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Critical evaluation of the impact of ssDNA cargo length on AAV stability – a case study
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DOI：10.1007/s11095-026-04176-3.png)
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Abstract
En 中文
To evaluate how ssDNA cargo size influences the physicochemical characteristics and stability behavior of AAVX vectors under thermal, chemical, and other accelerated stress conditions. AAVX vectors with differing ssDNA cargo length (i.e. 2.8 kb and 4.6 kb) were analyzed under manufacturing-relevant, storage-related, and accelerated stress conditions using complementary analytical methods to assess capsid stability, genome integrity, potency, and capsid chemical modifications. Thermal and chemical denaturation experiments showed similar capsid unfolding across the cargo sizes tested. Under accelerated thermal stress (40°C), the shorter-genome vector showed less ssDNA release and better preservation of capsid and genome titers than the longer-genome vector. Fragmentation of encapsulated ssDNA was also observed for the shorter cargo. Capsid chemical modifications, including asparagine deamidation and aspartic acid isomerization, increased markedly at 40°C. These findings provide a case-study view of how cargo size can affect AAV stability readouts in a condition-dependent behavior and highlight the value of multi-attribute characterization for evaluating AAV vector stability. In addition, our results also suggest that suggest that, under the conditions tested for AAVX, the same capsid may be useful for evaluating vector stability with different genome sizes.
Keywords:
AAV
degradation
gene therapy
PTM
stability
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