Strong Cortical and Spinal Cord Transduction After AAV7 and AAV9 Delivery into the Cerebrospinal Fluid of Nonhuman Primates

Abstract

The present study builds on previous work showing that infusion of adeno-associated virus type 9 (AAV9) into the cisterna magna (CM) of nonhuman primates resulted in widespread transduction throughout cortex and spinal cord. Transduction efficiency was severely limited, however, by the presence of circulating anti-AAV antibodies. Accordingly, we compared AAV9 to a related serotype, AAV7, which has a high capsid homology. CM infusion of either AAV7 or AAV9 directed high level of cell transduction with similar patterns of distribution throughout brain cortex and along the spinal cord. Dorsal root ganglia and corticospinal tracts were also transduced. Both astrocytes and neurons were transduced. Interestingly, little transduction was observed in peripheral organs. Our results indicate that intrathecal delivery of either AAV7 or AAV9 directs a robust and widespread cellular transduction in the central nervous system and other peripheral neural structures.

Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

“…Since the transcription efficiency and therefore the expression profiles of cell types change depending on the promoter used28,30 , an accurate comparison is only possible using the same promoter.We see a strong correlation between GFP mRNA levels and the corresponding protein levels observed by immunofluorescence. Both, the GFP mRNA levels as well as the percentage GFP/ChAT positive motor neurons is highest in the lumbar spinal cord, which is consistent with previous reports from other groups31,34 . The dose response of the mRNA levels was very similar between the scAAV9.CBA.SMN and scAAV9.CBA.GFP, indicating that GFP can be used to approximate SMN expression patterns when using the same promoter.…”

“…The use of different injection strategies, AAV serotypes, as well as dosing led to variable results in pigs and nonhuman primates 21,24,[30][31][32][33][34] . To determine the best injection method and to correctly estimate the effective dose needed in patients, an understanding of AAV transduction in brain and spinal cord in rodents and primates is required 21,[35][36][37] .…”

“…4. The dose could be increased in very severe patients by combining IV and CSF administration if needed.To date, few studies have evaluated the transduction pattern of scAAV9 delivered transgenes in the CNS of larger animal species after direct CSF delivery21,24,34, 47 . Furthermore, the use of different AAV serotypes, different promoters, as well as multiple injection sites and routes (IV versus cisterna magna versus lumbar puncture) make comparisons and straight forward conclusions for application in clinical trials difficult.…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…Routes include intracerebroventricular/intrathecal [17][18][19], intranasal [20], and systemic (intravenous and intra-arterial) injections [21]. The systemic delivery route for gene delivery vehicles is very promising, but has major caveats.…”

“…The field of CNS gene therapy is evolving rapidly with the discovery of new viral vectors, mainly AAV capsids, with remarkable CNS tropism after vascular [21,36,49,[96][97][98], and CSF administration [18,36,47]. A large range of AAV capsids has been investigated for their CNS gene transfer properties by direct intracranial injection [99][100][101][102].…”