Expression and distribution of rAAV9 intrathecally administered in juvenile to adolescent mice.

Abstract

Intrathecal (IT) lumbar puncture delivery of recombinant adeno-associated virus serotype 9 (rAAV9) is a gene therapy approach being explored in preclinical studies and ongoing gene therapy clinical trials for neurological diseases. Few studies address IT rAAV9 vector distribution, tropism, and expression with respect to age of administration. Therefore, we IT delivered a rAAV9/GFP vector in mice at ages ranging from early postnatal development through adulthood (P10-P90). Tissues were assessed for transgene expression, cell tropism, and vector distribution. In the CNS, transduction was highest when delivered at post-natal day 10 (P10) and there was an age-dependent decline in transduction. We found higher transduction of astrocytes relative to neurons when rAAV9 was administered at younger ages and a switch to higher neuronal transduction with delivery at older timepoints. Biodistribution analysis of peripheral tissues showed that when delivered at P10, rAAV9 has the greatest distribution to the heart. Conversely, at P90 rAAV9 liver distribution was highest. As rAAV9 IT-delivered gene therapies continue to emerge for neurological diseases, careful consideration of the age of delivery should be taken in relation to the expected distribution and cell expression in animal models, and how this may translate to human studies.