Gene Therapy for Wiskott-Aldrich Syndrome (TIGET-WAS)

A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome

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.

Study Overview

• Status: Completed
• Conditions: Wiskott-Aldrich Syndrome (WAS)
• Intervention / Treatment: Genetic: TLT003

Detailed Description

Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene which encodes the WAS protein (WASP), a cytoskeletal regulator which is expressed exclusively in hematopoietic cells.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 ≥ 3
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 who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months.
6. Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TLT003 gene therapy; Eligible subjects will receive intravenous (IV) infusion of TLT003 gene therapy. Subjects affected by WAS who don't have a suitable matched donor for allogenic hematopoietic stem cell transplantation will be included	Genetic: TLT003; TLT003 is an autologous CD34+ cells collected from bone marrow and/or peripheral blood and transduced with a lentiviral vector encoding Wiskott-Aldrich syndrome (WAS) protein; Other Names: Previously GSK2696275; Previously OTL-103

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of Reduced Conditioning Regimen	The absence of prolonged aplasia (defined as ANC <0.5×10^9/L [<500/μL] at Day +60, with no evidence of BM recovery and requiring backup administration) was assumed as demonstrating the safety of the RIC regimen.	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
Safety of Lentivirus Gene Transfer Into HSC	Safety and tolerability of lentiviral-transduced cell infusion. This will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion.	after 48 hours after Telethon003 infusion
Sustained Engraftment of Genetically Corrected Haematopoietic Stem Cells in Peripheral Blood and/or in Bone Marrow	Engraftment is characterized by the presence of gene modified cells in the BM or PB compartments. The main indicator of gene correction is detection of the WAS LVV sequences in the HSPCs and their progeny. The VCN, which is the mean number of integrated copies of the vector sequences per cell genome, was measured using PCR-based methods in DNA samples extracted from BM and PB cell populations at various timepoints post-treatment. Adequate engraftment was defined as either ≥0.04 VCN/cell in BM CD34+ cells or ≥0.01 VCN/cell in PB CD3+ cells.	at 1 year after Telethon003 infusion
Presence of Detectable Vector-derived WASP	The percentage of subjects who present the proportion of PB cells expressing WASP was assessed by flow cytometry analysis.	Median duration: 11.1 years (range: 8.01 -13.3 years)
Improved T-cell Functions	Improvement in in vitro T-cell proliferation was assessed upon stimulation with 3 doses of anti-immobilized CD3 (CD3i) monoclonal antibodies ≥1 year after Telethon003 infusion (as compared with pre-GT values) in PBMC and/or T-cell lines. The degree of correction was evaluated with respect to healthy controls.	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
Antigen-specific Responses to Vaccination	The ability to mount a protective humoral response to at least 4 out of 5 nominal antigens including antibodies to T-cell dependent antigens and conjugated or unconjugated polysaccharide antigens was measured after vaccination (planned >1 year after Telethon003 infusion). If results were available on n <5 antigens, the rule of at least n-1 applied to define success.	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
Improved Platelet Count and MPV Normalization	Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile	up to 3 years after Telethon003 infusion
Overall Survival	Participant survival was monitored throughout the study.	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lack of Immune Response to Transgene	Anti-WASP and anti-HIV-1 antibodies (anti-p24) were monitored to evaluate response to transgene and to vector, respectively.	up to 3 years after Telethon003 infusion
Reduced Frequency of Severe Infections	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.	up to 3 years after Telethon003 infusion
Reduced Bruising and Bleeding Episodes	Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history	3 years
Reduced Autoimmunity Phenomena and Eczema	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	3 years
Improved Quality of Life	Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.	3 year
Multilineage Engraftment of Genetically Corrected Cells	≥0.04 VCN/cell on all the available peripheral blood and/or bone marrow cell subpopulations (BM subpopulations: GlyA+, CD15+, CD61+, CD3+, CD19+, CD56+; PB subpopulations: CD15+, CD19+, CD56+)	3 years
Overall Safety of the Treatment	Recording of AE, AR, SAE/SAR, UAR, SUSAR	8 years

Collaborators and Investigators

• Sponsor: Fondazione Telethon
• Collaborators: Ospedale San Raffaele

Publications and helpful links

General Publications

• 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. doi: 10.1126/science.1233151. Epub 2013 Jul 11.
• 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. doi: 10.1056/NEJMoa0805817.
• Aiuti A, Roncarolo MG. Ten years of gene therapy for primary immune deficiencies. Hematology Am Soc Hematol Educ Program. 2009:682-9. doi: 10.1182/asheducation-2009.1.682.
• Bosticardo M, Marangoni F, Aiuti A, Villa A, Grazia Roncarolo M. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood. 2009 Jun 18;113(25):6288-95. doi: 10.1182/blood-2008-12-115253. Epub 2009 Apr 7.
• Boztug K, Dewey RA, Klein C. Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Curr Opin Mol Ther. 2006 Oct;8(5):390-5.
• Burns S, Cory GO, Vainchenker W, Thrasher AJ. Mechanisms of WASp-mediated hematologic and immunologic disease. Blood. 2004 Dec 1;104(12):3454-62. doi: 10.1182/blood-2004-04-1678. Epub 2004 Aug 12.
• Charrier S, Dupre L, Scaramuzza S, Jeanson-Leh L, Blundell MP, Danos O, Cattaneo F, Aiuti A, Eckenberg R, Thrasher AJ, Roncarolo MG, Galy A. Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients. Gene Ther. 2007 Mar;14(5):415-28. doi: 10.1038/sj.gt.3302863. Epub 2006 Oct 19.
• Dupre L, Trifari S, Follenzi A, Marangoni F, Lain de Lera T, Bernad A, Martino S, Tsuchiya S, Bordignon C, Naldini L, Aiuti A, Roncarolo MG. Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. Mol Ther. 2004 Nov;10(5):903-15. doi: 10.1016/j.ymthe.2004.08.008.
• Follenzi A, Sabatino G, Lombardo A, Boccaccio C, Naldini L. Efficient gene delivery and targeted expression to hepatocytes in vivo by improved lentiviral vectors. Hum Gene Ther. 2002 Jan 20;13(2):243-60. doi: 10.1089/10430340252769770.
• Galy A, Roncarolo MG, Thrasher AJ. Development of lentiviral gene therapy for Wiskott Aldrich syndrome. Expert Opin Biol Ther. 2008 Feb;8(2):181-90. doi: 10.1517/14712598.8.2.181.
• Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, Strina D, Patrosso MC, Ramenghi U, Sacco MG, et al. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet. 1995 Apr;9(4):414-7. doi: 10.1038/ng0495-414.
• Ferrua F, Cicalese MP, Galimberti S, Giannelli S, Dionisio F, Barzaghi F, Migliavacca M, Bernardo ME, Calbi V, Assanelli AA, Facchini M, Fossati C, Albertazzi E, Scaramuzza S, Brigida I, Scala S, Basso-Ricci L, Pajno R, Casiraghi M, Canarutto D, Salerio FA, Albert MH, Bartoli A, Wolf HM, Fiori R, Silvani P, Gattillo S, Villa A, Biasco L, Dott C, Culme-Seymour EJ, van Rossem K, Atkinson G, Valsecchi MG, Roncarolo MG, Ciceri F, Naldini L, Aiuti A. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 2019 May;6(5):e239-e253. doi: 10.1016/S2352-3026(19)30021-3. Epub 2019 Apr 10.
• 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 K, Aiuti A, Naldini L, Dupre 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. 2009 Jun;17(6):1073-82. doi: 10.1038/mt.2009.31. Epub 2009 Mar 3. Erratum In: Mol Ther. 2009 Jul;17(7):1300. doi: 10.1038/mt.2009.61.

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2010
• Primary Completion (Actual): October 4, 2023
• Study Completion (Actual): October 4, 2023

Study Registration Dates

• First Submitted: December 23, 2011
• First Submitted That Met QC Criteria: January 18, 2012
• First Posted (Estimated): January 24, 2012

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: March 17, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Gene therapy; Wiskott-Aldrich Syndrome; Lentiviral vector; Previously GSK2696275; TLT003; Previously OTL-103
• Additional Relevant MeSH Terms: Primary Immunodeficiency Diseases; Cytopenia; Pathologic Processes; Genetic Diseases, Inborn; Immune System Diseases; Disease; Leukocyte Disorders; Hematologic Diseases; Immunologic Deficiency Syndromes; Blood Coagulation Disorders; Hemorrhagic Disorders; Genetic Diseases, X-Linked; Blood Coagulation Disorders, Inherited; Leukopenia; Lymphopenia; Syndrome; Wiskott-Aldrich Syndrome
• Other Study ID Numbers: 201228; 2009-017346-32 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No