Gene Therapy for Wiskott-Aldrich Syndrome

Study Overview
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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.

Official Title
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A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome

Conditions
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Wiskott-Aldrich Syndrome (WAS)

Intervention / Treatment
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* Genetic: OTL-103


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OTL-103 gene therapy<br>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<br>* 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<br>* Other names: Previously GSK2696275;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Expression of vector-derived WASP | Detection of vector-derived WASP expression by FACS analyses and/or Western Blot | 1 year | 
| 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 | 
| 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 | 
| Improved platelet count and MPV normalization | Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile | 3 years | 
| Overall survival | Number of patients alive all over the trial | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lack of immune response to transgene | Immunoblot analysis | 3 years | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Overall safety of the treatment | Recording of AE, AR, SAE/SAR, UAR, SUSAR | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lentiviral vector, Gene therapy, Wiskott-Aldrich Syndrome, OTL-103, Previously GSK2696275