposed U01 Application to advance to IND submission and human clinical trials.