Descripción del proyecto
Terapia génica «ex vivo» para la gangliosidosis GM1
La gangliosidosis GM1 es un trastorno hereditario causado por mutaciones en el gen GLB1 que codifica la hidrolasa lisosomal β-galactosidasa. Los pacientes acumulan metabolitos no degradados en lisosomas, lo cual provoca daños celulares que afectan principalmente al sistema nervioso central. El proyecto financiado con fondos europeos GT-GM1 tiene por objeto desarrollar un método de terapia génica para la distribución del gen GLB1 solo o en asociación con un factor neuroprotector. Los científicos utilizarán un modelo murino de la enfermedad y vectores lentivíricos para la administración «ex vivo» del gen a las células madre o progenitoras hematopoyéticas. Las células modificadas genéticamente se volverán a infundir por vía intravenosa y en los ventrículos encefálicos de animales para obtener un efecto terapéutico.
Objetivo
"GM-gangliosidosis (OMIM #230500) is a rare, autosomal recessive, neurodegenerative Lysosomal Storage Disorder. It is caused by mutations in the GLB1 gene, encoding the lysosomal hydrolase β-galactosidase. Infantile GM1-gangliosidosis is characterized by neurodevelopmental delay, hypotonia, dysphagia, seizures and death by 3 years of life. Due to the rapid progression and severe nature of this disease, which involves storage of undegraded metabolites and secondary mechanisms of cell damage, correction requires a rapid and robust enzyme delivery to the whole central nervous system (CNS), possibly associated to reduction of local inflammation. Here we propose an ex vivo gene therapy (GT) strategy aimed at preventing or ameliorating the symptoms of the disease in the murine model. Multiple copies of GLB1, alone or in association with a neuroprotective factor, will be delivered ex vivo to hematopoietic stem/progenitor cells by lentiviral gene transfer to determine a sustained and robust expression of the therapeutic enzyme in the CNS of transplanted mice. Genetically modified HSPCs will be administered by a novel approach combining the conventional intravenous route with direct administration into the brain lateral ventricles, to anticipate the myeloid reconstitution in the brain and possibly the therapeutic effect. Our working hypothesis is that this optimized GT strategy could successfully control disease manifestations in the animal model. Moreover, a deep genome-wide genomics analysis will be performed on individual brain cells to elucidate the molecular mechanisms at the basis of the disease and mediating the therapeutic effect. The study will generate a proof of concept for a future clinical development of an efficacious ex vivo GT for infantile GM1-gangliosidosis and will inspire the development of therapies for other LSDs.
"
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
35122 Padova
Italia