Anna Villa
Anna Villa
e-mail:
affiliation: TIGET
research area(s): Stem Cells And Regenerative Medicine, Immunity And Infection
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
1993-1998 Senior Investigator , Institute of Biomedical Technology, Segrate (Milan) Italy
1999-2001 Researcher at Consiglio Nazionale delle Ricerche, Institute of Biomedical Technology, Segrate (Milan) Italy
1998-2002. Professor of Biotechnology, University of Milan, Pharmacology Faculty.
2002"2006 Associate Professor, CNR, Institute of Biomedical Technology, Segrate (Milan) Italy
2006- present Director of Research at CNR Institute of Biomedical Technology, Segrate (Milan) Italy
2006-present Group Leader of Omenn and Wiskott Aldrich group at Telethon Institute for Gene Therapy, San Raffaele, Milan, Italy

Dr Villa has published 110 papers in international scientific journals for a total citations of 3285 and Scopus "h" index of 30. 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, has 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 an 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.


Bosticardo M, Marangoni F, Aiuti A, Villa A, Roncarolo MG. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome.Blood. 113:6288-6295, 2009.

Schinke T, Schilling AF, Baranowsky A, Seitz S, Marshall RP, Linn T, Blaeker M, Huebner AK, Schulz A, Simon R, Gebauer M, Priemel M, Kornak U, Perkovic S, Barvencik F, Beil FT, Fattore AD, Frattini A, Streichert T, Pueschel K, Villa A, Debatin KM, Rueger JM, Teti A, Zustin J, Sauter G, Amling M.Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med.15: 674, 2009.

. Mazzolari E, Forino C, Razza A, Porta F, Villa A, Notarangelo LD.A single-center experience in 20 patients with infantile malignant osteopetrosis.Am J Hematol. 84(8):473-479,2009.

Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, Peterson P, Facchetti F. Human Peripheral Lymphoid Tissues Contain Autoimmune Regulator-Expressing Dendritic Cells.Am J Pathol. 2010 Jan 21. [Epub ahead of print]

Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations.Hum Mutat. 31:E1071-80,2010.

Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, Grunebaum E, Roifman CM, Cervi MC, Ambrosi A, Carlucci F, Roncarolo MG, Villa A, Rubinacci A, Aiuti A.ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency.Blood.114: 3216-3226,2009.

Cassani B, Poliani PL, Moratto D, Sobacchi C, Marrella V, Imperatori L, Vairo D, Plebani A, Giliani S, Vezzoni P, Facchetti F, Porta F, Notarangelo LD, Villa A*, Badolato R*. Defect of regulatory T cells in patients with Omenn syndrome.J Allergy Clin Immunol.125:209-216, 2010 * equal contribution

Trifari S, Scaramuzza S, Catucci M, Ponzoni M, Mollica L, Chiesa R, Cattaneo F, Lafouresse F, Calvez R, Vermi W, Medicina D, Castiello MC, Marangoni F, Bosticardo M, Doglioni C, Caniglia M, Aiuti A, Villa A, Roncarolo MG, Dupré L. Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: Analysis of function and distribution in lymphoid organs.J Allergy Clin Immunol.125: 439-448, 2010.

Couëdel C, Roman C, Jones A, Vezzoni P, Villa A, Cortes P.Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination. J Clin Invest.120: 1337-1344, 2010

Cassani B, Poliani PL, Marrella V, Schena F, Sauer AV, Ravanini M, Strina D, Busse CE, Regenass S, Wardemann H, et al Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. J Exp Med. 207 1525-1540,2010


Bosticardo M, Draghici E, Schena F, Sauer AV, Fontana E, Castiello MC, Catucci M, Locci M, Naldini L, Aiuti A, Roncarolo MG, Poliani PL, Traggiai E, Villa A. Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 127:1376-1384, 2011

Pangrazio A, Boudin E, Piters E, Damante G, Iacono NL, D'Elia AV, Vezzoni P, Van Hul W, Villa A, Sobacchi C.Identification of the first deletion in the LRP5 gene in a patient with Autosomal Dominant Osteopetrosis type I. Bone. 2011 May 11. [Epub ahead of print]

Project Title:
Gene Therapy and Basic Biology of Wiskott Aldrich Syndrome
The Wiskott-Aldrich Syndrome (WAS) is a monogenic X-linked immunodeficiency also characterized by thrombocytopenia, eczema, and a high susceptibility to develop tumours and multiple autoimmune manifestations. WAS is caused by mutations impairing the expression or function of the hematopoietic-specific WAS protein (WASP), a key regulator of actin cytoskeleton remodelling upon cell stimulation. WAS-associated immunodeficiency is due to dysfunction of many immune cell types, including T cells, NK cells, and DCs. In the past, our group has contributed to the understanding of the cellular basis of this complex immunodeficiency, demonstrating the role of WASp in the immunological synapse formation and in the maintenance of peripheral tolerance. Moreover, we have recently developed an alternative therapeutic approach based on the use of a third generation lentiviral vector carrying the human WAS cDNA driven by the autologous promoter (a 1.6kb long fragment of the endogenous promoter).

Our current research is now addressed to further understand the mechanisms underlying autoimmune manifestations in patients. In particular, we aim at:

- defining the contribution of WASP deficiency in DC functional impairment in the was-/- mouse model and, when available, in WAS patients.
- evaluating the role of WASP in the B lymphocyte development and function in the was-/- mouse model and in WAS patients.
- further investigating the contribution of WASP in differentiation and function of iNKT cells by ex vivo and in vivo experiments in the was-/- mouse model.
- Evaluating the role of viral infections in the pathogenesis of WAS autoimmunity
- validating the efficacy of gene therapy in restoration of new cellular defects identified during our studies.

References

Bosticardo M, Draghici E, Schena F, Sauer AV, Fontana E, Castiello MC, Catucci M, Locci M, Naldini L, Aiuti A, Roncarolo MG, Poliani PL, Traggiai E, Villa A.
Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2011 Jun;127(6):1376-1384.e5. Epub 2011 Apr 29.

Trifari S, Scaramuzza S, Catucci M, Ponzoni M, Mollica L, Chiesa R, Cattaneo F,
Lafouresse F, Calvez R, Vermi W, Medicina D, Castiello MC, Marangoni F,
Bosticardo M, Doglioni C, Caniglia M, Aiuti A, Villa A, Roncarolo MG, Dupré L.
Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: Analysis of
function and distribution in lymphoid organs. J Allergy Clin Immunol. Feb;
125(2):439-448.e8, 2010.

Bosticardo M, Marangoni F, Aiuti A, Villa A, Roncarolo MG. Recent advances in
understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood Jun 18;
113(25):6288-95, 2009.
Locci M, Draghici E, Marangoni F, Bosticardo M, Catucci M, Aiuti A, Cancrini C,
Marodi L, Espanol T, Bredius RG, Thrasher AJ, Schulz A, Litzman J, Roncarolo MG,
Casorati G, Dellabona P, Villa A. The Wiskott-Aldrich syndrome protein is required
for iNKT cell maturation and function. J Exp Med 2009, Apr 13; 206(4):735-42.
Marangoni F*, Bosticardo M*, Charrier S*, Draghici E, Locci M, Scaramuzza S,
Panaroni C, Ponzoni M, Sanvito F, Doglioni C, Liabeuf M, Gjata B, Montus M,
Siminovitch KA, Aiuti A, Naldini L, Dupré L, Roncarolo MG, Galy A, Villa A.
Evidence for long term efficacy and safety of gene therapy for Wiskott-Aldrich
syndrome in preclinical models. Mol Ther Jun; 17(6):1073-82, 2009.


Project Title:
Basic Biology and Therapy of Omenn Syndrome
Omenn Syndrome (OS) is a severe combined immunodeficiency characterized by
the presence of activated T cells infiltrating skin and gut and high levels of IgE in
spite of the absence of circulating B cells. Our group has identified the molecular
basis of the disease, demonstrating that hypomorphic mutations in Rag1 and
Rag2, impairing but no abolishing protein activity, are responsible for the disease.
Although the biochemical and molecular bases of OS have been extensively
studied, some aspects such as autoimmunity and Immunoglubulin production still
remain unsolved. To this aim, we have generated a mouse mutant carrying a
missense mutation in Rag2 which well reproduces the signs of the disease. Our
main efforts are now addressed to understand :
The contribution of B cells to the pathophysiology of the autoimmunity. In particular, we plan to evaluate :
• The role of Toll like receptor stimulation and thus encounter with live
pathogens in the onset of autoimmune manifestations
• how impairment of central and peripheral tolerance contribute to the
• pathogenesis of the disease
• the feasibility and efficacy of LV-mediated gene therapy
approach for the treatment of OS

References
Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, Benerini Gatta L,
Ochs HD, Schwarz K, Notarangelo L, Vezzoni P and Spanopoulou E. Partial V(D)J
recombination activity leads to Omenn syndrome. Cell 93: 885-896, 1998

Marrella V, Poliani PL, Casati A, Rucci F, Frascoli L, Gougeon ML, Lemercier B,
Bosticardo M, Ravanini M, Battaglia M, Roncarolo MG, Cavazzana-Calvo M,
Facchetti F, Notarangelo LD, Vezzoni P, Grassi F, Villa A. A hypomorphic R229Q
Rag2 mouse mutant recapitulates human Omenn syndrome. J Clin I 117:1260-9,
2007.

Villa A, Notarangelo LD, Roifman CM.Omenn syndrome: inflammation in leaky
severe combined immunodeficiency.J Allergy Clin Immunol. 2008 122:1082-
6,2008.

Marrella V, Poliani PL, Sobacchi C, Grassi F, Villa A.Of Omenn and mice. Trends
Immunol. 29:133-140, 2008.

Cassani B, Poliani PL, Marrella V, Schena F, Sauer AV… and Villa A. Homeosttaic
expansion of autoreactive immunolglubulin-secreting cells in teh Rag2 mosue
model of Omenn syndrome. J. Exp Med 207: 1525, 2010

Cassani B, Poliani PL, Moratto D, Sobacchi C, Marrella V, Imperatori L, Vairo D, Plebani A, Giliani S, Vezzoni P, Facchetti F, Porta F, Notarangelo LD, Villa A, Badolato R. Defect of regulatory T cells in patients with Omenn syndrome.
J Allergy Clin Immunol. 125:209, 2010