Gene Therapy for Wiskott-Aldrich Syndrome

NCT ID: NCT01515462

Last Updated: 2025-04-04

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

8 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-04-20

Study Completion Date

2023-10-04

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Wiskott-Aldrich Syndrome (WAS)

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

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
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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

Group Type EXPERIMENTAL

TLT003

Intervention Type GENETIC

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

Interventions

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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

Intervention Type GENETIC

Other Intervention Names

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Previously GSK2696275 Previously OTL-103

Eligibility Criteria

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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.
Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Ospedale San Raffaele

OTHER

Sponsor Role collaborator

Fondazione Telethon

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Milan, , Italy

Site Status

Countries

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Italy

References

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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.

Reference Type BACKGROUND
PMID: 23845947 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19179314 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20008254 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19351959 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17078381 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15308573 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17051251 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15509508 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11812281 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 18194074 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19259069 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 7795648 (View on PubMed)

Quaranta P, Basso-Ricci L, Jofra Hernandez R, Pacini G, Naldini MM, Barcella M, Seffin L, Pais G, Spinozzi G, Benedicenti F, Pietrasanta C, Cheong JG, Ronchi A, Pugni L, Dionisio F, Monti I, Giannelli S, Darin S, Fraschetta F, Barera G, Ferrua F, Calbi V, Ometti M, Di Micco R, Mosca F, Josefowicz SZ, Montini E, Calabria A, Bernardo ME, Cicalese MP, Gentner B, Merelli I, Aiuti A, Scala S. Circulating hematopoietic stem/progenitor cell subsets contribute to human hematopoietic homeostasis. Blood. 2024 May 9;143(19):1937-1952. doi: 10.1182/blood.2023022666.

Reference Type DERIVED
PMID: 38446574 (View on PubMed)

Scala S, Ferrua F, Basso-Ricci L, Dionisio F, Omrani M, Quaranta P, Jofra Hernandez R, Del Core L, Benedicenti F, Monti I, Giannelli S, Fraschetta F, Darin S, Albertazzi E, Galimberti S, Montini E, Calabria A, Cicalese MP, Aiuti A. Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy. Nat Commun. 2023 May 27;14(1):3068. doi: 10.1038/s41467-023-38448-y.

Reference Type DERIVED
PMID: 37244942 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30981783 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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2009-017346-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

201228

Identifier Type: -

Identifier Source: org_study_id

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