Technology Description

Current treatment for Hemophilia A consists of administering plasma derived or recombinant plasma clotting factor VIII (FVIII), or anticoagulation inhibitors. These treatments are expensive, may need to be administered at a treatment center, and require repeated dosing. Gene therapy is an attractive approach however an effective DNA delivery system remains elusive. Part of the challenge is efficient delivery of DNA to the nucleus of quiescent hepatocytes. The delivery of mRNA to the cytosol of hepatocytes circumvents the need for nuclear delivery, but mRNA is unstable in plasma and rapidly regraded.

Inventors at the University of Iowa have developed double stranded mRNA (dsmRNA) loaded-nanoparticles for the treatment of hemophilia A. Polyethylene glycol (PEG)-peptides containing Lys-Acr residues bind to dsmRNA constructs which are designed to be self-amplifying, providing long-term expression. Delivery of dsmRNA nanoparticles to the cytosol circumvents the major limitations of DNA delivery and provide 3000-fold metabolic stability in plasma compared to single stranded mRNA. Efficient hepatocyte targeting is achieved using a high-affinity triantennary N-glycan attached to the PEG-peptide, which mediates high affinity endocytosis into hepatocytes. These novel dsmRNA nanoparticles can be used for efficient delivery and expression of FVIII for the treatment of HA and may also be used to target other genetic conditions.

UIRF Case no. 2015-120

Stage of Development

DsmRNA-loaded nanoparticles have been synthesized and stability and expression tested in mice.

• Increased stability in plasma
• Reduced immune response
• Long-term expression

Poliskey JA, Crowley ST, Ramanathan R, White CW, Mathew B, Rice KG. Metabolically stabilized double-stranded mRNA polyplexes. Gene Ther. 2018;25(7):473–484. doi:10.1038/s41434-018-0038-3