Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles.
RNA therapy
factor VIII
gene delivery
gene transfer
hemophilia A
lipid nanoparticle
liver
mRNA
nonviral
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
05 Jun 2020
05 Jun 2020
Historique:
received:
13
03
2020
revised:
23
03
2020
accepted:
30
03
2020
pubmed:
25
4
2020
medline:
25
4
2020
entrez:
25
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32330871
pii: S2162-2531(20)30106-2
doi: 10.1016/j.omtn.2020.03.015
pmc: PMC7178004
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
534-544Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL134321
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL082600
Pays : United States
Organisme : NHLBI NIH HHS
ID : R33 HL089038
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123326
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL142019
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151077
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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