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

NCT ID: NCT04797260

Last Updated: 2024-04-18

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-23
• Study Completion Date: 2029-12-31

Brief Summary

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.

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.

Conditions

Severe Combined Immunodeficiency Due to RAG1 Deficiency

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Gene therapy

In this arm, 10 patients will be included for gene therarpy

Group Type: EXPERIMENTAL

Gene therapy

Intervention Type: GENETIC

Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).

Interventions

Gene therapy

Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).

Intervention Type: GENETIC

Eligibility Criteria

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

• Minimum Eligible Age: 8 Weeks
• Maximum Eligible Age: 24 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Horizon 2020 - European Commission

OTHER

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

alankester

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Arjan C Lankester, Prof.dr.

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

Locations

The Royal Childrens Hospital

Melbourne, , Australia

Site Status: NOT_YET_RECRUITING

Ospedale Pediatrico Bambino Gesù

Roma, , Italy

Site Status: NOT_YET_RECRUITING

Leiden University Medical Center

Leiden, , Netherlands

Site Status: RECRUITING

Wroclaw Medical University

Wroclaw, , Poland

Site Status: RECRUITING

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Site Status: RECRUITING

Erciyes Üniversitesi TIP Fakültesi

Kayseri, , Turkey (Türkiye)

Site Status: RECRUITING

University College London Great Ormond Street

London, , United Kingdom

Site Status: NOT_YET_RECRUITING

Countries

Australia; Italy; Netherlands; Poland; Spain; Turkey (Türkiye); United Kingdom

Central Contacts

Arjan C Lankester, Prof. Dr.

Role: CONTACT

A.Lankester@lumc.nl

0031715264871

Estefania Laney, MSc.

Role: CONTACT

e.laney@lumc.nl

0031715296242

Facility Contacts

Rachel Conyers, Dr

Role: primary

Franco Locatelli, Prof. Dr.

Role: primary

Arjan Lankester, prof dr

Role: primary

a.lankester@lumc.nl

0031715264131

Estefania Laney, MSc

Role: backup

e.laney@lumc.nl

0031715262806

Krysztof Kalwak, Prof. Dr.

Role: primary

Pere Soler-Palacín, Dr

Role: primary

Musa Karakükcü, Prof. Dr.

Role: primary

Claire Booth, Dr

Role: primary

References

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.

Reference Type: RESULT

PMID: 32322605 (View on PubMed)

Other Identifiers

L20.067

Identifier Type: -

Identifier Source: org_study_id