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Trial record 1 of 29 for:    "Wiskott-Aldrich syndrome"
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Gene Therapy for Wiskott-Aldrich Syndrome (TIGET-WAS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2012 by IRCCS San Raffaele
Fondazione Telethon
Information provided by (Responsible Party):
Alessandro Aiuti, IRCCS San Raffaele Identifier:
First received: December 23, 2011
Last updated: January 18, 2012
Last verified: January 2012

This is phase I/II protocol to evaluate the safety and efficacy of WAS gene transfer into hematopoietic stem/progenitor cells for the treatment of Wiskott Aldrich Syndrome.

Condition Intervention Phase
Wiskott-Aldrich Syndrome
Genetic: Autologous CD34 positive cells transduced with WAS encoding lentiviral vector.
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome

Resource links provided by NLM:

Further study details as provided by IRCCS San Raffaele:

Primary Outcome Measures:
  • Conditioning regimen-related safety [ Time Frame: two months after gene therapy ] [ Designated as safety issue: Yes ]
    Absence of engraftment failure or prolonged aplasia (<500/ul ANC with no evidence of bone marrow recovery) and surveillance of non haematological regimen related toxicity (for clinical features NCI >2, for metabolic/laboratory NCI >3)

  • Safety of lentivirus gene transfer into HSC [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

    short-term safety and tolerability of lentiviral-transduced cell infusion

    -long-term safety of lentiviral-transduced cell infusion (absence of Replication Competent Lentivirus (RCL) and abnormal clonal proliferation).

  • Sustained engraftment of genetically corrected haematopoietic stem cells in peripheral blood and/or in bone marrow [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    ≥ 0.04 Vector copy number (VCN)/cell in bone marrow CD34+ or ≥0.1 VCN/cell in peripheral blood T lymphocytes

  • Expression of vector-derived WASP [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Detection of vector-derived WASP expression by FACS analyses and/or Western Blot

  • Improved T-cell functions [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Improvement in in vitro T cell proliferation and/or IL-2 secretion upon stimulation with anti-CD3i as compared to pre-gene therapy values.

  • Antigen-specific responses to vaccination [ Time Frame: 1year ] [ Designated as safety issue: No ]
    Ability to mount a humoral response to nominal antigens including antibodies to T cell dependent antigens (Tetanus Toxoid) and unconjugated polysaccharide antigens (Peumococcus, Meningococcus), measured after vaccination (foreseen >1 year after gene therapy). Positive cellular response to Tetanus Toxoid after vaccination measured by in vitro proliferative response >1 year after gene therapy.

  • Improved platelet count [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Sustained increase in platelet count compared to baseline, analysing the individual longitudinal profile

Secondary Outcome Measures:
  • Lack of immune response to transgene [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
    Immunoblot analysis

  • Reduced frequency of severe infections [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Decrease in number of severe infections as evaluated in the second and third year after the treatment by clinical history, complete physical examinations, hematological and microbiological tests.

  • Reduced bruising and bleeding episodes [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history

  • Reduced autoimmunity phenomena and eczema [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Reduction in laboratory markers (number and titer of antibody when available) and/or clinical manifestations of autoimmunity, as evaluated by organ-specific and systemic autoantibodies, imaging and clinical follow-up, compared to clinical history. Reduction in eczema as evaluated by clinical score

  • Improved quality of life [ Time Frame: 3 year ] [ Designated as safety issue: No ]
    Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.

Estimated Enrollment: 6
Study Start Date: April 2010
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Intervention Details:
    Genetic: Autologous CD34 positive cells transduced with WAS encoding lentiviral vector.
    The Medicinal Product consists of autologous CD34+ cells collected from the bone marrow and/or peripheral blood and transduced with a lentiviral vector encoding WASP controlled by WAS promoter sequences (w1.6W). Dosage indications: a minimum dose of 2x10^6 CD34+ cells/Kg (maximum 20x10^6 CD34+ cells/Kg) and an optimal dose of 5-10x10^6 CD34+ cells/Kg will be infused i.v.
Detailed Description:

We expect to treat 6 patients with autologous cells collected from bone marrow and/or mobilized from peripheral blood, transduced with a lentiviral vector encoding for WAS and reinfused. The patients are selected according to disease severity (genetic mutation, WASP expression and clinical score), absence of an HLA-identical sibling or adequate unrelated donor, age and clinical features. A conditioning regimen based on low doses of iv Busulfan, Fludarabine and anti-CD20 antibody will be administered to the patients to make space in the bone marrow for gene corrected stem cells, deplete the lymphoid compartment of potentially autoreactive lymphocytes and prevent lymphoproliferative disorder. Patients with autoimmune manifestations will also receive ATG Thymoglobuline to target auto-reactive memory T lymphocytes. This reduced intensity conditioning schedule will provide less toxicity than current preparatory regimens, used in standard allogeneic HSC transplantation. The treated patients will be followed for 3 years and thereafter monitored for the safety for additional 5 years.


Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Diagnosis of WAS defined by genetic mutation and at least one of the following criteria:

    • Severe WAS mutation
    • Absence of WASP expression
    • Severe clinical score (Zhu clinical score ≥
  2. No HLA-identical sibling donor
  3. Negative search for a matched unrelated donor (10/10) or an adequate unrelated cord blood donor (5-6/6) within 4-6 months

    • Patients of > 5 years of age who are not candidate to unrelated allogeneic transplant based on clinical conditions.
  4. Parental/guardian/patient signed informed consent.

Exclusion Criteria:

  1. Patients positive for HIV-infection.
  2. Patients affected by neoplasia.
  3. Patients with cytogenetic alterations typical of MDS/AML.
  4. Patients with end-organ functions or any other severe disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study.
  5. Patients with revertant mutations in > 5% of lymphoid cells.
  6. Patients who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months.
  7. Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01515462

Contact: Alessandro Aiuti, MD, PhD +390226434671
Contact: Luciano Callegaro +390226436321

Pediatric clinical research unit, San Raffale Telethon Institute of Gene Therapy Recruiting
Milano, Italy, 20132
Principal Investigator: Alessandro Aiuti, MD, PhD         
Sponsors and Collaborators
IRCCS San Raffaele
Fondazione Telethon
Principal Investigator: Alessandro Aiuti, MD, PhD San Raffaele Telethon Institute of Gene Therapy, Milan, Italy
Principal Investigator: Maria Grazia Roncarolo, MD San Raffaele Telethon Institute of Gene Therapy, Milan, Italy
  More Information


Additional publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Alessandro Aiuti, Head Pediatric Clinical Research Unit, IRCCS San Raffaele Identifier: NCT01515462     History of Changes
Other Study ID Numbers: Eudract 2009-017346-32
Study First Received: December 23, 2011
Last Updated: January 18, 2012
Health Authority: Italy: National Institute of Health
Italy: The Italian Medicines Agency

Keywords provided by IRCCS San Raffaele:
Wiskott-Aldrich Syndrome
Lentiviral vector
Gene therapy

Additional relevant MeSH terms:
Wiskott-Aldrich Syndrome
Blood Coagulation Disorders
Blood Coagulation Disorders, Inherited
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Hematologic Diseases
Hemorrhagic Disorders
Immune System Diseases
Immunologic Deficiency Syndromes
Leukocyte Disorders
Lymphopenia processed this record on March 03, 2015