First in Human Liver Biopsy Study Following Gene Therapy for Hemophilia A


Over the past couple of years, the excitement and energy surrounding the potential availability of gene therapy as a treatment option for patients living with hemophilia A have grown. ISTH has created an educational initiative known as Gene Therapy in Hemophilia, which has developed educational resources to learn about gene therapy in hemophilia, improve understanding of the fundamentals, and stay abreast of the latest clinical advances, including safety data, as it relates to gene therapy in hemophilia in a global capacity.

One gene therapy candidate for hemophilia A, AAV5-hFVIII-SQ (valoctocogene roxaparvovec), in clinical trials has shown to increase factor VIII (FVIII) levels, reduce annualized bleeding rate, and decrease FVIII utilization. Durable expression may be associated with the presence of circularized vector DNA episomes in hepatocytes, but this has not been confirmed in vivo in humans. On Sunday, Sylvia Fong, Ph.D., of BioMarin Pharmaceuticals presented findings from liver biopsies following intravenous administration of AAV5-hFVIII-SQ in humans.

Two biopsies were obtained, one at week 201 post infusion from one participant and another at week 140 post infusion from another participant. Biopsy samples underwent histopathological examination, in situ hybridization to detect vector genomes, and DNA and RNA extraction for molecular analyses. Levels of full-length, ITR-fused, circular vector genomes were quantified using drop-phase droplet digital PCR (ddPCR). Histopathological examination revealed normal liver architecture with mild steatosis and no evidence of steatohepatitis or significant inflammation in either participant. Hepatocytes stained positive for vector genomes in a pan-lobular distribution, similar to previous observations in nonhuman primates. Circular vector genomes and FVIII-SQ RNA were both present in a dose-dependent manner. Fong concluded that long-term FVIII expression is associated with the presence of circularized, full-length genomes in human liver, which persist several years after a single AAV5-hFVIII-SQ infusion.

Read the full abstract here.

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