Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMN

Neurotropic AAV serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously at high doses. This observation led to the recent successful application of intravenous AAV9 delivery to treat infants with spinal muscular atrophy (SMA), an inherited deficiency of the survival of motor neuron (SMN) protein characterized by selective death of lower motor neurons. To evaluate the efficiency of motor neuron transduction with an AAV9 variant (AAVhu68) using this approach, we treated three juvenile nonhuman primates (NHPs; age 14 months) and three piglets (age 7-30 days) with an intravenous injection of an AAVhu68 vector carrying a human SMN transgene at a dose similar to that employed in the SMA clinical trial. Administration of 2x1014 genome copies per kilogram body weight resulted in widespread transduction of spinal motor neurons in both species. However, severe toxicity occurred in both NHPs and piglets. All three NHPs exhibited marked transaminase elevat...