Malignancy and gene therapy in hemophilia

TL;DR

This paper examines the potential cancer risk from AAV gene therapy in hemophilia, finding no clear evidence of AAV causing tumors in humans.

Contribution

The paper highlights the variability in evidence quality and advocates for standardized long-term monitoring of AAV gene therapy outcomes.

Findings

AAV integration does not consistently cause tumors in humans, as seen in cancer cases studied.

Comprehensive analyses can rule out AAV as a causative factor in some cancers, like hepatocellular carcinoma.

Poor sample quality limits conclusive results in some cases, such as spinal cord tumors.

Abstract

Despite the misconception that adeno-associated virus (AAV) gene therapy vectors are nonintegrating, they can integrate into the host genome at a low but nonnegligible frequency, posing a theoretical risk of tumorigenesis. While AAV integration can trigger hepatocellular carcinoma in mice, no such association has been established in humans. None of the 10 cancer cases reported in AAV vector recipients so far has shown evidence that AAV integration drives tumorigenesis. However, the strength of the evidence from molecular analyses differed significantly across these cases. The scope and conclusiveness of causality assessments depended on sample quality and cross-validation using complementary analytical methods. For example, poor sample quality precluded a conclusive analysis in a case of a spinal cord tumor. Conversely, comprehensive analyses provided strong evidence that AAV integration was not the causative factor in a case of hepatocellular carcinoma. These findings underscore the need for standardization, global long-term follow-up, and careful communication of outcomes.