Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles
Open accessAbstract
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.
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mRNA-based protein replacement therapies have been applied to haematological diseases, central nervous system disorders, skin diseases and hearing loss in preclinical studies.
“In addition, mRNA-based protein replacement therapies have been applied to haematological diseases (for example, haemophilia A232, haemophilia B91,104,233 and thrombotic thrombocytopaenic purpura234), central nervous system disorders67,152 (for example, Friedreich’s ataxia67), skin diseases235,236 (for example, elastin deficiency235) and hearing loss237 in preclinical”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [232]
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Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076 · see citing works
- Authors
- Chen, C.-Y., Tran, D. M., Cavedon, A., Cai, X., Rajendran, R., Lyle, M. J., Martini, P. G. V., & Miao, C. H.
- Affiliations
- Seattle Children's Research Institute (US)
- Moderna Therapeutics (United States) (US)
- University of Washington (US)
- Corresponding author
- Miao, Carol H.
- Venue
- Molecular Therapy Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 20
- Pages
- 534-544
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC7178004
- OpenAlex
- W3015503845
- Cited by
- 89
- References
- 62
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 25 · 2023: 19 · 2022: 13 · 2021: 9 · 2020: 3
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Moderna Therapeutics
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- hemophilia A, factor VIII, lipid nanoparticle mRNA delivery, mRNA therapeutics, B-domain-deleted factor VIII, prophylaxis, immunodeficient mice
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