Hemophilia A is a X-linked recessive bleeding disorder with genetic mutations of coagulation factor VIII (fVIII) gene, followed by a defect of fVIII in the patients plasma, and resulting in the failure of blood clotting. Replacement of therapeutic fVIII is currently applied as a therapy but ~30% of severe Hemophilia A patients suffer with the rise of anti-fVIII neutralizing antibody (fVIII inhibitor antibody), which blocks clotting activity of replaced fVIII in the plasma. Immune tolerance induction (ITI) or systemic immunosuppression by administration of high dose fVIII, or general immunosuppressive drugs, are currently standard treatments but these are very expensive and could cause adverse events (e.g., undesired systemic immunosuppression) compared to those prophylactic and therapeutic effects. Therefore, fVIII-specific clinical Treg cell therapy has been considered as an ideal alternative to control fVIII inhibitor antibody. Our team has demonstrated solid proof of concepts of Treg infusion therapy using fVIII-specific TCR (T cell receptor), CAR (chimeric antigen receptor), and BAR (B cell antibody receptor) Tregs. In this project, TeraImmune, in collaborations with the Scott lab and Dr. Michael Guerrera, will develop personalized clinical-grade fVIII TCR-Tregs using lentiviral gene transfer system. Furthermore, we will develop GMP ancillary materials (AMs) and related cGMP-compliant ex vivo manufacturing protocols for clinical-grade fVIII TCR-Tregs by combining of ODNps25 Treg stabilization technology.
Public Health Relevance Statement: Project Narrative A major problem in the treatment of hemophilia A patients with coagulation factor VIII (FVIII) is that up to 30% of these patients produce antibodies called inhibitors to therapeutic FVIII, that block the pro-coagulant function. The project is to develop clinical-grade engineered therapeutic Tregs, which directly suppress fVIII- specific B cells in Hemophilia A patients with inhibitors. With successful completion of the project, we anticipate to provide a valuable alternative treatment option to refractory hemophilia patients as well as for pharmaceutical drug development to apply to bring engineered T regulatory cell technology to the market.
Project Terms: Adverse event; alternative treatment; Antibodies; antibody inhibitor; Antibody Response; Autoimmune Diseases; Autologous; B-Lymphocytes; base; Blood coagulation; Blood Coagulation Disorders; Blood Coagulation Factor; Cell Therapy; Cells; Child; chimeric antigen receptor; Clinic; Clinical; clinical application; clinical development; Clinical Protocols; Clinical Trials; Cloning; Coagulation Process; Collaborations; cost; Cyclic GMP; Defect; Development; DNA Sequence Alteration; Dose; drug development; drug standard; Engineering; Evaluation; experience; F8 gene; Factor VIII; Failure; Fc Receptor; Gene Transfer; Genes; Hemophilia A; Hemorrhage; Human; Immune response; Immune Tolerance; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; in vivo; Infusion procedures; inhibitor/antagonist; innovation; Lead; Legal patent; Link; manufacturing process; Medical center; Methods; Mutation; neutralizing antibody; Oligonucleotides; Outcome; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Procedures; prophylactic; Protocols documentation; Receptors, Antigen, B-Cell; Recombinants; reconstruction; Refractory; Regulatory T-Lymphocyte; Replacement Therapy; response; Side; skills; Solid; standard care; System; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Tumorigenicity; Virus Diseases
