Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 10, Pages E1941-E1950Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1619653114
Keywords
lipid nanoparticles; nonviral mRNA delivery; hemophilia B therapy; systemic delivery; hepatic diseases
Categories
Funding
- Waitt Advanced Biophotonics Core Facility of the Salk Institute for Biological Studies
- NIH National Cancer Institute Cancer Center Support Grant [P30 014195]
- National Institute of Neurological Disorders and Stroke Neuroscience Core Grant
- Waitt Foundation
- NIH Cancer Center Core Grant [P30 CA014195-38]
- Ipsen
- H. N. and Frances C. Berger Foundation
- Glenn Center for Aging Research
- Leona M. and Harry B. Helmsley Charitable Trust Grant [2012-PG-MED002]
- California Institute for Regenerative Medicine [(CIRM-TR4-06809)]
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Safe and efficient delivery of messenger RNAs for protein replacement therapies offers great promise but remains challenging. In this report, we demonstrate systemic, in vivo, nonviral mRNA delivery through lipid nanoparticles (LNPs) to treat a Factor IX (FIX)-deficient mouse model of hemophilia B. Delivery of human FIX (hFIX) mRNA encapsulated in our LUNAR LNPs results in a rapid pulse of FIX protein (within 4-6 h) that remains stable for up to 4-6 d and is therapeutically effective, like the recombinant human factor IX protein (rhFIX) that is the current standard of care. Extensive cytokine and liver enzyme profiling showed that repeated administration of the mRNA-LUNAR complex does not cause any adverse innate or adaptive immune responses in immune-competent, hemophilic mice. The levels of hFIX protein that were produced also remained consistent during repeated administrations. These results suggest that delivery of long mRNAs is a viable therapeutic alternative for many clotting disorders and for other hepatic diseases where recombinant proteins may be unaffordable or unsuitable.
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