The results from the first nonhuman primate study provide strong evidence for supporting the evaluation of lobe-specific hydrodynamic gene delivery to the liver in clinical trials with subjects with hemophilia.
“In this study, we demonstrate that the appropriate hydrodynamic parameters, including injection volumes and speed, achieved the therapeutic level of hFIX [human factor IX] in baboons,” the study’s authors wrote in Molecular Therapy – Nucleic Acids.
“The impact of the hydrodynamic injection is generated by the combined effects of injection volume and speed, which resulted in rapid liver expansion, stretching of the hepatocytes, and increase of hepatocyte cell membrane permeability, allowing gene-containing solution to enter cell interior.”
By using image-guided, liver lobe-specific gene delivery of an hFIX-expressing plasmid in baboons, the researchers accomplished site-specific gene delivery and achieved coagulation activity above the therapeutic threshold of 10%.
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Gene expression returned to therapeutic levels with repeated administration 210 days after the first injection.
Furthermore, the approach allowed the researchers to achieve a plasma concentration of hFIX greater than 1.0 mg/mL in the baboon, lasting for more than 100 days without persistent negative events. The only adverse event reported was a transient increase in blood concentration of liver enzymes immediately after the injection.
Hemophilia gene therapy has been conducted using adeno-associated virus (AAV) vectors, which are capable of successful gene delivery and induction of coagulation activity above the therapeutic threshold. However, host immune responses against the vector, due to preexisting anti-AAV neutralizing antibodies, remain one of the main hurdles of the AAV system.
Moreover, previous studies in animal models suggest that integration of the AAV genome may occur after AAV vector administration, leading to clonal expansion and cancer.
On the other hand, hydrodynamic delivery of naked DNA offers the advantage of eliciting only residual immunological response, thereby allowing repeated administration once the transgene expression return to basal levels, and, in the light of current evidence, it does not cause genome integration.
Kamimura K, Kanefuji T, Suda T, et al. Liver lobe-specific hydrodynamic gene delivery to baboons: a preclinical trial for hemophilia gene therapy. Mol Ther – Nucleic Acids. Published on line May 16, 2023. doi:10.1016/j.omtn.2023.05.018