Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles

• Published in: Molecular therapy. Nucleic acids 2020-06, Vol.20, p.534-544
• Main Authors: Chen, Chun-Yu, Tran, Dominic M., Cavedon, Alex, Cai, Xiaohe, Rajendran, Raj, Lyle, Meghan J., Martini, Paolo G.V., Miao, Carol H.
• Format: Article
• Language: English
• Subjects: factor VIII; gene delivery; gene transfer; hemophilia A; lipid nanoparticle; liver; mRNA; nonviral; RNA therapy
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2020.03.015

Hemophilia A (HemA) patients are currently treated with costly and inconvenient replacement therapy of short-lived factor VIII (FVIII) protein. Development of lipid nanoparticle (LNP)-encapsulated mRNA encoding FVIII can change this paradigm. LNP technology constitutes a biocompatible and scalable system to efficiently package and deliver mRNA to the target site. Mice intravenously infused with the luciferase mRNA LNPs showed luminescence signals predominantly in the liver 4 h after injection. Repeated injections of LNPs did not induce elevation of liver transaminases. We next injected LNPs carrying mRNAs encoding different variants of human FVIII (F8 LNPs) into HemA mice. A single injection of B domain-deleted F8 LNPs using different dosing regimens achieved a wide range of therapeutic activities rapidly, which can be beneficial for various usages in hemophilia treatment. The expression slowly declined yet remained above therapeutic levels up to 5–7 days post-injection. Furthermore, routine repeated injections of F8 LNPs in immunodeficient mice produced consistent expression of FVIII over time. In conclusion, F8 LNP treatment produced rapid and prolonged duration of FVIII expression that could be applied to prophylactic treatment and potentially various other treatment options. Our study showed potential for a safe and effective platform of new mRNA therapies for HemA. [Display omitted] Messenger RNA (mRNA) encapsulated in lipid nanoparticles (LNPs) can be efficiently delivered into the liver. LNPs carrying FVIII mRNA (F8 LNPs) produced rapid and prolonged duration of FVIII expression in hemophilia A mice. This safe and effective platform of new mRNA therapies could be used for prophylactic treatment and potentially various other treatment options for hemophilia A patients.