Shahrukh, Muhammad, Sweeney, Julianne, Del Rio, Tony and Ozsolak, Fatih (2026) Metadata Assessment of Preclinical Non-Human Primate Studies of AAV9 Uncovers Potential Tissue Specific Variation in Expression Efficiency. Gene therapy. ISSN 1476-5462; 0969-7128

Abstract

Adeno-associated virus (AAV)-based gene therapies have garnered significant attention and investment in recent years due to their clinical success and their potential to address underlying causes of many diseases. These AAV vectors can provide effective delivery of therapeutic genetic material to disease relevant tissues. When evaluating safety and efficacy of recombinant AAV vectors, the biodistribution profile plays a critical role in novel therapy development. Herein, a biodistribution metadata analysis was performed on eight preclinical studies involving 49 cynomolgus macaques (Macaca fascicularis). The macaques were administered a self-complementary or single-stranded AAV9 capsid vector containing chicken ß-actin (CBA) or cytomegalovirus (CMV173) promoters expressing fluorescent reporters or a human SMN1 gene. These studies cover various routes of administration (ROA) including intravenous (IV), intracisternal magna (ICM), and lumbar puncture intrathecal (IT) injection. Through metadata analysis of AAV9 biodistribution we show relatively uniform vector genome delivery throughout spinal cord tissues over multiple timepoints and ROA. In addition, distinct trends emerge that showcase decreased expression efficiency of viral DNA in liver regardless of the ROA, NHP age, or viral constructs used. To understand the observed difference in transcriptional productivity in liver versus other tissues, epigenetic profiling of tissue-localized AAV9 vector genome DNA was performed. Experimental evidence supports potential partial silencing/repression of transgene expression in liver. These findings point to plausible strategies to consider in preclinical development of AAV9 mediated gene therapies.

Item Type:	Article
Date Deposited:	21 Jan 2026 00:45
Last Modified:	21 Jan 2026 00:45
URI:	https://oak.novartis.com/id/eprint/55963