Gene therapy for children with RAG1-deficient SCID

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

This study is testing a new gene therapy to help young children with a rare immune disorder called RAG1-deficient SCID by using their own modified cells to improve their immune system.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 8 Weeks to 24 Months
• Sex: All
• Sponsor: Leiden University Medical Center (Academic / other)
• Drugs / interventions: fludarabine
• Locations: 7 sites (Melbourne and 6 other locations)
• Trial ID: NCT04797260 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to treat children under 24 months with RAG1-deficient severe combined immunodeficiency (SCID) who do not have an HLA-matched donor for hematopoietic stem cell transplantation. The approach involves infusing autologous CD34+ cells that have been genetically modified using a lentiviral vector to express the human RAG1 gene. The study is non-randomized and open-label, conducted at two centers, and will include five patients. The goal is to restore T and B cell development and function, which are severely impaired in these patients.

Who should consider this trial

Good fit: Ideal candidates are infants and young children under 2 years old diagnosed with RAG1-deficient SCID and lacking an HLA-matched donor.

Not a fit: Patients who have an available HLA-matched donor or those with significant organ dysfunction may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a curative option for children with RAG1-deficient SCID who lack suitable donors for traditional transplantation.

How similar studies have performed: Previous studies have shown success with gene therapy approaches for other forms of SCID, indicating potential for this novel treatment.

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

Where this trial is running

Melbourne and 6 other locations

• The Royal Childrens Hospital — Melbourne, Australia (Not_yet_recruiting)
• Ospedale Pediatrico Bambino Gesù — Roma, Italy (Not_yet_recruiting)
• Leiden University Medical Center — Leiden, Netherlands (Recruiting)
• Wroclaw Medical University — Wroclaw, Poland (Recruiting)
• Hospital Universitari Vall d'Hebron — Barcelona, Spain (Recruiting)
• Erciyes Üniversitesi TIP Fakültesi — Kayseri, Turkey (Türkiye) (Recruiting)
• University College London Great Ormond Street — London, United Kingdom (Not_yet_recruiting)

Study contacts

• Principal investigator: Arjan C Lankester, Prof.dr. — Leiden University Medical Center
• Study coordinator: Arjan C Lankester, Prof. Dr.

Conditions Severe Combined Immunodeficiency Due to RAG1 Deficiency; SCID; RAG1; Gene Therapy