Gene Therapy for Wiskott-Aldrich Syndrome

Phase 1

Completed

Conditions: Wiskott-Aldrich Syndrome (WAS)

Interventions: Genetic: OTL-103

Registration Number: NCT01515462

Lead Sponsor: Fondazione Telethon

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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
OTL-103 gene therapy	OTL-103	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

Primary Outcome Measures

Name	Time	Method
Safety of Reduced Conditioning Regimen	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)	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.
Presence of Detectable Vector-derived WASP	Median duration: 11.1 years (range: 8.01 -13.3 years)	The percentage of subjects who present the proportion of PB cells expressing WASP was assessed by flow cytometry analysis.
Overall Survival	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)	Participant survival was monitored throughout the study.
Safety of Lentivirus Gene Transfer Into HSC	after 48 hours after Telethon003 infusion	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.
Improved Platelet Count and MPV Normalization	up to 3 years after Telethon003 infusion	Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile
Sustained Engraftment of Genetically Corrected Haematopoietic Stem Cells in Peripheral Blood and/or in Bone Marrow	at 1 year after Telethon003 infusion	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.
Improved T-cell Functions	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)	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.
Antigen-specific Responses to Vaccination	Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)	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.

Secondary Outcome Measures

Name	Time	Method
Lack of Immune Response to Transgene	up to 3 years after Telethon003 infusion	Anti-WASP and anti-HIV-1 antibodies (anti-p24) were monitored to evaluate response to transgene and to vector, respectively.
Improved Quality of Life	3 year	Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.
Overall Safety of the Treatment	8 years	Recording of AE, AR, SAE/SAR, UAR, SUSAR
Reduced Frequency of Severe Infections	up to 3 years after Telethon003 infusion	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.
Reduced Bruising and Bleeding Episodes	3 years	Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history
Reduced Autoimmunity Phenomena and Eczema	3 years	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
Multilineage Engraftment of Genetically Corrected Cells	3 years	≥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+)