Live-cel Platforms
The Live-cell technology is being applied to three enzyme deficiency disorders - Fabry, Pompe and Gaucher diseases.
Fabry Live-cel Program (GLA: alpha-galactosidase A):
Treating Fabry disease caused by GLA deficiency - a condition affecting over 800,000 persons worldwide.
Pompe Live-cel Program (GAA: acid maltase):
Treating Pompe disease caused by GAA deficiency - a condition affecting over 400,000 persons worldwide.
Gaucher Live-cel Program (GBA1: acid glucosylceramidase):
Treating Gaucher disease caused by GLB1 deficiency - a condition affecting over 160,000 persons worldwide.
Our Live-cel programs create a cell-based gene therapy starting with stem cells harvested from the patient’s blood (ex vivo, autologous-derived). Hematopoietic stem cells (HSCs) are mobilized in the patient’s bone marrow after exposure to G-CSF (filgrastim) and Plerixafor (Mozobil). Leukapheresis is performed to harvest white blood cell population containing the mobilized HSCs. The harvested cells are exposed to CD34+ beads to isolate and retrieve the HSCs (the “CD34+ cells”). The CD34+ cells are exposed to a lentiviral vector that contains a working copy of the missing enzyme (alpha-galactosidase A driven by EF1A promoter). Conditions are optimized to provide a genomic integration of transgene at a 1 to 1 vector copy number (VCN) and the resulting cell product is cryopreserved for future use in the patient. Prior to receiving the cell product, the patient is conditioned with a Reduced Intensity Condition (RIC) protocol using low dose melphalan (mel100). After patient conditioning, the cell product is thawed and infused into the patient. Bone marrow engraftment of the modified cells ensues and the patient start to produce modified white blood cells. The modified cells disseminate systemically and produce enzyme throughout the body. Neighboring cells actively uptake the secreted enzyme by a M6P receptor mediated uptake pathway that restores enzymatic function to the neighboring cell lysosomes and they can stop the build up of toxic lipid metabolites. The entire procedure is delivered in an outpatient setting.
Live-cel Therapy Detail
The Live-cel procedure involves induction of HSC mobilization in the patient.
Mobilized cells are then harvested from the patient by apheresis.
In the lab the HSCs are isolated by CD34+ selection.
Lentivector transduction of CD34+ cells is performed.
The resulting cells contain a working copy of the target gene.
The modified HSCs are reintroduced into the patient as a transplant procedure where engraftment into the bone marrow ensues.
The resulting modified blood cells secrete the normal enzyme which leads to restoration of gene function.
Our Live-cel therapy approach is an improvement over intermittent enzyme exposure with recombinant protein transfusion. Unlike traditional enzyme replacement therapy (ERT), our Live-cel therapy provides uninterrupted cross-correction - the patient obtains a more continuous supply of the replacement enzyme lasting for at least 5 years in a Canadian clinical trial (PMID 39794302). Furthermore, the transplant leukocytes are known spread systemically to a wide variety of compartments in the body, including the brain, thus the blood brain barrier problem with traditional recombinant protein transfusions is a much lower obstacle. As a result, successful treatment of neurological complication of enzyme deficiency can be expected.
