Challenging the more-is-better dogma: A precision-optimized AAV gene therapy for SMA.

Spinal muscular atrophy (SMA) is a severe neurogenetic disorder and the leading inherited cause of infant mortality. Although the available gene therapy has shown substantial efficacy in treating SMA, safety concerns, including hepatotoxicity, underscore the need for optimization. In this study, our findings challenge the prevailing "more-is-better" paradigm, demonstrating that both insufficient and excessive transgene expression are suboptimal. To maximize therapeutic benefit while minimizing risk, we extensively optimized the expression cassette in adeno-associated virus (AAV)-based constructs and selected EXG001-307, an intra-cerebrospinal fluid (intra-CSF)-delivered AAV9 gene therapy engineered for tissue-selective and quantitatively controlled SMN expression. Comparative studies demonstrated that intra-CSF-administered EXG001-307 may offer improved efficacy and safety relative to the other candidates. In subsequent investigational new drug-enabling studies, EXG001-307 demonstrated dose-dependent improvements in survival, body weight gain, and motor function in SMA model mice. Safety evaluations in rats and juvenile nonhuman primates further confirmed a favorable safety profile, with no evidence of systemic toxicity or sustained dorsal root ganglion pathology. Analyses in vector genome biodistribution and transgene expression revealed robust central nervous system transduction consistent with therapeutic benefit. These findings support clinical translation of EXG001-307 and highlight the importance of vector genome engineering and targeted delivery for safe and effective gene therapies.