ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID

NCT00598481 | Completed Phase 2 Results

• 2 other identifiers: STRIM-00415386-PRE21
• Study Type: interventional
• Target: 12
• Locations: 2 countries
• Sites: 2

Brief Summary

This is a phase I/II protocol to evaluate the safety and efficacy of ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of adenosine deaminase (ADA)-deficiency. This condition is an autosomal recessive form of Severe Combined Immunodeficiency (SCID) characterized by impaired immune responses, recurrent infections, failure to thrive and systemic toxicity due to accumulation of purine metabolites. Transplants from an human leukocyte-antigen (HLA)-identical sibling donor is the treatment of choice, but available for a minority of patients. The use of alternative bone marrow donors or enzyme replacement therapy is associated with important drawbacks. The drug product studied in this protocol consists of autologous cluster of differentiation (CD)34+ hematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding the therapeutic gene ADA. The engineered CD34+ cells are infused following a nonmyeloablative conditioning with busulfan to make space in the bone marrow. The study objectives are: a) to evaluate the safety and the clinical efficacy of gene therapy, in the absence of enzyme replacement therapy; b) to evaluate the biological activity (engraftment, ADA expression) of ADA transduced CD34+ cells and their hematopoietic progeny. c) to evaluate the immunological reconstitution and purine metabolism after gene therapy.

Conditions

Immunologic Deficiency Syndromes

Keywords

SCID; gene therapy; Adenosine deaminase; retroviral vector

Outcome Measures

Primary Outcomes (1)

• Survival

  From post-treatment to up to 3 years

  baseline to 3 years post gene therapy

Secondary Outcomes (2)

• Rate of Severe Infections

  Before Treatment and 3-months post-treatment up to 3 years

• CD3+ Cell Counts

  baseline up to 3 years post gene therapy

Study Arms (1)

Gene Therapy

EXPERIMENTAL

Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan

Genetic: Gene Therapy; Drug: Busulfan

Interventions

Gene Therapy GENETIC

Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan

Also known as: Gene transduced CD34+ cells, GSK2696273, Strimvelis

Gene Therapy

Busulfan DRUG

Busulfan is used for non-myeloablative conditioning

Gene Therapy

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• ADA-SCID with no HLA-identical sibling donor available
• pediatric age and at least one of the following criteria:
• inadequate immune response after PEG-ADA for \> 6 months
• patients who discontinued PEG-ADA due to intolerance, allergy or auto-immunity
• patients for whom enzyme replacement therapy is not a life long therapeutic option

You may not qualify if:

• HIV infection
• history or current malignancy
• Patients who received a previous gene therapy treatment in the 12 months prior to receiving Strimvelis
• any other conditions dangerous for the patients according to the investigator

Sponsors & Collaborators

• Fondazione Telethon: lead

Study Sites (2)

Investigational Site

Jerusalem, Israel

Location

Ospedale San Raffaele

Milan, Lombardy, 20132, Italy

Location

Related Publications (8)

• Migliavacca M, Barzaghi F, Fossati C, Rancoita PMV, Gabaldo M, Dionisio F, Giannelli S, Salerio FA, Ferrua F, Tucci F, Calbi V, Gallo V, Recupero S, Consiglieri G, Pajno R, Sambuco M, Priolo A, Ferri C, Garella V, Monti I, Silvani P, Darin S, Casiraghi M, Corti A, Zancan S, Levi M, Cesana D, Carlucci F, Pituch-Noworolska A, AbdElaziz D, Baumann U, Finocchi A, Cancrini C, Ladogana S, Meinhardt A, Meyts I, Montin D, Notarangelo LD, Porta F, Pasquet M, Speckmann C, Stepensky P, Tommasini A, Rabusin M, Karakas Z, Galicchio M, Leonardi L, Duse M, Guner SN, Di Serio C, Ciceri F, Bernardo ME, Aiuti A, Cicalese MP. Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. Nat Med. 2024 Feb;30(2):488-497. doi: 10.1038/s41591-023-02789-4. Epub 2024 Feb 14.

  PMID: 38355973 DERIVED

• Carriglio N, Klapwijk J, Hernandez RJ, Vezzoli M, Chanut F, Lowe R, Draghici E, Nord M, Albertini P, Cristofori P, Richards J, Staton H, Appleby J, Aiuti A, Sauer AV. Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice. Hum Gene Ther Clin Dev. 2017 Mar;28(1):17-27. doi: 10.1089/humc.2016.191.

  PMID: 28319446 DERIVED

• Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016 Jul 7;128(1):45-54. doi: 10.1182/blood-2016-01-688226. Epub 2016 Apr 29.

  PMID: 27129325 DERIVED

• Sauer AV, Brigida I, Carriglio N, Hernandez RJ, Scaramuzza S, Clavenna D, Sanvito F, Poliani PL, Gagliani N, Carlucci F, Tabucchi A, Roncarolo MG, Traggiai E, Villa A, Aiuti A. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood. 2012 Feb 9;119(6):1428-39. doi: 10.1182/blood-2011-07-366781. Epub 2011 Dec 19.

  PMID: 22184407 DERIVED

• Cassani B, Montini E, Maruggi G, Ambrosi A, Mirolo M, Selleri S, Biral E, Frugnoli I, Hernandez-Trujillo V, Di Serio C, Roncarolo MG, Naldini L, Mavilio F, Aiuti A. Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Blood. 2009 Oct 22;114(17):3546-56. doi: 10.1182/blood-2009-02-202085. Epub 2009 Aug 3.

  PMID: 19652199 DERIVED

• Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, Grunebaum E, Roifman CM, Cervi MC, Ambrosi A, Carlucci F, Roncarolo MG, Villa A, Rubinacci A, Aiuti A. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood. 2009 Oct 8;114(15):3216-26. doi: 10.1182/blood-2009-03-209221. Epub 2009 Jul 24.

  PMID: 19633200 DERIVED

• 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 DERIVED

• Cassani B, Mirolo M, Cattaneo F, Benninghoff U, Hershfield M, Carlucci F, Tabucchi A, Bordignon C, Roncarolo MG, Aiuti A. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood. 2008 Apr 15;111(8):4209-19. doi: 10.1182/blood-2007-05-092429. Epub 2008 Jan 24.

  PMID: 18218852 DERIVED

MeSH Terms

Conditions

Immunologic Deficiency Syndromes

Interventions

Genetic Therapy; Busulfan

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Genetic Engineering; Genetic Techniques; Investigative Techniques; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Fondazione Telethon
• Organization: Fondazione Telethon

cvezzali@telethon.it

Study Officials

• Fondazione Telethon

  Fondazione Telethon

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2008
• First Posted: January 22, 2008
• Study Start: October 2, 2002
• Primary Completion: July 10, 2011
• Study Completion: June 19, 2019
• Last Updated: January 29, 2024
• Results First Posted: July 31, 2020

Record last verified: 2023-11

Locations

IL (1); IT (1)