San Raffaele Telethon Institute for Gene Therapy

Gene and neural stem cell therapy for lysosomal storage diseases


Head of Unit

Angela Gritti


The overarching goal of the lab is to study and treat rare genetic diseases affecting the CNS, with a special focus on Lysosomal Storage Disorders (LSDs), including leukodystrophies - Metachromatic leukodystrophy (MLD), Globoid-cell Leukodystrophy (GLD) and Alexander's disease (AxD) - and GM2 gangliosidosis -  Sandhoff Disease (SD) and Tay-Sachs Disease (TSD). Our projects span from basic to translational research, using murine and human models, and testing different therapeutic platforms (i.e. in vivo GT, ex vivo GT; cell therapy, gene addition, gene editing).

Research activity

Our active projects fall within three research areas:

  1. Enhance gene therapy strategies for LSDs. Over the past 10 years we have shown the safety and efficacy of intracerebral LV GT in supplying therapeutic levels of functional lysosomal enzymes to ameliorate/rescue the pathology in murine and NHP models of LSDs. The main goals for this area will be: i) to move forward the clinical testing of intracerebral LV GT in MLD patients; ii) to enhance the efficacy of GT strategies, coupling enzyme overexpression achieved in effector cells with enhanced transgene bioavailability and more efficient metabolic correction of enzyme-deficient cells
  2. Modelling LSDs using iPSC-based systems. The lab has optimized culture conditions, transduction and neural differentiation protocols of human iPSCs derived from LSD patients (and non-affected controls). We have used these cells to test cell/gene therapy approaches and to model diseases, as patient-specific iPSC-derived neural populations recapitulate key biochemical features of the disease and allow for the identification of early defects in human neuronal/glial cell populations. Our goal in this area is to exploit and adapt/optimize these models to generate hiPSC-based platforms that are relevant in the context of LSDs by developing: i) co-cultures obtained by mixing defined neuronal and/or glial cell population; 3D systems (brain organoids generated using different protocols).
  3. Developing gene editing strategies to treat CNS disease. This area started less than two years ago under the supervision of Dr. V. Meneghini (Project Leader) and benefits from our unique expertise in CNS biology/disease to implement state-of-the art gene and base editing strategies that are being extensively tested in other tissues (i.e. liver, hematopoietic system) at SR-Tiget and worldwide. Our initial focus is Alexander's Disease, a rare autosomal dominant leukodystrophy caused by missense mutations in the gene encoding the glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes. We aim to provide in vivo proof-of-concept of safety, efficiency and efficacy of a novel approach based on gene editing/base editing strategies targeting GFAP mutational hotspots to correct pathological phenotypes in astrocytes. If successful, these new editing platforms for in vitro and in vivo targeting of the CNS could be prospectively applied for disease modeling and treatment of other glial and neurodegenerative diseases.