Guibinga, Ghiabe, Do, Janet, Chu, Binh, Gu, Yin-1, Kikkawa, Rie, Li, Xiaoguang, Ozsolak, Fatih and MacLachlan, Timothy (2024) Comparative assessment of the efficacy and safety associated with the delivery of AAV9-GFP vector via lumbar puncture route to juvenile Cynomolgus Macaques with and without anti-AAV9 preexisting IgG antibodies. Molecular therapy: Methods and Clinical Development.

Abstract

Administration of AAV-based gene therapies into the intra-cerebrospinal fluid (CSF) compartments via routes such as lumbar puncture (LP) has been implemented as an alternative to intravenous dosing to target the CNS regions. This allows to lower doses, decrease toxicity, and circumvent intravascular pre-existing anti-AAV antibodies. In this study, AAV9-GFP vector was administered via LP to juvenile cynomolgus macaques with and without pre-existing anti-AAV9 IgG antibodies at a 5.0 x 1013 vector genome (vg) dose and examined for 28 days. CNS and peripheral tissues were surveyed for vector genome, mRNA, and protein expression. Histopathology, clinical pathology, and the humoral immune response to the viral capsid and transgene were also assessed. In addition, serum and CSF samples were analyzed to examine 276 proteomic markers curated to evaluate neural injury, organ damage, and inflammatory response. This study reveals no noticeable difference in AAV9-mediated gene transfer in the CNS tissues examined between the two groups, however qualitative and quantitative differences were observed for endpoints such as liver enzyme activities, histopathology, and levels of protein markers in the serum and CSF. These findings provide a view into nonclinical efficacy and safety following LP-delivered AAV9-GFP to juvenile cynomolgus macaques with and without pre-existing anti-AAV9 IgG antibodies.

Item Type:	Article
Keywords:	AAV9, pre-existing immunity, safety, toxicity
Date Deposited:	21 Nov 2024 00:45
Last Modified:	21 Nov 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52808