Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by mutations in a single gene ,the Wiskott-Aldrich Syndrome Protein (WASP). WAS is characterised by micro-thrombocytopenia, recurrent infections,eczema and associated with a high incidence of auto-immunity and of lymphoid malignancies. Over 150 unique mutations in the WAS gene have been identified.Loss-of-function mutations in this gene have widespread consequences on hematopoietic lineages. MedDRA version: 19.1 Level: PT
Conditions
Sponsors
Genethon
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. a. Males of all ages b. Severe WAS (clinical score 3 – 5) or absence of WAS protein in peripheral blood mononuclear cells determined by Western blotting and flow cytometry c. Molecular confirmation by WAS gene DNA sequencing 2. Lack of HLA-genotypically identical bone marrow OR of a 10/10 antigen HLA-matched unrelated donor or cord blood after 3 month search 3. Parental, guardian, patient signed informed consent/assessment 4. Willing to return for follow-up during the 2 year study 5. Only for patients who have received previous allogenic haematopoietic stem cell transplant: a. Failed allogenic haematopoietic stem cell transplant b. Contraindication to repeat allogeneic transplantation for example severe graft versus host disease Are the trial subjects under 18? yes Number of subjects for this age range: 5 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range ;Inclusion criteria: 1. a. Males of all ages b. Severe WAS (clinical score 3 – 5) or absence of WAS protein in peripheral blood mononuclear cells determined by Western blotting and flow cytometry c. Molecular confirmation by WAS gene DNA sequencing 2. Lack of HLA-genotypically identical bone marrow OR of a 10/10 antigen HLA-matched unrelated donor or cord blood after 3 month search 3. Parental, guardian, patient signed informed consent/assessment 4. Willing to return for follow-up during the 2 year study 5. Only for patients who have received previous allogenic haematopoietic stem cell transplant: a. Failed allogenic haematopoietic stem cell transplant b. Contraindication to repeat allogeneic transplantation for example severe graft versus host disease Are the trial subjects under 18? yes Number of subjects for this age range: 5 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range ;Inclusion criteria: 1. a. Males of all ages b. Severe WAS (clinical score 3 – 5) or absence of WAS protein in peripheral blood mononuclear cells determined by Western blotting and flow cytometry c. Molecular confirmation by WAS gene DNA sequencing 2. Lack of HLA-genotypically identical bone marrow OR of a 10/10 antigen HLA-matched unrelated donor or cord blood after 3 month search 3. Parental, guardian, patient signed informed consent/assessment 4. Willing to return for follow-up during the 2 year study 5. Only for patients who have received previous allogenic haematopoietic stem cell transplant: a. Failed allogenic haematopoietic stem cell transplant b. Contraindication to repeat allogeneic transplantation for example severe graft versus host disease Are the trial subjects under 18? yes Number of subjects for this age range: 5 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. a. Patient with HLA-genotypically identical bone marrow b. Patient with 10/10 antigen HLA-matched unrelated donor or cord blood 2. a. Contraindication to leukapheresis i. anaemia (Hb < 8g/dl) ii. cardiovascular instability iii. severe coagulopathy b. Contraindication to bone marrow harvest c. Contraindication to administration of conditioning medication 3. HIV positive patient ;Exclusion criteria: 1. a. Patient with HLA-genotypically identical bone marrow b. Patient with 10/10 antigen HLA-matched unrelated donor or cord blood 2. a. Contraindication to leukapheresis i. anaemia (Hb < 8g/dl) ii. cardiovascular instability iii. severe coagulopathy b. Contraindication to bone marrow harvest c. Contraindication to administration of conditioning medication 3. HIV positive patient ;Exclusion criteria: 1. a. Patient with HLA-genotypically identical bone marrow b. Patient with 10/10 antigen HLA-matched unrelated donor or cord blood 2. a. Contraindication to leukapheresis i. anaemia (Hb < 8g/dl) ii. cardiovascular instability iii. severe coagulopathy b. Contraindication to bone marrow harvest c. Contraindication to administration of conditioning medication 3. HIV positive patient
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy of heamatopoietic stem cell gene therapy in WAS patients based on the clinical improvement in at least one of the following clinical parameters, depending on the patient’s symptomatology at study entry: eczema status, frequency and severity of infections, of bruising and bleeding episodes and of autoimmune disorders and consequently to assess the number of disease-related days of hospitalisation;Secondary Objective: - To assess the safety of heamatopoietic stem cell gene therapy in WAS patients - To asses the efficacy of heamatopoietic stem cell gene therapy on the evolution of microthrombocytopenia and its treatment - To assess the efficacy of heamatopoietic stem cell gene therapy on the evolution of the other haematological parameters including WASP expression ;Primary end point(s): -Improvement at 24 months in at least one of the following clinical conditions depending on the patient’s clinical symptomatology at study entry: - Improvement in the eczema status at 24 months as compared with the baseline status at study entry - Reduction in the frequency and severity of infection episodes at 24 months as compared with the baseline status and the patient’s historical data collected over the 24 months prior to study entry - Reduction in the frequency and severity of bruising and bleeding episodes at 24 months evaluated by clinical examination as compared with the baseline status at study entry and the patient’s historical data collected over the 24 months prior to study entry - Reduction in the frequency and severity of autoimmune disorders at 24 months as compared with the baseline status at study entry - Reduction in the number of disease-related days of hospitalisation as compared with the patient’s historical data collected over the 24 months prior to study entry ;Timepoint(s) of evaluation of this end point: 24 months;Main Objective: To assess the efficacy of heamatopoietic stem cell gene therapy in WAS patie | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Safety Safety of gene therapy will be assessed through the occurrence of adverse events reported during the course of the study. In addition, any change in medical conditions including weight, vital signs (Blood pressure, pulse rate), ECG and laboratory exams will also be assessed during the course of the study. Safety of gene therapy will be assessed by lack of the detection of replication competent lentivirus (RCL) at 3, 6, 12 and 24 months post gene therapy. Safety of gene therapy will be assessed by the analysis of the lentivirus integration sites performed in different cell subpopulations to investigate specific clonal expansions at 6, 12, 18 and 24 months post gene therapy and quantification of transgene copy numbers determined on sorted cell populations by real-time PCR methodology at 6 weeks and 1, 3, 6, 9, 12, 18 and 24 months post gene therapy. 2- Efficacy Improvement of microthrombocytopenia at 3, 6, 12 and 24 months as compared with the baseline evaluation at study entry Decrease in the number and volume of platelet transfusions at 24 months as compared with the patient’s historical data collected over the 24 months prior to study entry Evidence of sustained engraftment of WASP-expressing tranduced cells at 6 weeks and 1, 3, 6, 9, 12, 18 and 24 months post gene therapy Reconstitution of humoral and cell mediated immunity at 9, 12, 18 and 24 months as compared with baseline evaluation at study entry ;Timepoint(s) of evaluation of this end point: 1, 3, 6, 9, 12, 18 and 24 months depending on the endpoint.;Secondary end point(s): 1. Safety Safety of gene therapy will be assessed through the occurrence of adverse events reported during the course of the study. In addition, any change in medical conditions including weight, vital signs (Blood pressure, pulse rate), ECG and laboratory exams will also be assessed during the course of the study. Safety of gene therap | — |
Countries
United Kingdom
Contacts
Public ContactClinical Trials Information;Clinical Trials Information;Clinical Trials Information ;;
Genethon;Genethon;Genethon
Outcome results
None listed