Factor VIII (fVIII)-specific therapeutic Tregs and related cGMP manufacturing process for hemophilia A patients with inhibitors

Project Summary Abstract Hemophilia A is a X linked recessive bleeding disorder with genetic mutations of coagulation factor VIIIfVIIIgenefollowed by a defect of fVIII in the patient s plasmaand resulting in the failure of blood clottingReplacement of therapeutic fVIII is currently applied as a therapy butof severe Hemophilia A patients suffer with the rise of anti fVIII neutralizing antibodyfVIII inhibitor antibodywhich blocks clotting activity of replaced fVIII in the plasmaImmune tolerance inductionITIor systemic immunosuppression by administration of high dose fVIIIor general immunosuppressive drugsare currently standard treatments but these are very expensive and could cause adverse eventse gundesired systemic immunosuppressioncompared to those prophylactic and therapeutic effectsThereforefVIII specific clinical Treg cell therapy has been considered as an ideal alternative to control fVIII inhibitor antibodyOur team has demonstrated solid proof of concepts of Treg infusion therapy using fVIII specific TCRT cell receptorCARchimeric antigen receptorand BARB cell antibody receptorTregsIn this projectTeraImmunein collaborations with the Scott lab and DrMichael Guerrerawill develop personalized clinical grade fVIII TCR Tregs using lentiviral gene transfer systemFurthermorewe will develop GMP ancillary materialsAMsand related cGMP compliant ex vivo manufacturing protocols for clinical grade fVIII TCR Tregs by combining of ODNpsTreg stabilization technology Project Narrative A major problem in the treatment of hemophilia A patients with coagulation factor VIIIFVIIIis that up toof these patients produce antibodies calledinhibitorsto therapeutic FVIIIthat block the pro coagulant functionThe project is to develop clinical grade engineered therapeutic Tregswhich directly suppress fVIIIspecific B cells in Hemophilia A patients with inhibitorsWith successful completion of the projectwe 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