Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system

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

Optical properties of epitaxial SrHfO3 thin films grown on Si

The perovskite SrHfO3 can be a potential candidate among the high-permittivity materials for gate oxide replacement in future metal-oxide semiconductor field-effect transistor technology. Thin films of SrHfO3 were grown by molecular beam epitaxy and compared with SrTiO3 films. Their optical properties were investigated using spectroscopic ellipsometry and analyzed with respect to their structural properties characterized by x-ray diffractometry, atomic force microscopy, and transmission electron microscopy. A band gap of E-g=6.1 +/- 0.1 eV is measured optically, which renders this material better suited for gate dielectric applications than SrTiO3 with E-g similar to 3.4 eV. At similar equivalent oxide thickness, SrHfO3 also exhibits lower gate leakage current than SrTiO3 does.status: publishe