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

RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

RAG1-deficient SCID as confirmed by genetic analysis

Peripheral blood T cells < 300/μL and/or naïve T cells < 1/μL

Age < 2 years

Age at least 8 weeks by the time of busulfan and fludarabine administration

Lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)

Signed informed consent (parental or guardian)

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

Availability of an HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)

RAG1 deficiency with peripheral blood T cells > 300/μL and/or naïve T cells > 1/μL

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

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 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

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Eligibility

Age eligible for study : 8 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2021-07-23

Primary completion: 2029-12-31

Study completion finish: 2029-12-31

Study type

TREATMENT

Phase

Trial ID

NCT04797260

Intervention or treatment

GENETIC: Gene therapy

Conditions

• Severe Combined Immunodeficiency Due to RAG1 Deficiency

Image related to Severe Combined Immunodeficiency Due to RAG1 Deficiency

Condition: Severe Combined Immunodeficiency Due to RAG1 Deficiency
GENETIC: Gene therapy
Melbourne, Not Specified, Australia
Sponsor: Leiden University Medical Center

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

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Find a site

Closest Location:

The Royal Childrens Hospital

Research sites nearby

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The Royal Childrens Hospital
Melbourne, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

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

Primary Outcome Measure	Primary Outcome Description	Primary Outcome 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

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome 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

Frequently Asked Questions

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References

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