Gene Therapy for Neurologic Forms of Gaucher Disease – GTnGD

Gaucher disease results from mutations that alter the enzyme beta-glucocerebrosidase, involved in the metabolism of glycosphingolipids. This defect in lipid homeostasis affects macrophage function. The phenotypic expression of the disease is variable but predominantly affects the liver, spleen and bone. In some forms of the disease, neurological involvement is observed progressively, or early in the newborn. Treatment with enzyme therapy does not stop it. The aim of the project is to have beta-glucorebrosidase produced not only by leukocytes, to treat peripheral damages, but also, in high quantities, by microglial cells to transport the enzyme to the neurons of the central nervous system. Indeed, hematopoietic cells are capable of replacing the existing microglia after a myeloablative transplant of hematopoietic stem cells. They should therefore be able to provide the required amount of enzyme to neurons that lack it after transplantation of genetically modified autologous stem cells. There is no animal model that recapitulates the severe neuronal damages and that can be used for hematopoietic transplantation studies. We have developed a three-dimensional, multicellular disease model of Gaucher Disease using induced pluripotent stem cells from patients as well as isogenic genetically modified cells. We are also developing lentiviral vectors capable of producing supra-physiological amounts of enzyme. The mini-brain pathology model will allow us to evaluate the benefit of a gene therapy based on the delivery of the missing protein to the central nervous system by lentiviral vector-modified microglial cells. It will also make it possible to clarify the role of the different cellular components in neuronal death in Gaucher disease patients and the underlying molecular mechanisms.