Wiskott-Aldrich Syndrome (WAS) Clinical Trial
— TIGET-WASOfficial title:
A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome
| Verified date | January 2024 |
| Source | Fondazione Telethon |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 8 |
| Est. completion date | October 4, 2023 |
| Est. primary completion date | October 3, 2018 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | N/A and older |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| Italy | Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET) | Milan |
| Lead Sponsor | Collaborator |
|---|---|
| Fondazione Telethon | Ospedale San Raffaele |
Italy,
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
* Note: There are 12 references in all — Click here to view all references
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Conditioning regimen-related safety | 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) | Two months after gene therapy | |
| Primary | Safety of lentivirus gene transfer into HSC | 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). | 3 years | |
| Primary | Sustained engraftment of genetically corrected haematopoietic stem cells in peripheral blood and/or in bone marrow | = 0.04 Vector copy number (VCN)/cell in bone marrow CD34+ or =0.1 VCN/cell in peripheral blood T lymphocytes | 1 year | |
| Primary | Expression of vector-derived WASP | Detection of vector-derived WASP expression by FACS analyses and/or Western Blot | 1 year | |
| Primary | Improved T-cell functions | Improvement in in vitro T cell proliferation and/or IL-2 secretion upon stimulation with anti-CD3i as compared to pre-gene therapy values. | 3 years | |
| Primary | Antigen-specific responses to vaccination | 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. | >1year | |
| Primary | Improved platelet count and MPV normalization | Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile | 3 years | |
| Primary | Overall survival | Number of patients alive all over the trial | 3 years | |
| Secondary | Lack of immune response to transgene | Immunoblot analysis | 3 years | |
| Secondary | 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. | 3 years | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | Overall safety of the treatment | Recording of AE, AR, SAE/SAR, UAR, SUSAR | 8 years |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00774358 -
Interleukin-2 Treatment for Wiskott-Aldrich Syndrome
|
Phase 1 |