Lot-to-Lot Variation in Adeno-Associated Virus Serotype 9 (AAV9) Preparations.

Area of Science:

• Gene therapy manufacturing
• Viral vector technology
• Neuroscience

Background:

• Viral vectors are complex biologics with inherent manufacturing challenges.
• Lot-to-lot variability in vector preparations is common, potentially affecting biological activity.
• Conflicting reports on vector transduction patterns suggest variability may play a role.

Purpose of the Study:

• To investigate lot-to-lot variability in spinal cord gray matter transduction.
• To assess the impact of intrathecal delivery of self-complementary adeno-associated virus serotype 9 (scAAV9) vectors.

Main Methods:

• Evaluation of eleven scAAV9 vector lots from six vector cores.
• Intrathecal delivery in relevant animal models.
• Assessment of spinal cord gray matter transduction efficiency.

Main Results:

• Significant lot-to-lot variation in gray matter transduction was observed.
• Eight of eleven scAAV9 vector lots failed to transduce spinal cord gray matter.
• Transduction variability did not correlate with vector titer, buffer composition, or purification method.

Conclusions:

• Lot-to-lot variability in scAAV9 vector potency is a critical issue for gene therapy.
• The underlying cause of this variability remains unidentified.
• Improved production and quality control strategies are essential to ensure consistent vector potency and therapeutic efficacy.