Recent advances in the field of gene therapy have led to a resurgence of clinical development programs and the approval of multiple gene therapy products for a range of genetic diseases. As opposed to protein infusion therapy, most alternative gene therapy products/product candidates are designed to provide long-term (>5 year), if not life-long, efficacy resulting from a single treatment.

Hemophilia A and B are ideal candidate disease for gene therapy approaches due to 1) the functional location of FVIII and FIX in blood, 2) the relatively low blood concentrations necessary for therapeutic benefit, as well as 3) the possibility to dramatically improve upon or alleviate the constraints of factor infusion therapy. Gene therapy can be defined as the use of nucleic acids (DNA/RNA) as pharmaceutical agents to induce therapeutic gene/protein expression in a patient. ‘Vectors’ are the vehicles used to transfer the genetic material.

They can be administered ex vivo (outside the body) to extracted cells prior to transplantation into the patient or in vivo (inside the body) via intravenous infusion. The therapeutic effect of a gene therapy can be acute or durable depending on the choice and design of the vector as well as the cell type targeted. Two of the leading clinical gene therapies strategies involve the use of recombinant adeno-associated viral (AAV) vectors for in vivo gene therapy and recombinant retroviral/lentiviral vectors (RV/LV) for ex vivo gene therapy. Preclinical research has demonstrated that ET’s core expression technologies are enabling to both AAV and RV/LV-based gene therapy approaches. ET is pursuing independent development programs for an ex vivo stem cell-LV-FVIII gene therapy product for hemophilia A as well as a liver-directed in vivo AAV- FIX gene therapy product for hemophilia B.

 

Ex Vivo Stem Cell-LV-FVIII Gene Therapy

A founding goal of ET has been to develop a cure for hemophilia A. Our lead product candidate is designed to accomplish this goal through life-long FVIII production from genetically-modified blood cells derived from the patient themselves. Briefly, white blood cells are harvested from the blood of a patient through a process called apheresis. Then in the laboratory, hematopoietic (blood) stem and progenitor cells are enriched through a process termed CD34+ selection. Subsequently, the CD34+ cells are genetically-modified (transduced) using our proprietary LV-FVIII vector and then transplanted back into the patient via a simple peripheral vein infusion. The LV-CD68-ET3 CD34+ cell product functions by engrafting back into the stem cell compartment within the bone marrow and resuming its normal function of blood cell production. However following the genetic modification procedure, these millions of daughter blood cells now provide a continuous supply of functional FVIII to the bloodstream.

 

In Vivo AAV-FIX Gene Therapy

In collaboration and/or licensing arrangements with partnering entities, ET is pursuing the development of AAV-FVIII and AAV-FIX gene therapy products for hemophilia A and hemophilia B, respectively.