From dose quantity to dose quality: elevating rAAV genome integrity as a CMC attribute

Vector genome (vg) titer has provided a practical dosing metric for recombinant AAV (rAAV) programs. However, because vg conflates productive and non‑productive rAAV DNA species, it does not represent biologically effective exposure. Here we outline a mechanism-based framework for DNA‑related dose quality that focuses on rAAV vector genome integrity. We summarize analytical limitations that obscure absolute quantitation of intact ITR→ITR genomes, describe platform‑dependent genome outcomes that affect dose quality, and propose a phase‑appropriate path to incorporate integrity into development and CMC decision‑making. Improving the fraction of intact genomes offers a direct lever to reduce clinical vg dose while maintaining effect, an increasingly important objective, especially for indications that require systemic administration at high doses.

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