Gene Therapy for Wiskott-Aldrich Syndrome

NCT01515462 | Completed Phase 1 Results

• 2 other identifiers: 2012282009-017346-32
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Wiskott-Aldrich Syndrome (WAS)

Keywords

Lentiviral vector; Gene therapy; Wiskott-Aldrich Syndrome; TLT003; Previously GSK2696275; Previously OTL-103

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (7)

• Lack of Immune Response to Transgene

  up to 3 years after Telethon003 infusion

• Reduced Frequency of Severe Infections

  up to 3 years after Telethon003 infusion

• Reduced Bruising and Bleeding Episodes

  3 years

• Reduced Autoimmunity Phenomena and Eczema

  3 years

• Improved Quality of Life

  3 year

Study Arms (1)

TLT003 gene therapy

EXPERIMENTAL

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

Interventions

TLT003 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

Also known as: Previously GSK2696275, Previously OTL-103

TLT003 gene therapy

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione Telethon: lead
• Ospedale San Raffaele: collaborator

Study Sites (1)

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

Milan, 20132, Italy

Location

Related Publications (15)

• 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.

  PMID: 23845947 BACKGROUND

• 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.

  PMID: 19179314 BACKGROUND

• 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.

  PMID: 20008254 BACKGROUND

• 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.

  PMID: 19351959 BACKGROUND

• 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.

  PMID: 17078381 BACKGROUND

• 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.

  PMID: 15308573 BACKGROUND

• 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.

  PMID: 17051251 BACKGROUND

• 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.

  PMID: 15509508 BACKGROUND

• 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.

  PMID: 11812281 BACKGROUND

• 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.

  PMID: 18194074 BACKGROUND

• 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.

  PMID: 19259069 BACKGROUND

• 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.

  PMID: 7795648 BACKGROUND

• 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.

  PMID: 38446574 DERIVED

• 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.

  PMID: 37244942 DERIVED

• 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.

  PMID: 30981783 DERIVED

MeSH Terms

Conditions

Wiskott-Aldrich Syndrome

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphopenia; Leukopenia; Cytopenia; Hemorrhagic Disorders; Leukocyte Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Sean Russell
• Organization: Fondazione Telethon ETS

srussell@telethon.it

+39 02 2022 17210

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: December 23, 2011
• First Posted: January 24, 2012
• Study Start: April 20, 2010
• Primary Completion: October 4, 2023
• Study Completion: October 4, 2023
• Last Updated: April 4, 2025
• Results First Posted: April 4, 2025

Record last verified: 2025-03

Locations

IT (1)