Research projects in progress

Development of new gene therapy strategies to treat mitochondrial diseases

Development of a GENE THERAPY strategy for the combined deficiency of oxidative phosphorylation type 1 due to mutations in GFM

Hepatoencephalopathy due to the combined deficiency of oxidative phosphorylation type 1 (COXPD1) is caused by mutations in the nuclear gene GFM1, which encodes the mitochondrial translation elongation factor G1 (EFG1). Therefore, it is a mitochondrial disease caused by defects in the mitochondrial protein translation process. The disease manifests itself very early after birth with a hepatoencephalopathic clinical picture and progresses rapidly. There is no treatment for this disease and patients die during the first months of life, although some cases that survive beyond 6 years of age have been reported.

Our hypothesis proposes that gene therapy by introducing a copy of the GFM1 gene into the patient’s cells or by gene editing is able to correct or stop the development of the disease.
The objectives of this study are partly to evaluate the effect of the use of viral vectors for the expression of EFG1 in patient cells and in the mouse disease model.

To do this, we will transduce induced pluripotent cells (iPSCs) from patients with a lentiviral vector that contains a copy of the GFM1 gene, previously validated in our laboratory in several patients fibroblasts, and study their ability to restore mitochondrial protein synthesis and recover their mitochondrial function. In addition, we will treat a murine model that contains the mutated Gfm1 gene (mouse
Gfm1R671C / KO) with adeno-associated vectors that allow the expression of EFG1 in the liver and brain, and evaluate its ability to correct the disease phenotype.

This proposal also aims to test the gene edition by using the S. pyogenes CRISPR / Cas9 system to genetically correct the punctual mutation in GFM1 most prevalent in this disease and which is present in patients with COXPD1 hepatoencephalopathy with greater survival. For this, we will use fibroblasts from three patients with the c.2011C> T mutation in which we will validate the elements of the CRISPR / Cas9 system of S. pyogenes designed for gene therapy by means of gene editing for COXPD1 and evaluate its ability to correct the defect of the mitochondrial function present in the fibroblasts of patients.

To develop this project, a

MULTICENTRIC CONSORTIUM

composed of four different research centers, led by the following researchers:

Execution: 50%