Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system
Name
Anderson_Therapeutic efficacy.pdf
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2.2 MB
Format
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Checksum (MD5)
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Author(s)
DeRosa, F
Guild, B
Karve, S
Smith, L
Zhang, J
Yahalom, B
Heartlein, M W
Love, Kerry R.
Dorkin, Joseph Robert
Kauffman, Kevin John
Date Issued
June 2016
Journal
Gene Therapy
Publisher
Nature Publishing Group
Citation
DeRosa, F et al. “Therapeutic Efficacy in a Hemophilia B Model Using a Biosynthetic mRNA Liver Depot System.” Gene Therapy 23.10 (2016): 699–707.
Version
Final published version
Abstract
DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1038/gt.2016.46
