Executive Summary

Selecting an appropriate AAV serotype for in vivo gene delivery requires a data-driven approach that accounts for species-specific variations in vector tropism and immune response. Direct extrapolation from certain preclinical data to human clinical outcomes can be unreliable; non-human primate (NHP) models provide a more predictive translational bridge. Understanding these differences, particularly in tissue-specific transduction patterns and immunogenicity, is fundamental to de-risking a program and designing a viable path toward a successful IND submission.

The Translational Challenge in Vector Design

A persistent challenge in developing AAV-based therapies is the translational dissonance between preclinical models. Data generated in some models frequently fails to predict vector behavior in primates, leading to costly delays and program setbacks. This is particularly evident in liver-directed gene therapy, where the specific zonation of hepatocyte transduction can dictate therapeutic success or failure.

Analysis of AAV8, for example, reveals a stark, inverse zonation pattern between species. While this serotype effectively transduces pericentral hepatocytes in some preclinical models, it preferentially targets periportal hepatocytes in NHPs. This finding underscores the necessity of validating serotype performance in higher-order species to ensure the vector engages the correct cellular machinery required for the intended therapeutic effect. Relying on data from lower-order models alone can lead to a fundamental miscalculation of a candidate’s clinical potential.

Designing for Durable Expression and Controlled Immunogenicity

Beyond tissue tropism, a vector’s interaction with the host immune system is a primary consideration. The capsid must be designed to minimize neutralization by pre-existing antibodies while effectively delivering its genetic payload to generate a durable therapeutic response. NHP studies provide the most relevant context for evaluating these dynamics.

This consultative process, backed by our >100,000 sq ft of manufacturing, analytics, and in vivo study areas, helps sponsors navigate these complexities to achieve a typical 18-24 month IND timeline. A partner recently noted this continuity of expertise: “The key people from UPenn Vector Core joined Franklin Biolabs and our partnership transitioned without interruption… Franklin Biolabs is a key collaborator in our AAV-vector based gene therapy candidate development and we hope to continue the partnership for years to come.”

Our Commitment to Animal Welfare

All in vivo studies at Franklin Biolabs are conducted with an unwavering commitment to animal welfare, adhering to the highest ethical standards. We rigorously implement the 3Rs (Reduce, Refine, Replace) to ensure the most humane and scientifically sound outcomes.

Featured Resource: Responsibility and Animal Welfare

This video details Franklin Biolabs’ commitment to animal care, highlighting our adherence to international guidelines and the three Rs (Reduce, Refine, Replace) of animal research.
(Internal Asset: FBL-VID-09-Approved_enhanced_responsibility_clip_long.mp4)