Gene therapy for hemoglobinopathies and neurometabolic diseases caused by β-Galactosidase deficiency

Research Activity

Valentina Poletti’s laboratory is focused on the development of innovative, safe and efficient GT strategies for hemoglobinopathies and neurometabolic diseases caused by β-Galactosidase deficiency. β-Thalassemia and Sickle Cell Disease are the most common monogenic diseases worldwide, with >317,000 newborn/year, caused by defects of β-globin expression or structure. Ex vivo Hematopoietic Stem/Progenitor Cells (HSPCs) gene therapy (GT), i.e. autologous transplantation of HSCs modified by lentiviral (LV) gene-transfer to express a therapeutic protein, is an extremely promising approach for patients not eligible to allogeneic HSPC transplantation. Only partial clinical efficacy has been achieved so far by the only approved GT for β-thalassemia, i.e. Zynteglo®, mainly due to suboptimal Hb production and inner LV restraints. Here we propose to develop an original, forward-looking GT strategy for β-globin defects to overcome these limitations, based on 1) gene-cassette optimization for enhanced production of a potent anti-sickling β-globin; 2) the usage of novel hyper-functional transposon-vectors to safely integrate multiple copies of complex gene-cassettes into HSPCs; 3) the implementation of a new, cost-effective, scalable and standardized vector-production generating ready-to-use minicircle DNAs. Another focus of the lab. is the generation of novel synthetic hyper-functional enzymes for GT by molecular evolution. In particular, the use of a novel synthetic hyper-functional human β-Galactosidase (β-Gal) could enable the HSC GT for two lysosomal storage diseases caused by β-Gal deficiency, i.e. GM1 Gangliosidosis and Mucopolysaccharidosis type IVB, with an increased efficacy and reduced dose and cost. This molecular evolution approach could set a new modality for the development of novel therapies for orphan genetic diseases.