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. 2022 Jun 10;30(8):2646–2663. doi: 10.1016/j.ymthe.2022.06.004

Table 4.

Summary of recommendations from the 2021 ASGCT-FDA Liaison Meeting

Criterion Expert recommendations
Theoretical risk
  • the risk of oncogenesis associated with rAAV chromosomal integration in humans is theoretical based on current data and information

  • the current lack of observed rAAV-associated HCC in large animals and humans suggests that the risk is low compared with neonatal mice and does not outweigh the potential benefit from many AAV vector-based gene therapies, especially for serious and life-threatening conditions with no alternative therapy

  • given the current diseases targeted with AAV gene therapy, and the actual documented risks, the risk/benefit ratio would suggest that many trials should be able to proceed in parallel with additional investigation

Animal models
  • the use of sensitive mouse models of oncogenesis may provide information about the relative risk of different vector designs; however, translatability of any murine oncogenic events to humans remains unclear

  • if longer-term pharmacodynamic studies are conducted, the background rates of HCC must be considered, and risks must be understood

  • while additional studies assessing the oncogenesis of strongly transactivating vectors in large animals will be needed to better understand these issues, these studies are impractical as a near-term solution and may require one to two decades of research

  • recent observations of clonal expansions of rAAV integrations in canine hepatocytes in the absence of tumor formation warrant additional studies in the field. These may or may not reflect natural clonal dynamics in aging animals, and additional studies could help determine the nature of these clonal expansions

Methods for assessment
  • performing integration site analysis, whole-genome sequencing, and gene expression analysis on tumor tissue samples from patients

  • limitations to these methods may potentially be mitigated by rapid and ongoing improvements in sequencing technologies such as target enrichment and long-read sequencing methods. These methods may help provide greater insight into concatemeric and highly rearranged integrated vector genome structures

  • propose that an expert group should be convened to make recommendations regarding improving methods used to assess oncogenic events

  • cfDNA should be further evaluated as a potential safety biomarker

Clinical assessment
  • biopsies of neoplastic nodules and surrounding non-tumor tissue should be conducted to further investigate any positive signal picked up by non-invasive methods

  • long-term follow-up studies should last for at least 5 years, consistent with FDA guidance, and possibly longer depending on the safety profile of the product. Enrollment in patient registries for longer-term data collection is also encouraged