Bioengineered factor VIII gene therapy for hemophilia A

DESCRIPTION provided by applicant The overall goal of this proposal is to conduct a gene therapy clinical trial incorporating genetically modified hematopoietic stem cells HSCs for persons with hemophilia A In a series of recent studies we have shown that the transplantation of genetically engineered HSCs can restore factor VIII fVIII activity to curative levels in hemophilia A mice and that human HSCs are readily transduced with recombinant lentivector encoding a genetically engineered fVIII transgene Our gene therapy approach uses a bioengineered fVIII transgene designed at Emory University and contains critical high expression sequences which we have shown are necessary and sufficient to achieve therapeutic curative fVIII expression levels Using the bioengineered fVIII construct designated ET in preclinical murine studies we routinely observe normal fVIII activity levels unit ml i mice engrafted with genetically modified hematopoietic cells These engraftment levels are similar to those that have already been achieved in human HSC based clinical gene therapy trials In contrast we and others have shown that similar strategies using fully human fVIII sequences do not achieve these robust fVIII activity levels in the hemophilia A mouse preclinical model We have generated extensive preclinical data using the ET transgene which demonstrate proof of concept that HSCs genetically engineered with ET encoding lentivector coupled with a non myeloablative transplant regimen can be used to treat and possibly cure hemophilia A In addition a favorable pre IND meeting was held that provided the necessary guidance needed to finalize our preclinical data package and vector manufacturing We now propose to generate late stage preclinical data using clinical grade GMP lentivector product complete the regulatory submissions necessary for approval to conduct a pilot gene therapy clinical trial and recruit and treat patients with hemophilia A in the proposed trial Four organizations have partnered to accomplish these aims including i Expression Therapeutics LLC a biotechnology company founded on the high expression fVIII technology ii Emory University where the majority of the preclinical studies have been performed iii Childrenandapos s Healthcare of Atlanta a financial supporter of the Gene Therapy Program at Emory University and investor in Expression Therapeutics and iv Lentigen Corporation a company dedicated to the successful clinical application of lentivectors Lentigen will generate the clinical lentivecto product that will be used in the proposed studies including the clinical trial and the trial will e conducted at Emory University by expert principal investigators with clinical expertise in stem cell transplantation and the treatment of hemophilia A The chief milestone of the current Phase II SBIR proposal is the translation of the ET gene therapy concept and project from the late pre clinical study phase into a first in man trial PUBLIC HEALTH RELEVANCE Insufficient circulating blood clotting factor VIII activity results in the bleeding disorder hemophilia A Current treatment for this disease consists of a difficult life long intravenous infusion regimen of plasma derived or recombinant factor VIII product to restore factor VIII activity Gene therapy offers a potential cure for this debilitating and in mot of the world lethal disease Expression Therapeutics is developing a transformational approach to hemophilia A care in the form of hematopoietic stem cell transplantation gene therapy incorporating a bioengineered factor VIII transgene designed for improved expression This transgene and strategy have shown feasibility efficacy and safety in preclinical studies leading to the current project which encompasses a pilot clinical study to demonstrate first in man safety of a hematopoietic stem cell transplantation gene therapy for hemophilia A