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Prof. Villa has published 188 papers in international scientific journals. The main focus of her research has been the molecular and cellular dissection of severe combined immunodeficiencies. In her early career, Anna Villa identified the genes responsible for different forms of severe combined immunodeficiency (SCID). In particular, she identified Jak3 as the gene responsible for T+B –  SCID published on Nature in 1995 and later she discovered mutations in WAS gene in patients suffering from X – linked thromobocytopenia (Nature Genetics,1995). During the following years, she addressed her studies to a peculiar form of SCID, named Omenn syndrome, characterized by activated T cells and absence of B cells in the presence of high level of IgE (Cell, 1998). She was able to characterize the molecular defects underlying this enigmatic immunodeficiency.

In parallel with the identification of genes involved in SCID, Anna Villa has addressed her studies to the efficacy and safety of gene therapy of Wiskott Aldrich syndrome, a complex and severe X – linked disorder characterized by micro – thrombocytopenia, eczema, immunodeficiency, and increased risk to develop autoimmunity. Using third generation of lentiviral vector carrying human WAS gene driven by its own promoter, she demonstrated that gene therapy can restore functional defects in T cells and more recently in B cells. Thanks to the preclinical studies, a lentiviral vector based clinical trial for the human WAS disease is now undergoing at the San Raffaele Institute (Science, 2013, JCI 2015, JACI 2015). In parallel with gene therapy studies, she has also analyzed the pathophisiology of Wiskott Aldrich syndrome demonstrating that the lack of WASp causes a defect in maturation and function of iNKT cells (JEM, 2009), dendritic cells and B cells (JEM 2013, JACI 2014, JCI 2015). She is currently evaluating the follow up of gene therapy patients focusing on B cell and platelet defects.

Anna Villa has also strongly contributed to the molecular dissection of another important genetic disease. In the last years, she has directed her interests to a heterogeneous group of bone diseases, named Osteopetrosis. These studies represent the beginning of the molecular dissection of this complex and heterogenous inherited bone defects.

Currently, Villa’s group is involved in the identification of candidate genes responsible for novel forms of ARO and ADO by genome wide sequencing and in parallel testing novel gene correction approaches. To this end, her lab has recently established a cellular data bank of induced Pluripotent stem cells (iPSC) obtained from patients carrying defects in the main genes involved in ARO forms. The generation of this cellular lines source represents a disease modelling relevant for the comprehension of the molecular and cellular bases of the disease and for testing novel cellular therapeutic approaches (Stem Cell Reports, 2015). To this regard, in the past Villa’s group has performed pioneer studies aimed at understaining the feasibility and efficacy of in utero stem cell transplantation in the murine model of osteopetrosis (Proc Natl Acad Sci, 2005). More recently, her group has tested and optimized a novel strategy to correct TCIRG1 gene defect by gene targeting in murine iPSC obtained from the murine model of osteoepetrosis (oc/oc mouse). Finally, Villa’s group has generated a third generation lentiviral vector carrying human RANKL gene to cure osteoclast – poor form of ARO casued by defects in rankl molecule. Experiments to test the efficacy of this gene therapy approach to cure RANKL defective osteopetrosis are currently ongoing.


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