The product that will result from this proposal is a nucleoside-modified mRNA encoding erythropoietin for treatment of red blood cell deficiency (anemia). In vitro transcribed mRNAs encoding physiologically important proteins have considerable potential for therapeutic applications. However, mRNA is naturally labile, inefficiently translated and immunogenic and has therefore been traditionally unsuited for therapy. RNARx is developing a technology that modifies mRNA by incorporating non-classical nucleosides, such as pseudouridine. Our preliminary data suggest that this improves the translational efficiency and overall stability of mRNA, as well as diminishing its immunogenicity in vivo. These favorable new properties provide an opportunity to develop deliverable pseudouridine-modified mRNAs as vectors for expressing clinically beneficial proteins safely and effectively in vivo. RNARx will collaborate with the University of Pennsylvania in this Fast-track proposal to develop the first of these therapeutic vectors for delivery of human erythropoietin (EPO). In Phase 1, nucleoside-modified mRNA encoding EPO will be developed, characterized and delivered to mice for verification of biological EPO activity in the absence of immune activation. In Phase 2, a suitable (preferably non-injection) delivery system will be developed and modified mRNA will be tested in small and large animal systems. In addition, based on new models of autoimmunity immunopathogenesis, we will investigate the potential of mRNA to exacerbate a model of autoimmunity (SLE) and whether non-immunogenic nucleoside-modified mRNA avoids this potential. At the completion of these studies, we plan to file an IND to initiate clinical trials of EPO-encoding modified mRNA. Future objectives will include the use of the mRNA platform for other biologics and for intracellular protein delivery (gene therapy), an important therapeutic need for which there are currently no products beyond human clinical trials. Deliverable proteins such as erythropoietin, insulin, and clotting factors are an enormously important arsenal of medical therapies that nevertheless carry a risk of dangerous allergic reactions. In addition, many proteins in the human body, including cell structural proteins, cannot be replaced by conventional protein administration and alternative therapies, such as gene therapy, have not performed to expectation. The product we are developing, a structurally-modified messenger RNA (the intermediary between DNA and protein), is an alternative to protein delivery and gene therapy that will enable the safe (non-allergic) and efficient replacement or enhancement of proteins (in this proposal erythropoietin) including cell structural proteins.
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