Spinal Muscular Atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. The authors have previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus 9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, they evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. Widespread transgene expression was found throughout the spinal cord in mice and nonhuman primates when using a ten times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. A detailed analysis is presented of transduction levels throughout the brain, brainstem and spinal cord of nonhuman primates, providing new guidance for translation towards therapy for a wide range of neurodegenerative disorders.
