Gene Therapy for WAS

Phase I/II Clinical Trial of Haematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome

This is a phase I/II study to evaluate the safety and efficacy of Hematopoietic Stem Cell genetherapy for the Wiskott-Aldrich Syndrome.

Study Overview

• Status: Completed
• Conditions: Wiskott-Aldrich Syndrome
• Intervention / Treatment: Genetic: Autologous CD34 positive cells transduced with a lentiviral vector containing human WAS gene

Detailed Description

This clinical trial is an ex vivo gene therapy trial. The investigational product corresponds to autologous CD34+ cells transduced with a lentiviral vector harboring the human WASP gene.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker-Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• males of all ages
• severe WAS (clinical score 3-5) or absence of WAS protein in peripheral blood mononuclear cells determined by Western blotting and flow cytometry
• molecular confirmation by WAS gene DNA sequencing
• lack of HLA-genotypically identical bone marrow after 3 month search
• lack of a 10/10 or 9/10 antigen HLA-matched unrelated donor after 3 month search
• lack of a HLA-matched cord blood after 3 month search
• parental, guardian, patient signed informed consent/assent
• willing to return for follow-up
• only for patients who have received previous allogenic hematopoietic stem cell transplant:
• failed allogenic hematopoietic stem cell transplant
• contraindication to repeat transplantation

Exclusion Criteria:

• patient with HLA-genotypically identical bone marrow
• patient with 10/10 or 9/10 antigen HLA-matched unrelated donor or with HLA-matched cord blood
• contraindication to leukapheresis
• contraindication to bone marrow harvest
• contraindication to administration of conditioning medication
• HIV positive patient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in the frequency and severity of infection episodes	Reduction in the frequency and severity of infection episodes as compared with the baseline status and the patient's historical data collected over the 2 years prior to study entry	2 years
Reduction in the frequency and severity of bruising and bleeding episodes	Reduction in the frequency and severity of bruising and bleeding episodes as compared with the baseline status and the patient's historical data collected over the 2 years prior to study entry	2 years
Reduction in the frequency and severity of autoimmune disorders	Reduction in the frequency and severity of autoimmune disorders as compared with the baseline status at study entry	2 years
Reduction in the number of disease related days of hospitalization	Reduction in the number of disease related days of hospitalization as compared with the patient's historical data collected over the 2 years prior to study entry	2 years
Improvement in the eczema status	Improvement in eczema status as compared with the baseline status at study entry on clinical evaluation	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence and type of adverse events	Occurrence and type of adverse events reported during the course of the study	2 years
Change in medical conditions	Assessment of weight, vital signs, ECG and laboratory exams during the course of the study	2 years
Safety of lentivirus gene transfer into Hematopoietic Stem Cells	Detection of replication competent lentivirus (RCL) and lentivirus integration sites analysis	3, 6, 12, 24 months / 6, 12, 18, 24 months
Improvement of microthrombocytopenia	Improvement of microthrombocytopenia as compared with the baseline evaluation at study entry	3, 6, 12, 24 months
Decrease in the number and volume of platelets transfusions	Decrease in the number and volume of platelets transfusions as compared with patient's historical data collected over the 2 years prior to study entry	2 years
Reconstitution of humoral and cell mediated immunity	Reconstitution of humoral and cell mediated immunity as compared with the baseline evaluation at study entry	9, 12, 18 & 24 months
Evidence of sustained engraftment of WASP-expressing transduced cells	Quantification of vector copy numbers and detection of vector-derived WASP expression	6 weeks, 1, 3, 6, 9, 12, 18 & 24 months

Collaborators and Investigators

• Sponsor: Genethon
• Collaborators: Hôpital Necker-Enfants Malades

Publications and helpful links

General Publications

• Magnani A, Semeraro M, Adam F, Booth C, Dupre L, Morris EC, Gabrion A, Roudaut C, Borgel D, Toubert A, Clave E, Abdo C, Gorochov G, Petermann R, Guiot M, Miyara M, Moshous D, Magrin E, Denis A, Suarez F, Lagresle C, Roche AM, Everett J, Trinquand A, Guisset M, Bayford JX, Hacein-Bey-Abina S, Kauskot A, Elfeky R, Rivat C, Abbas S, Gaspar HB, Macintyre E, Picard C, Bushman FD, Galy A, Fischer A, Six E, Thrasher AJ, Cavazzana M. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome. Nat Med. 2022 Jan;28(1):71-80. doi: 10.1038/s41591-021-01641-x. Epub 2022 Jan 24. Erratum In: Nat Med. 2022 Oct;28(10):2217.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): January 13, 2016
• Study Completion (ACTUAL): January 9, 2017

Study Registration Dates

• First Submitted: May 3, 2011
• First Submitted That Met QC Criteria: May 3, 2011
• First Posted (ESTIMATE): May 4, 2011

Study Record Updates

• Last Update Posted (ACTUAL): May 22, 2018
• Last Update Submitted That Met QC Criteria: May 18, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: hematopoietic stem cells; Wiskott-Aldrich Syndrome; Primary immune deficiency; ex vivo gene therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Immunologic Deficiency Syndromes; Immune System Diseases; Disease; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Leukopenia; Leukocyte Disorders; Primary Immunodeficiency Diseases; Lymphopenia; Syndrome; Wiskott-Aldrich Syndrome
• Other Study ID Numbers: GTG003.08; 2009-011152-22 (EUDRACT_NUMBER)