Shahrukh, Muhammad, Sweeney, Julianne, Del Rio, Tony and Ozsolak, Fatih (2026) Metadata assessment of non-human primate studies of AAV9 uncovers potential tissue specific variation in expression efficiency. Gene therapy, 32 (6). pp. 1476-5462. ISSN 1476-5462

Abstract

Adeno-associated virus (AAV)-based gene therapies have garnered significant attention and investment due to their clinical success and potential to address underlying causes of many diseases. AAV vectors provide effective delivery of therapeutic genetic material to disease-relevant tissues. When evaluating safety and efficacy of recombinant AAV vectors, biodistribution profiles play a critical role in novel therapy development. Herein, a biodistribution metadata analysis was performed on ten studies involving 51 cynomolgus macaques (Macaca fascicularis). The macaques received a self-complementary or single-stranded AAV9 vector containing chicken ß-actin (CBA) or cytomegalovirus (CMV173) promoters expressing fluorescent reporters or a human SMN1 gene. These studies covered various routes of administration (ROA) including intravenous (IV), intracisternal magna (ICM), and lumbar puncture intrathecal (IT) injection. Metadata analysis of AAV9 biodistribution showed relatively uniform vector genome delivery throughout spinal cord tissues over multiple timepoints and ROAs. Moreover, decreased expression efficiency of viral DNA in liver was observed regardless of the ROA, macaque age, or viral construct used. To understand this trend, epigenetic profiling of tissue-localized AAV9 vector genome DNA was performed. Experimental evidence supports partial silencing and repression of transgene expression in macaque liver. These findings point to plausible strategies to consider in preclinical development of AAV9 mediated gene therapies.

Item Type:	Article
Date Deposited:	03 Feb 2026 00:45
Last Modified:	03 Feb 2026 00:45
URI:	https://oak.novartis.com/id/eprint/56962