Fit-for-purpose analytical considerations to support the clinical readiness of engineered AAV vectors

Jorge Santiago-Ortiz (left), Andrew Steinsapir (right)

Engineered AAV capsids are designed to improve tropism, enhance immune evasion, and increase manufacturability, yet these modifications can introduce unique analytical challenges that, if unaddressed, may limit the safe and efficacious use of engineered capsids in AAV gene therapies. Compared to natural AAV serotypes, engineered capsids may exhibit altered physicochemical properties, including reduced thermostability and changes in binding affinity to antibodies used for purification or detection. These differences necessitate the development of fit-for-purpose analytical methods to ensure accurate quantification and characterization of key quality attributes for AAV gene therapies. Here, we outline which commonly used assays are expected to be robust across capsids and which may require adaptation, and propose a fit-for-purpose, orthogonal analytical strategy to reliably characterize engineered AAV vectors, a critical step towards their safe and efficacious use in gene therapy products.

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