Severe Combined Immunodeficiency Due to RAG1 Deficiency
Conditions
Keywords
SCID, RAG1, Gene Therapy
Brief 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. 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.
Interventions
GENETICGene therapy
Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).
Sponsors
Videja B.V.
CR2O B.V.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
8 Weeks to 24 Months
Healthy volunteers
No
Inclusion criteria
1. RAG1-deficient SCID as confirmed by genetic analysis 2. Peripheral blood CD3+T cells \< 300/μL 3. Absence of peripheral blood naïve CD4+ T cells 4. Age \< 2 years 5. Age at least 8 weeks by the time of busulfan and fludarabine administration 6. Lack of an available HLA-identical sibling/family donor 7. Signed informed consent (parental or guardian) 8. 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
Exclusion criteria
1. Omenn syndrome 2. Previous allogeneic HSCT 3. 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 4. 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. 5. Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the effect of RAG1 gene therapy on overall survival. | 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. | 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. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the effect of RAG1 gene therapy on event-free survival. | 1 year | Event-free survival (survival without the need for rescue treatment defined as infusion of autologous unmanipulated backup stem cell product and/or allogeneic HSCT) |
| To evaluate the efficacy of RAG1 gene therapy in achieving independence of Immunoglobulin substitution | 2 years | Ability to mount humoral immune responses will be assessed by measuring the levels of IgG, IgA, IgM and IgE antibody production, following standard practice. |
| To evaluate the long-term efficacy of RAG1 gene therapy in reconstituting the immune system in patients with RAG1-SCID. | 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months | 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 |
| To evaluate the pharmacodynamic effects of RAG1 gene therapy. | 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months | * 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 |
| To evaluate the effects of RAG1 gene therapy on quality of life | 2 years | Quality of life at 2 years (assessed using PedsQL by proxy). |
| To evaluate the efficacy of RAG1 gene therapy in enabling a successful serologic response to vaccination | 2 years | Measured as protective antibody titers elicited upon vaccination against tetanus and pneumococcus conjugate |
Countries
Netherlands, Poland, Spain, Turkey (Türkiye)
Contacts
PRINCIPAL_INVESTIGATORArjan C Lankester, Prof.dr.
Leiden University Medical Center
Outcome results
None listed