Severe Combined Immunodeficiency Due to RAG1 DeficiencyPhase 1/2RAG1-SCIDNCT04797260
Phase I/II Clinical Trial Stem Cell Gene Therapy in RAG1-Deficient SCID
A Phase 1/2 study testing Gene therapy in people with Severe Combined Immunodeficiency Due to RAG1 Deficiency, run by Videja B.V. at 4 sites in 4 countries.
Trial summary
This trial is a prospective, non-randomized, open-label, multicentre single-arm phase I/II intervention trial in children up to 24 months of age with RAG1-deficient SCID and an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. Read more about this study
- Who is it for?
- Ages 8 weeks to 24 months
- Conditions the study is for
- Severe Combined Immunodeficiency Due to RAG1 Deficiency
- What is being tested?
- Gene therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 4 sitesin 4 countries
- Study dates
- 23 Jul 2021to 31 Dec 2031
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 weeks to 24 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- RAG1-deficient SCID as confirmed by genetic analysis
- Peripheral blood CD3+T cells < 300/μL
- Absence of peripheral blood naïve CD4+ T cells
- Age < 2 years
- Age at least 8 weeks by the time of busulfan and fludarabine administration
- Lack of an available HLA-identical sibling/family donor
- Signed informed consent (parental or guardian)
- Able to return to the local HSCT centre for follow-up (per protocol) during the 5-year trial and up to at least 15-year long-term follow-up after IMP administration
Who cannot join
- Omenn syndrome
- Previous allogeneic HSCT
- Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below):
- Mechanical ventilation
- Shortening fraction on echocardiogram <25%
- Renal failure defined as dialysis dependence
Show all 9Show fewer
- Uncontrolled seizure disorder
- 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.
- Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection
Trial locations and contacts
4 sites in 4 countries.
4 sites in 4 countries
About this study
Official title: Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency
This trial is a prospective, non-randomized, open-label, multicentre single-arm phase I/II intervention trial in children up to 24 months of age with RAG1-deficient SCID and an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The trial involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in up to 10 patients with RAG1-deficient SCID. Patients will be regularly monitored for 5 years after infusion. Follow up as part of routine clinical care for post-transplant patients will be annual after this, for at least 15 years after IMP infusion.
Read the 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, life-threatening 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 intervention trial safety and efficacy of gene therapy using gene-corrected autologous CD34+-selected mobilized peripheral cells will be investigated in patients with RAG1-deficient SCID with an indication for allogeneic HSCT but lacking an HLA-identical sibling/ family donor.
- Being tested
- Gene therapy
- Keywords
- SCID, RAG1, Gene Therapy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gene therapyGenetic
Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).
| Study group | Role | What they receive |
|---|---|---|
| Gene therapy | Experimental | In this arm, 10 patients will be included for gene therarpy Receives: Genetic: Gene therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
To evaluate the effect of RAG1 gene therapy on overall survival.
Overall survival
Measured: 5 years
To evaluate the efficacy of RAG1 gene therapy in achieving reconstitution of the T and B cell immune system in patients with RAG1-SCID at 6 months.
Evaluation of immune reconstitution at Month 6 defined as
- Presence of naive CD4+ T cells
- Total CD3+ T-cells > 300 cells/μL
- Total CD4+ T-cells > 200 cells/μL
Measured: 6 Months
To evaluate the safety and tolerability of the RAG1 gene therapy product, including identification of short- and long-term adverse events.
- Number of patients with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs, e.g. insertional mutagenesis) and relatedness of the events to intervention, treatment and/or investigational drug
- Incidence of new or worsening abnormalities in laboratory safety parameters and clinical assessments (including hematology, biochemistry, endocrinology, physical examination findings, vital signs, cardiac ultrasound, and Lansky performance score).
Measured: 5 years
Secondary outcomes (6)
To evaluate the effect of RAG1 gene therapy on event-free survival.
Event-free survival (survival without the need for rescue treatment defined as infusion of autologous unmanipulated backup stem cell product and/or allogeneic HSCT)
Measured: 1 year
To evaluate the efficacy of RAG1 gene therapy in achieving independence of Immunoglobulin substitution
Ability to mount humoral immune responses will be assessed by measuring the levels of IgG, IgA, IgM and IgE antibody production, following standard practice.
Measured: 2 years
To evaluate the long-term efficacy of RAG1 gene therapy in reconstituting the immune system in patients with RAG1-SCID.
Immune system reconstitution
- T-cell repopulation:
- Total CD3+ T-cells > 300 cells/μL (at Month 12, 18, 24, 30, 36, 42, 48, 54, 60)
- Total CD4+ T-cells > 200 cells/μL (at Month 12, 18, 24, 30, 36, 42, 48, 54, 60)
- Presence of naive CD4+ T cells (at Month 12, 18, 24, 30, 36, 42, 48, 54, 60)
- B-cell repopulation:
- Total B-cell counts (at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60)
- Memory B-cell count (at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60)
- Switched memory B-cell count (at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60)
- Immune function:
- Level of IgG (at Month 6, 12, 18, 24, 36, 48, 60)
- Level of IgA (at Month 6, 12, 18, 24, 36, 48, 60)
- Level of IgM (at Month 6, 12, 18, 24, 36, 48, 60)
- IG repertoire and T cell receptor (TCR) repertoire on PBMCs at Month 12
Measured: 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months
To evaluate the pharmacodynamic effects of RAG1 gene therapy.
- Vector copy number (VCN) in PBMCs and granulocytes at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60
- TRECs and KRECs at Month 12 and 24
Measured: 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months
To evaluate the effects of RAG1 gene therapy on quality of life
Quality of life at 2 years (assessed using PedsQL by proxy).
Measured: 2 years
To evaluate the efficacy of RAG1 gene therapy in enabling a successful serologic response to vaccination
Measured as protective antibody titers elicited upon vaccination against tetanus and pneumococcus conjugate
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Mar 2021
- Study start23 Jul 2021
- Primary completion31 Dec 2031 (estimated)
- Study completion31 Dec 2031 (estimated)
Why it stopped: Trial is on a temporarily recruitment hold as a result of a reported SAE for one of the patients. Further data analysis has started with safety data currently being evaluated to assess a relationship with the IMP.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Severe Combined Immunodeficiency Due to RAG1 DeficiencyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Participants will receive a single administration of autologous gene-modified CD34+ hematopoietic stem cells, following ex vivo transduction with the pCCL.MND.coRAG1.wpre lentiviral vector. In case of failure of hematopoietic reconstitution after infusion, the autologous backup graft will be infused to rescue the patient from aplasia. Alternatively, a conventional allogeneic HSCT procedure may be scheduled. After infusion, participants will be followed for safety and efficacy over 5 years as per study protocol. Follow up as part of the routine clinical care for post-transplant patients will be annual after this, for at least 15 years after infusion.
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Videja B.V.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- CR2O B.V.
- Responsible party
- Sponsor
- Investigators
- Arjan C Lankester, Prof.dr., Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04797260
- Sponsor's protocol ID
- RAG1-2019-01
- Other IDs
- 2023-510204-50-00, 2019-002343-14, 2019, 2023
- Acronym
- RAG1-SCID
- Status last verified
- Jul 2026
- First submitted
- 11 Mar 2021
- Last updated
- 16 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 32322605
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency
- ClinicalTrials.gov ID
- NCT04797260
- Acronym / sponsor ID
- RAG1-SCID / RAG1-2019-01
- Keywords
- SCID, RAG1, Gene Therapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Trial is on a temporarily recruitment hold as a result of a reported SAE for one of the patients. Further data analysis has started with safety data currently being evaluated to assess a relationship with the IMP.
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- Videja B.V.Industry (pharma, biotech, devices)
- Collaborators
- CR2O B.V.
- Study start
- 23 Jul 2021 (actual)
- Primary completion
- 31 Dec 2031 (estimated)
- Study completion
- 31 Dec 2031 (estimated)
- First posted
- 15 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This trial is a prospective, non-randomized, open-label, multicentre single-arm phase I/II intervention trial in children up to 24 months of age with RAG1-deficient SCID and an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The trial involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in up to 10 patients with RAG1-deficient SCID. Patients will be regularly monitored for 5 years after infusion. Follow up as part of routine clinical care for post-transplant patients will be annual after this, for at least 15 years after IMP infusion.
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, life-threatening 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 intervention trial safety and efficacy of gene therapy using gene-corrected autologous CD34+-selected mobilized peripheral cells will be investigated in patients with RAG1-deficient SCID with an indication for allogeneic HSCT but lacking an HLA-identical sibling/ family donor.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Participants will receive a single administration of autologous gene-modified CD34+ hematopoietic stem cells, following ex vivo transduction with the pCCL.MND.coRAG1.wpre lentiviral vector. In case of failure of hematopoietic reconstitution after infusion, the autologous backup graft will be infused to rescue the patient from aplasia. Alternatively, a conventional allogeneic HSCT procedure may be scheduled. After infusion, participants will be followed for safety and efficacy over 5 years as per study protocol. Follow up as part of the routine clinical care for post-transplant patients will be annual after this, for at least 15 years after infusion.
| Arm | Type | Receives |
|---|---|---|
| Gene therapy | Experimental | Genetic: Gene therapyIn this arm, 10 patients will be included for gene therarpy |
Who may qualify
- Ages
- 8 weeks to 24 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (8 listed)
- RAG1-deficient SCID as confirmed by genetic analysis
- Peripheral blood CD3+T cells < 300/μL
- Absence of peripheral blood naïve CD4+ T cells
- Age < 2 years
- Age at least 8 weeks by the time of busulfan and fludarabine administration
Key exclusion criteria (9 listed)
- Omenn syndrome
- Previous allogeneic HSCT
- Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below):
- 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.
- Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gene therapyPatients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells). | Genetic | Gene therapy |
Primary outcome
To evaluate the effect of RAG1 gene therapy on overall survival.
Time frame: 5 years
Overall survival
To evaluate the efficacy of RAG1 gene therapy in achieving reconstitution of the T and B cell immune system in patients with RAG1-SCID at 6 months.
Time frame: 6 Months
Evaluation of immune reconstitution at Month 6 defined as * Presence of naive CD4+ T cells * Total CD3+ T-cells > 300 cells/μL * Total CD4+ T-cells > 200 cells/μL
To evaluate the safety and tolerability of the RAG1 gene therapy product, including identification of short- and long-term adverse events.
Time frame: 5 years
* Number of patients with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs, e.g. insertional mutagenesis) and relatedness of the events to intervention, treatment and/or investigational drug * Incidence of new or worsening abnormalities in laboratory safety parameters and clinical assessments (including hematology, biochemistry, endocrinology, physical examination findings, vital signs, cardiac ultrasound, and Lansky performance score).
6 secondary outcomes
To evaluate the effect of RAG1 gene therapy on event-free survival.
Time frame: 1 year
To evaluate the efficacy of RAG1 gene therapy in achieving independence of Immunoglobulin substitution
Time frame: 2 years
To evaluate the long-term efficacy of RAG1 gene therapy in reconstituting the immune system in patients with RAG1-SCID.
Time frame: 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months
To evaluate the pharmacodynamic effects of RAG1 gene therapy.
Time frame: 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months
To evaluate the effects of RAG1 gene therapy on quality of life
Time frame: 2 years
To evaluate the efficacy of RAG1 gene therapy in enabling a successful serologic response to vaccination
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jul 2026.
- Results publication: PubMed 32322605Garcia-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Arjan C Lankester, Prof.dr. principal investigator
Leiden University Medical Center
4 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Gene therapy in people with Severe Combined Immunodeficiency Due to RAG1 Deficiency, run by Videja B.V. at 4 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 16 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Netherlands, Poland, Spain, Turkey (Türkiye). Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To evaluate the effect of RAG1 gene therapy on overall survival. (time frame: 5 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04797260, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jul 2026.