The development of transformative therapeutics, including the possibility of a cure though gene therapy, is the sole mission of Expression Therapeutics and continues to be a major research and development activity in the overall $10 B USD hemophilia market space. However, progress in the field has been limited by significant hurdles including the size, complexity, instability, immunogenicity and biosynthetic inefficiency of coagulation factor VIII (FVIII). Through the study of existing vertebrate species and, even more recently, predicted ancestral FVIII variants, we have identified differentials in molecular, cellular, immunological and biochemical properties that are predicted to be pharmacologically beneficial. Based on these data, as well as existing knowledge of FVIII biosynthesis and mechanism of action, we have bioengineered a novel FVIII candidate, An-53, for both protein infusion and gene-based therapies. In the current proposal, we seek to compare the performance of An-53 to existing FVIII candidates including the hybrid human/porcine FVIII, ET3, and B domain deleted human FVIII in lentiviral vector and adeno-associated viral vector gene therapy platforms. Additionally, we will perform critical immunogenicity assessments that, together with the gene transfer performance data will facilitate lead candidate selection by Expression Therapeutics.
Public Health Relevance Statement: NARRATIVE The milestones of this project are the identification of a lead candidate coagulation factor VIII transgene. Expression TherapeuticsÂ’ scientific team has identified a bioengineered ancestral factor VIII molecule that displays superior pharmacological properties to existing factor VIII products. The milestones of the current project are to complete performance validation studies and a rigorous immunogenicity assessment of this novel product candidate prior to initiation of IND-enabling studies for both hematopoietic stem cell-directed lentiviral gene therapy as well as liver directed adeno-associated viral gene therapy programs.
Project Terms: adeno-associated viral vector; Amino Acids; Anabolism; Antibodies; Area; base; Binding; Biochemical; Bioinformatics; Biological Products; Biomedical Engineering; Blood Coagulation Disorders; Blood Coagulation Factor; candidate selection; candidate validation; Clinical; Clinical assessments; commercialization; comparative efficacy; Computer Simulation; Culture Media; Data; design; Development; Directed Molecular Evolution; DNA Recombinant Proteins; Effectiveness; Engineering; Epitopes; Evaluation; experimental study; Factor VIII; Family suidae; Formulation; Future; gene therapy; Gene Transfer; Genetic; Half-Life; Harvest; Hematopoietic stem cells; Hemophilia A; Homologous Gene; Housing; Human; Hybrids; Immune; Immune response; immunogenic; immunogenicity; Immunologics; improved; In Vitro; in vivo; Infusion procedures; Knowledge; Laboratories; Lead; Lentivirus Vector; Liver; Maps; Marketing; Methods; Minor; Mission; Molecular; Molecular Evolution; Monoclonal Antibodies; Mus; Mutagenesis; Natural Selections; Nature; novel; Orthologous Gene; Output; Performance; Pharmacologic Substance; Pharmacology; Phase; Plasma; pre-clinical; preclinical efficacy; preclinical evaluation; predictive modeling; prevent; Production; programs; Property; Proteins; Publishing; Recombinant Proteins; reconstruction; research and development; Research Design; Resolution; Rh Factors; Risk; Safety; Sales; Scanning; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; success; System; Tertiary Protein Structure; Testing; Therapeutic; Transgenes; validation studies; Variant; Viral; Viral Genes
