Recombinant adeno-associated virus integration profiles in nonhuman primates and gene therapy participants after treatment with valoctocogene roxaparvovec.

Recombinant adeno-associated viruses (AAVs) are clinically relevant vectors for gene therapy that persist largely as extrachromosomal episomes but also infrequently integrate into host genomes. Valoctocogene roxaparvovec is an approved AAV-based gene therapy for severe hemophilia A. We present a molecular characterization of the vector integration profiles in 5 human biopsy samples from valoctocogene roxaparvovec clinical trials as well as in samples from valoctocogene roxaparvovec-treated nonhuman primates (NHPs). The number of genomic integrations was substantially below the previously reported number of transgene-expressing cells, and integration profiles were similar between human and NHP samples. The integration profiles were polyclonal, similarly distributed across the genome, and demonstrated a small bias toward regions of open chromatin and actively transcribed genes, with no relative enrichment in cancer-associated genes. These observations were replicated between species and support the concept that preclinical assessment of AAV vector integration in NHPs is representative of outcomes in humans.

Citation

Russell CB, Vettermann C, Agarwal S, Witt E, Clark W, Arens J, Fronza R, Obrochta Moss KM, Kasprzyk T, Robinson TM, Tran H, Kenet G, Raheja P, Lester W, Eggan K, Zoog S. Recombinant Adeno-Associated Virus Integration Profiles in Nonhuman Primates and Gene Therapy Participants after Treatment with Valoctocogene Roxaparvovec. Hum Gene Ther. 2025 Jul;36(13-14):945-955. doi: 10.1089/hum.2024.236. Epub 2025 Jun 4.

Type

Article