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

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ClinicalTrials.gov Identifier: NCT01515462

Recruitment Status : Active, not recruiting

First Posted : January 24, 2012

Last Update Posted : February 6, 2023

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

Ospedale San Raffaele

Information provided by (Responsible Party):

Orchard Therapeutics

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Wiskott-Aldrich Syndrome (WAS)	Genetic: OTL-103	Phase 1 Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	8 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Intervention Model Description:	This will be a single-arm study. All subjects will receive OTL-103 gene therapy and will be followed up for 15 years post gene therapy
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome
Actual Study Start Date :	April 20, 2010
Actual Primary Completion Date :	October 3, 2018
Estimated Study Completion Date :	September 11, 2030

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Wiskott-Aldrich syndrome

MedlinePlus related topics: Genes and Gene Therapy

Genetic and Rare Diseases Information Center resources: Wiskott Aldrich Syndrome

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: OTL-103 gene therapy Eligible subjects will receive intravenous (IV) infusion of OTL-103 gene therapy. Subjects affected by WAS who don't have a suitable matched donor for allogenic hematopoietic stem cell transplantation will be included	Genetic: OTL-103 OTL-103 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 Name: Previously GSK2696275

Outcome Measures

Primary Outcome Measures :

Conditioning regimen-related safety [ Time Frame: Two months after gene therapy ]
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 ]
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 ]
≥ 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 ]
Detection of vector-derived WASP expression by FACS analyses and/or Western Blot
Improved T-cell functions [ Time Frame: 3 years ]
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 ]
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 and MPV normalization [ Time Frame: 3 years ]
Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile
Overall survival [ Time Frame: 3 years ]
Number of patients alive all over the trial

Secondary Outcome Measures :

Lack of immune response to transgene [ Time Frame: 3 years ]
Immunoblot analysis
Reduced frequency of severe infections [ Time Frame: 3 years ]
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 ]
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 ]
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 ]
Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.
Multilineage engraftment of genetically corrected cells [ Time Frame: 3 years ]
≥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+)
Overall safety of the treatment [ Time Frame: 8 years ]
Recording of AE, AR, SAE/SAR, UAR, SUSAR

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	Child, Adult, Older Adult
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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
No HLA-identical sibling donor
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.
Parental/guardian/patient signed informed consent.

Exclusion Criteria:

Patients positive for HIV-infection.
Patients affected by neoplasia.
Patients with cytogenetic alterations typical of MDS/AML.
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.
Patients who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months.
Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01515462

Locations

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

Sponsors and Collaborators

Orchard Therapeutics

Ospedale San Raffaele

Investigators

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Study Director:	Orchard Clinical Trials	Orchard Therapeutics

More Information

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Orchard Therapeutics
ClinicalTrials.gov Identifier:	NCT01515462
Other Study ID Numbers:	201228 2009-017346-32 ( EudraCT Number )
First Posted:	January 24, 2012 Key Record Dates
Last Update Posted:	February 6, 2023
Last Verified:	April 2022

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Orchard Therapeutics:


Lentiviral vector Gene therapy Wiskott-Aldrich Syndrome OTL-103 Previously GSK2696275

Additional relevant MeSH terms:

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Wiskott-Aldrich Syndrome Syndrome Disease Pathologic Processes Blood Coagulation Disorders, Inherited Blood Coagulation Disorders Hematologic Diseases Hemorrhagic Disorders	Lymphopenia Leukopenia Leukocyte Disorders Genetic Diseases, Inborn Genetic Diseases, X-Linked Primary Immunodeficiency Diseases Immunologic Deficiency Syndromes Immune System Diseases

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