Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery.

Area of Science:

• Oncology
• Genetics
• Neurology

Background:

• Recombinant adeno-associated virus (AAV) vectors are generally nonintegrating gene therapy tools.
• Rare instances of AAV integration have been linked to oncogenesis in preclinical models.
• Mucopolysaccharidosis type I (MPSI) is a rare genetic disorder treatable with gene therapy.

Purpose of the Study:

• To report a rare case of tumor development following AAV gene therapy.
• To investigate the molecular mechanisms of AAV integration and potential oncogenesis in a human patient.
• To assess the therapeutic efficacy of AAV gene therapy in mitigating MPSI symptoms.

Main Methods:

• Case report of a pediatric patient receiving AAV serotype 9 gene therapy for MPSI.
• Surgical resection of a neuroepithelial tumor.
• Molecular analysis of tumor tissue, including DNA sequencing and transcript analysis.

Main Results:

• A neuroepithelial tumor developed 4 years after AAV9 gene therapy administration.
• Tumor molecular analysis revealed clonal integration of rearranged AAV vector elements into the PLAG1 gene.
• A chimeric AAV-PLAG1 transcript was identified, suggesting a potential oncogenic mechanism.
• Post-operative cognitive function indicated successful MPSI symptom mitigation.

Conclusions:

• This case highlights a rare instance of AAV vector integration associated with tumor formation in a human patient.
• AAV gene therapy can be effective in treating genetic disorders like MPSI, but long-term safety monitoring for oncogenesis is crucial.
• Further research is needed to understand the mechanisms and minimize the risks of AAV vector integration.