Ultrasound-mediated gene delivery (UMGD) successfully transferred factor VIII (FVIII) plasmids through a hepatocyte-specific promoter into the livers of mice with hemophilia and achieved persistent and therapeutic levels of FVIII expression, according to a new study published in Molecular Therapy: Nucleic Acid.
Hemophilia A is an X-linked disease caused by a deficiency in FVIII. Conventional therapy involves replacing the deficient FVIII, but scientists are increasingly looking into other methods to help patients with hemophilia achieve normal expressions of FVIII.
“Gene therapy as an alternative approach for hemophilia treatment that allows a wide therapeutic window has drawn significant interest, as even a continuous modest increase of FVIII levels (>1%) can result in dramatic improvement of severe bleeding phenotype,” Song and colleagues wrote.
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They have previously demonstrated the preliminary feasibility of applying UMGD in plasmid DNA gene therapy. This convinced them to test the usefulness of UMGD for gene therapy in patients with hemophilia A. They hence conducted a study exploring the UMGD of therapeutic FVIII plasmid in mouse models with hemophilia A.
They conducted a host of tests to determine the efficacy of this treatment, such as blood loss during a tail transection, the plasmid copy number in the mouse models, FVIII expression, and the presence of liver damage.
The results demonstrated that the treated mouse models achieved 25% to 150% of FVIII gene expression between days 1 to 7, with only transient liver damage that was resolved within 3 days. In addition, therapeutic levels of FVIII can be maintained in the hemophilia A mouse models, without the development of inhibitors.
“The current report constitutes a proof of principle study and demonstrates successful transfer of FVIII plasmid into a hemophilia A mouse model by UMGD to achieve significant and persistent FVIII expression levels,” the authors concluded.
“This study provides a promising strategy for efficient and safe treatment of hemophilia A, which is the first step towards clinical application UMGD and sustainable treatment of hemophilia A.”
Song S, Lyle MJ, Noble-Vranish ML, et al. Ultrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in mice. Mol Ther Nucleic Acids. Published online January 7, 2022. doi:10.1016/j.omtn.2022.01.006