Clinical research Unit
The Clinical Research Unit (CRU) was established in 1999 to create an infrastructure with dedicated staff and in house expertise for conducting clinical trials for genetic diseases. The overall goal of this Unit is the application of basic research discoveries and innovative gene and cell therapy approaches to the treatment of genetic diseases focusing on primary immunodeficiencies, genetic autoimmune diseases, hemoglobinopathies, and lysosomal storage disorders. It provides a suitable environment to translate the results from basic and clinical research into clinical practice and viceversa. The Unit was established through a dedicated grant of the Fondazione Telethon to SR-TIGET and is led by Alessandro Aiuti. During these years, the CRU has been recognized as a center of excellence for the treatment of pediatric and adult patients affected by genetic disorders.
The Unit is composed by a Clinical Haematology Research Unit (CHRU) and a Pediatric Clinical Research Unit (PCRU) and a Clinical Trial Office, dedicated to the unit activity. All together the staff of the CRU has the required expertise for carrying in-house advanced therapies-based clinical trials according to GCP. The CRU acts in strict cooperation with the Pediatric Immuno‐Hematology Unit of IRCCS Ospedale San Raffaele and the San Raffaele Stem Cell Program.
The CHRU and PCRU have dedicated spaces and personnel, including physician scientists, hematologists, pediatricians, resident fellows in Pediatrics, physiotherapist, psychologist, and nurses.
The use of standardized processes and SOP guarantees high quality of the clinical trials. The approach to the patients is holistic, taking charge of all the medical, nursing and psychological aspects thanks to a multidisciplinary team. The management of patients and their families takes into account the handling of emotional issues, the different cultural, social and economic backgrounds as well as the logistical problems related to the prolonged stay of patients and families in Milan
Clinical research activities are focused on the implementation of experimental protocols based on gene or cell therapy for the treatment of genetic blood disorders such as ADA-SCID, Wiskott-Aldrich Syndrome, Metachromatic Leukodystrophy, Beta-thalassemia, Chronic granulomatous disease, Mucopolysaccharidosis Type I (Hurler).
Studies to improve the knowledge of genetic diseases include the natural history study for MLD, advanced diagnosis and natural history of primary immunodeficiencies and immunedysregulatory disorder, and immune reconstitution after hematopoietic stem cell transplantation for genetic disorders.
For more detailed information about research activity of Clinical research Unit click here.
The CRU and its cooperating Units obtained different accreditation, ensuring high quality standards for its activities:
- ISO 9001 certification for Pediatric Immuno–Hematology Unit, Hematology and Bone Marrow Transplant Unit and SR-TIGET Clinical Trial office
- AIFA self-certification for conduction of Fase I clinical Trial
- JACIE certification for the Stem Cell Program European Blood and Marrow Transplantation group
- Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP)
- Gruppo Italiano Trapianto Midollo Osseo (GITMO)
- European Reference Network_Rare Immunodeficiency, autoinflammatory and autoimmune disease Network (ERN-RITA)
The Unit participates to the scientific activity of: Società Italiana di Pediatria, Società Italiana di Ematologia, American Society of Hematology (ASH), American Society of Gene Therapy (ASGCT), European Society of Cell and Gene Therapy (ESGCT).
The SR‐Tiget Clinical Trial Office (TCTO) is the Clinical Research Office of SR‐Tiget. It is part of the research area of IRCCS Ospedale San Raffaele and reports directly to the Head of the CRU.
TCTO main objectives are to support its customers in the creation, approval, management, organization and closure of clinical trials. In particular, its objectives are reached thanks to the following activities:
- Promoting quality in all aspects of clinical research, through a certified Quality System, a clinical research monitoring service, internal AUDITs on specific processes and providing support during inspections carried out by other entities.
- Acting as reference point for communication with internal and external committees (e.g. Ethical Committees, San Raffaele Clinical Research Office, Data Safety Monitoring Board) and competent authorities (e.g European Medicine Agency-EMA, Agenzia Italiana del Farmaco–AIFA)
- Providing data management services, inclusive of CRF design, data entry, support in interpretation of data, writing and revision of study reports.
- Acting as reference point for the management of the patient involved in clinical trial, both from a clinical, cultural and organizational point of view. TCTO is coordinated by Stefano Zancan and the staff (responding to requirements of a Clinical Trial Quality Team) is composed by a Quality Manager, Clinical Study Managers, a Clinical Research Associate, Clinical Research Nurses, Regulatory Affair Officers, Data Managers, an Administrative Assistant and a Cultural/Linguistic mediator.
The SR-Tiget Clinical Lab is a certified laboratory, in which tests required for clinical trial endpoints are performed following GCLP requirements. The SR-Tiget Clinical Lab can perform tests for all phases Clinical Trials, including phase I trials. The SR-Tiget Clinical Lab reports directly to the Institute Director Luigi Naldini and is coordinated by Stefano Zancan; it is not part of the CRU, but it’s a fundamental partner.
The laboratory staff is composed of biologists and technicians who are responsible for the activities related to the clinical trial assays. The personnel is in charge of storing patients’ biological samples, manipulating and purifying cells, and performing specific clinical research assays. All activities are regulated by a Quality System managed by a dedicated Quality Manager.
The SR-Tiget Clinical Lab strictly collaborates with the GLP test facility and its QA team.
Ferrua F, Aiuti A. Twenty-five years of gene therapy for ADA SCID: from bubble babies to an approved drug. Hum Gene Ther. 2017 Nov;28(11):972-981.
Maccari ME, Scarselli A, Di Cesare S, Floris M, Angius A, Deodati A, Chiriaco M, Cambiaso P, Corrente S, Colafati GS, Utz PJ, Angelini F, Fierabracci A, Aiuti A, Carsetti R, Rosenberg JM, Cappa M, Rossi P, Bacchetta R, Cancrini C. Severe Toxoplasma gondii infection in a member of a NFKB2-deficient family with T and B cell dysfunction. Clin Immunol. 2017 Oct;183:273-277.
Azario I, Pievani A, Del Priore F, Antolini L, Santi L, Corsi A, Cardinale L, Sawamoto K, Kubaski F, Gentner B, Bernardo ME, Valsecchi MG, Riminucci M, Tomatsu S, Aiuti A, Biondi A, Serafini M. Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I. Sci Rep. 2017 Aug 25;7(1):9473.
Marktel S, Cicalese MP, Giglio F, Scaramuzza S, Calbi V, Casiraghi M, Ciotti F, Lidonnici MR, Rossi C, Masera N, D'Angelo E, Mirra N, Origa R, Tartaglione I, Mandelli , Milani R, Gattillo S, Coppola M, Viarengo G, Santoleri L, Calabria A, Perrotta S, Montini E, Graziadei G, Naldini L, Cappellini MD, Ciceri F, Aiuti A, Ferrari G. Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector. Blood 2017 130:355.
Penati R*, Fumagalli F*, Calbi V, Bernardo ME, Aiuti A. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. J Inherit Metab Dis. 2017 Jul;40(4):543-554. (*Equal contribution)
Speckmann C, Doerken S, Aiuti A, Albert MH, Al-Herz W, Allende LM, Scarselli A, Avcin T, Perez-Becker R, Cancrini C, Cant A, Di Cesare S, Finocchi A, Fischer A, Gaspar HB, Ghosh S, Gennery A, Gilmour K, González-Granado LI, Martinez- Gallo M, Hambleton S, Hauck F, Hoenig M, Moshous D, Neven B, Niehues T, Notarangelo L, Picard C, Rieber N, Schulz A, Schwarz K, Seidel MG, Soler- Palacin P, Stepensky P, Strahm B, Vraetz T, Warnatz K, Winterhalter C, Worth A, Fuchs S, Uhlmann A, Ehl S; PCID-study of the Inborn Errors Working Party of the EBMT. A prospective study on the natural history of patients with profound combined immunodeficiency (P-CID): an interim analysis. J Allergy Clin Immunol. 2017 Apr;139(4):1302-1310.e4.
Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017 Jun; 9(6): 737–740.
Monaco LF, Faccio L. Patient-driven search for rare disease therapies: the Fondazione Telethon success story and the strategy leading to Strimvelis. EMBO Molecular Medicine 2017 Mar; 9(3): 289–292.
Carriglio N, Klapwijk J, Hernandez RJ, Vezzoli M, Chanut F, Lowe R, Draghici E, Nord M, Albertini P, Cristofori P, Richards J, Staton H, Appleby J, Aiuti A, Sauer AV. GLP-preclinical safety studies for GSK2696273 (MLV vector-based ex vivo gene therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG mice. Human Gen Ther Clin Dev. 2017 Mar;28(1):17-27.
Sauer AV, Hernandez RJ, Fumagalli F, Bianchi V, Poliani PL, Dallatomasina C, Riboni E, Politi LS, Tabucchi A, Carlucci F, Casiraghi M, Carriglio N, Cominelli M, Forcellini CA, Barzaghi F, Ferrua F, Minicucci F, Medaglini S, Leocani L, la Marca G, Notarangelo LD, Azzari C, Comi G, Baldoli C, Canale S, Sessa M, D'Adamo P, Aiuti A. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Sci Rep 2017 Jan 11;7:40136.
Bernardo ME, Aiuti A. The role of conditioning in hematopoietic stem cell gene therapy. Hum Gene Ther 2016 Oct;27(10):741-748.
Visigalli I, Delai S, Ferro F, Cecere F, Vezzoli M, Sanvito F, Chanut F, Benedicenti F, Spinozzi G, Wynn R, Calabria A, Naldini L, Montini E, Cristofori P, Biffi A. Preclinical testing of the safety and tolerability of LV-mediated above normal alpha-L-iduronidase expression in murine and human hematopoietic cells using toxicology and biodistribution GLP studies. Hum Gene Ther. 2016 Oct;27(10):813-829.
Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 2016 Jul 7;128(1):45-54.
Sessa M, Lorioli L, Fumagalli , Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A, Fiori R, Silvani P, Rancoita PM, Gabaldo M, Benedicenti F, Antonioli G, Assanelli A, Cicalese MP, Del Carro U, Sora MG, Martino S, Quattrini A, Montini E, Di Serio C, Ciceri F, Roncarolo MG, Aiuti A, Naldini L, Biffi A. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 2016 Jul 30;388(10043):476-87.
Aiuti A, Naldini L. Safer conditioning for blood stem cell transplants. Nat Biotechnol. 2016 Jul 12;34(7):721-3.
Chiriaco M, Brigida I, Ariganello P, Di Cesare S, Di Matteo G, Taus F, Cittaro D, Lazarevic D, Scarselli A, Santilli V, Attardi E, Stupka E, Giannelli S, Fraziano M, Finocchi A, Rossi P, Aiuti A, Palma P, Cancrini C. A case of APDS patient: defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment. Clin Immunol. 2017 May;178:20-28. Epub 2015 Dec 28.
Oliveira G, Ruggiero E, Stanghellini MT, Cieri N, D'Agostino M, Fronza R, Lulay C, Dionisio F, Mastaglio S, Greco R, Peccatori J, Aiuti A, Ambrosi A, Biasco L, Bondanza A, Lambiase A, Traversari C, Vago L, von Kalle C, Schmidt M, Bordignon C, Ciceri F, Bonini C. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory. Sci Transl Med. 2015 Dec 9;7(317):317ra198.
Lorioli L, Cicalese MP, Silvani P, Assanelli A, Salvo I, Mandelli A, Fumagalli F, Fiori R, Ciceri F, Aiuti A, Sessa M, Roncarolo MG, Lanzani C, Biffi A. Abnormalities of acid-base balance and predisposition to metabolic acidosis in Metachromatic Leukodystrophy patients. Mol Genet Metab. 2015 May;115(1):48-52.
Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 2013 Aug 23;341(6148):1233151.
Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013 Aug 23;341(6148):1233158.
Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene Therapy for Immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58.
Clinical study manager
Maria Ester Bernardo
Research nurse coordinator
Maria Pia Cicalese
Clinical study manager
Samih El Hossary
Clinical study manager
Clinical trial office Coordinator