Phase I/II Clinical Trial Stem Cell Gene Therapy in RAG1-Deficient SCID (RAG1-SCID)

Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency

This study is a prospective, non-randomized, open-label, two-centre phase I/II intervention study designed to treat children up to 24 months of age with RAG1-deficient SCID with an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The study involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in five patients with RAG1-deficient SCID.

Study Overview

• Status: Recruiting
• Conditions: Severe Combined Immunodeficiency Due to RAG1 Deficiency
• Intervention / Treatment: Genetic: Gene therapy

Detailed Description

Severe combined immunodeficiency (SCID) is a genetically heterogeneous life-threatening disease characterized by severely impaired T cell development with or without impaired natural killer (NK) and B cell development or function depending on the genetic defect. Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) represent about 20% of all types of SCID. SCID is a paediatric emergency since it leads to severe and recurrent infections often in combination with protracted diarrhoea and failure to thrive. When left untreated, it is usually fatal within the first year of life. Currently, the only curative treatment option for RAG-deficient SCID is allogeneic hematopoietic stem cell transplantation (HSCT). Despite improvements in HSCT in recent years, this treatment is associated with serious potential complications like graft-versus-host disease which results in an unfavourable outcome, particularly in patients who lack a human leukocyte antigen (HLA)-matched donor. In recent years, gene therapy based on transplantation of autologous gene-corrected hematopoietic stem cells (HSC) has evolved as an effective and safe therapeutic option for X-linked and ADA-deficient forms of SCID. We have recently demonstrated that gene therapy using lentiviral (LV) self-inactivating (SIN) vectors expressing codon-optimized human RAG1 in a mouse model for RAG1-deficient SCID effectively restores T and B cell development and function. In this phase I/II explorative intervention study feasibility, safety and efficacy of gene therapy using gene-corrected autologous CD34+-selected mobilized peripheral blood or bone marrow cells will be investigated in patients with RAG1-deficient SCID with an indication for allogeneic HSCT but lacking an human leukocyte antigen (HLA)-matched donor.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Arjan C Lankester, Prof. Dr.; Phone Number: 0031715264871; Email: A.Lankester@lumc.nl
• Study Contact Backup: Name: Estefania Laney, MSc.; Phone Number: 0031715296242; Email: e.laney@lumc.nl

Study Locations

• Australia
  • Melbourne, Australia, 3052
    • Not yet recruiting
    • The Royal Childrens Hospital
    • Contact: Rachel Conyers, Dr
    • Principal Investigator: Rachel Conyers, Dr
• Italy
  • Roma, Italy
    • Not yet recruiting
    • Ospedale Pediatrico Bambino Gesù
    • Contact: Franco Locatelli, Prof. Dr.
    • Principal Investigator: Franco Locatelli, Prof. Dr.
• Netherlands
  • Leiden, Netherlands, 2300RC
    • Recruiting
    • Leiden University Medical Center
    • Contact: Arjan Lankester, prof dr; Phone Number: 0031715264131; Email: a.lankester@lumc.nl
    • Contact: Estefania Laney, MSc; Phone Number: 0031715262806; Email: e.laney@lumc.nl
• Poland
  • Wroclaw, Poland, 50-556
    • Recruiting
    • Wroclaw Medical University
    • Contact: Krysztof Kalwak, Prof. Dr.
    • Principal Investigator: Krysztof Kalwak, Prof. Dr.
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
    • Contact: Pere Soler-Palacín, Dr
    • Principal Investigator: Pere Soler-Palacín, Dr
• Turkey
  • Kayseri, Turkey
    • Recruiting
    • Erciyes Üniversitesi TIP Fakültesi
    • Contact: Musa Karakükcü, Prof. Dr.
    • Principal Investigator: Musa Karakükcü, Prof. Dr.
• United Kingdom
  • London, United Kingdom
    • Not yet recruiting
    • University College London Great Ormond Street
    • Contact: Claire Booth, Dr
    • Principal Investigator: Clare Booth, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 2 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. RAG1-deficient SCID as confirmed by genetic analysis
2. Peripheral blood T cells < 300/μL and/or naïve T cells < 1/μL
3. Age < 2 years
4. Age at least 8 weeks by the time of busulfan and fludarabine administration
5. Lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
6. Signed informed consent (parental or guardian)
7. Able to return to the study centre for follow-up (per protocol) during the 2-year study and the 15-year long-term off study review

Exclusion Criteria:

1. Availability of an HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
2. RAG1 deficiency with peripheral blood T cells > 300/μL and/or naïve T cells > 1/μL
3. Omenn syndrome
4. Previous allogeneic HSCT

5. Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below):

   1. Mechanical ventilation
   2. Shortening fraction on echocardiogram <25%
   3. Renal failure defined as dialysis dependence
   4. Uncontrolled seizure disorder
6. Any other condition that the investigator considers is a contraindication to collection and/or infusion of trans-duced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication f to busulfan, major congenital abnormalities, ineligible to receive anaesthesia, or documented refusal or inability of the family to return for scheduled visits.
7. Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gene therapy; In this arm, 10 patients will be included for gene therarpy	Genetic: Gene therapy; Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of successful generation of RAG1 LV CD34+ cells	IMP (RAG1 LV CD34+ cells) that meets the release criteria as defined in the IMPD.	2 years
Safety of RAG1 lentiviral gene therapy	Overall survival and event-free survival (EFS) after infusion of the IMP with events	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T cell reconstitution	CD3 T cells > 300/μL and CD4 > 200/μL at 1 year	1 year
Thymic function	presence of naïve CD4 T cells at 1 year	1 year
T and B cell receptor repertoire	Molecular T and B cell receptor repertoire at 1 year	1 year
Immunoglobulin dependence	Immunoglobulin supplementation dependence at 2 years	2 years
Persistence of gene marking	Gene marking in myeloid and lymphoid lineages in blood at six months and one year and in bone marrow at one year	1 year
Occurrence of Infections	Frequency of serious/invasive infections	2 years
Failure to thrive	Recovery from failure to thrive	2 years
Quality of life	Quality of life at 2 years (assessed using PedsQL by proxy).	2 years

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Horizon 2020 - European Commission
• Investigators: Principal Investigator: Arjan C Lankester, Prof.dr., Leiden University Medical Center

Publications and helpful links

General Publications

• Garcia-Perez L, van Eggermond M, van Roon L, Vloemans SA, Cordes M, Schambach A, Rothe M, Berghuis D, Lagresle-Peyrou C, Cavazzana M, Zhang F, Thrasher AJ, Salvatori D, Meij P, Villa A, Van Dongen JJM, Zwaginga JJ, van der Burg M, Gaspar HB, Lankester A, Staal FJT, Pike-Overzet K. Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID. Mol Ther Methods Clin Dev. 2020 Mar 31;17:666-682. doi: 10.1016/j.omtm.2020.03.016. eCollection 2020 Jun 12.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2021
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: March 11, 2021
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Estimated): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; SCID; RAG1
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency
• Other Study ID Numbers: L20.067

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No