Regulatory Framework for AAV Biodistribution in Switzerland

Swissmedic’s guidance for gene therapy products mandates a thorough evaluation of biodistribution and shedding. The objective is to build a comprehensive safety profile that characterizes where the AAV vector travels in the body and how it is cleared. Data from semen analysis are scrutinized to understand the potential for vector presence in male reproductive organs and the associated risk of transmission.

Designing these studies requires a forward-looking regulatory strategy. Key considerations include:

• Time Points: Selecting appropriate sample collection intervals to capture the peak and clearance phases of shedding.
• Assay Sensitivity: Ensuring the lower limit of quantification (LLOQ) is sufficient to meet regulatory expectations for “no detection.”
• Sample Integrity: Implementing robust collection and processing protocols to prevent sample degradation and ensure accurate quantification.

Our bioanalytical teams operate within our >100,000 sq ft facility to develop and validate assays that meet these stringent requirements, providing the high-quality data necessary for regulatory review.

The Influence of Vector Design on Shedding Profiles

The biodistribution of an AAV vector is not generic: it is dictated by its underlying biology. Capsid selection is a primary factor influencing tissue tropism and, consequently, shedding patterns. As demonstrated in comparative studies, engineered capsids like AAV3B can exhibit transduction profiles distinct from other serotypes, highlighting the need for program-specific assessments rather than relying on platform data (PMID: 26412589). A capsid with high liver tropism may present a different shedding risk compared to one that targets muscle or the central nervous system.

Beyond the capsid, other vector elements contribute to the safety profile. Strategies such as the use of short promoters or self-targeting mechanisms can increase the specificity of transgene expression, reducing activity in non-target tissues (PMID: 33359790). While focused on efficacy, these modifications also contribute to the overall risk assessment by limiting potential effects in off-target cell types, a concept that complements biodistribution data.

“We started collaborating with UPenn Vector core in 2023 and the AAV vector which they manufactured laid a foundation for development of a gene therapy candidate which will enter soon preclinical studies. The key people from UPenn Vector Core joined Franklin Biolabs and our partnership transitioned without interruption from UPenn Vecor Core to Franklin Biolabs Research Vector Division. Franklin Biolabs is our trusted partner in our AAV-vector based gene therapy candidate development and we hope to continue the partnership for years to come.”
— Biotech Partner