Anna Villa

Pathogenesis and treatment of immune and bone diseases

SR-Tiget Unit
Anna Villa, Head of Unit

villa.anna@hsr.it



The main goal of our Unit is to investigate the mechanisms underlying autoimmune manifestations occurring in two syndromes, Wiskott-Aldrich syndrome and Omenn Syndrome, characterized by severe infections associated with immune dysregulation. To this end, we will take advantage of mouse models that well recapitulate the clinical phenotype of the diseases. In parallel, we are studying the efficacy of gene therapy in correcting the defective phenotypes revealed in our analysis.

Curriculum vitae

  • 2006-present Head of Unit of Wiskott-Aldrich group at Telethon Institute for Gene Therapy, San Raffaele, Milan, Italy
  • 2005 Winner, 2005 Descartes Prize for Research
  • 2002-present Associate Professor, CNR, Institute of Genetic Research (IRGB)
  • 1998-2002 Professor of Biotechnology, University of Milan, Pharmacology Faculty

Scientific activity

Dr. Villa is author of 124 papers. She is reviewer for Primary Immunodeficiency Association (PiA) and Association Française contre les Myopathies (AFM). Dr. Villa is responsible for data bank of Rag Defects and Osteopetrosis: http://www.uta.fi/bioinfo and Secretary of the European Society of Immunodeficiencies (ESID).

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 thrombocytopenia X linked (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. Indeed she showed that hypomorphic mutations in Rag1 and Rag2 genes impairing but not abolishing the protein activity, are responsible for this SCID form. She focused her analysis on the molecular and biochemical effects of these mutations trying to correlate the clinical signs of Omenn syndrome with the molecular defects. To further address the pathophysiology of this disease, she recently generated a murine model carrying an hypomorphic mutation in Rag2 gene found in an Omenn patient. Thanks to the availability of this mouse model, which well recapitulates the human phenotype, she was able to demonstrate defects in the mechanisms of central and peripheral tolerance. She also performed studies on regulatory T cells in patients demonstrating a defect in suppression activity function. 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,>with an 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. In parallel with gene therapy studies, she has also addressed her interest to the pathophisiology of Wiskott Aldrich syndrome demonstrating that the lack of WASp caused a defect in maturation and function of iNKT cells.

Anna Villa has also strongly contributed to the molecular dissection of an important genetic disease. In the last ten years, she has directed her interests to a heterogeneous group of bone diseases, named Osteopetrosis. Her group has indeed identified TCRG1 as the gene responsible for autosomal recessive form of osteopetrosis (ARO) (Nature Genetics, 2000) and later on contributed to the characterization of two other forms of ARO due to defect in Grey Lethal and Pleckstrin genes, respectively (Nature Medicine, 2003; Journal of Clinical Investigation, 2007). More recently her group has described RANKL and RANK as genes responsible for the osteoclast poor Osteopetrosis (Nature Genetics, 2007; Am J Human Genetics, 2008). The molecular dissection of ARO has important implication not only for the molecular diagnosis, but also for the treatment of the disease. Indeed RANKL dependent ARO forms cannot be cured by bone marrow transplantation and the recognition of this molecular defect could candidate these patients to alternative therapeutic approaches.

 

  Villa home | Curriculum | Lab members | Research | Publications