Gene Therapy for Severe Combined Immunodeficiency

Overseen By Morton Cowan, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, San Francisco

Disqualifiers: Liver dysfunction, HIV, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 17

Duration: 1 day

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco in this single-site trial and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment AProArt for Artemis-Deficient Severe Combined Immunodeficiency?

Research shows that using a lentiviral vector to deliver the Artemis gene into stem cells can restore normal immune function in mice with Artemis deficiency, leading to the development of healthy B and T cells. This suggests that the gene therapy approach used in AProArt could be effective in treating Artemis-Deficient Severe Combined Immunodeficiency. ^{1 2 3 4 5}

Is gene therapy for Artemis-deficient SCID safe for humans?

Preclinical studies in mice show that gene therapy for Artemis-deficient SCID using a lentiviral vector is generally safe, with no evidence of toxicity or cancer development related to the treatment. However, one mouse developed a thymoma, likely due to the genetic background rather than the therapy itself, suggesting the need for careful monitoring in humans. ^{1 2 4 5 6}

How is the treatment AProArt with Busulfan unique for Artemis-deficient SCID?

This treatment is unique because it uses gene therapy to correct the immune system by modifying the patient's own stem cells with a lentiviral vector, offering a potentially safer and more effective alternative to traditional bone marrow transplants, especially for those without a suitable donor. ^{1 2 3 4 7}

Research Team

Morton Cowan, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for patients with Artemis-deficient Severe Combined Immunodeficiency (ART-SCID) who haven't been treated with high-dose busulfan, don't have a suitable sibling donor, and are over 2 months old. It's also open to those who didn’t respond well to a previous transplant if they meet certain conditions.

Inclusion Criteria

I have ART-SCID and my previous transplant did not work.

I am at least 2 months old starting the busulfan treatment.

I have never been treated with high dose busulfan.

Exclusion Criteria

You have tested positive for HIV using specific testing methods.

I have a sibling who is a medical match for me (newly diagnosed patients only).

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive sub-ablative, dose-targeted busulfan conditioning prior to infusion

2 days

Treatment

Participants receive an infusion of stem cells transduced with a self-inactivating lentiviral vector containing a normal copy of the DCLRE1C gene

1 day

1 visit (in-person)

Initial Follow-up

Participants are evaluated for evidence of gene transduced peripheral blood mononuclear cells and cell lineages

24 weeks

Visits at 4, 6, 8, 16, and 24 weeks

Long-term Follow-up

Participants are monitored for toxicity and durable reconstitution of T and B cell immunity, with assessments continuing for 15 years

15 years

Weekly through 12 weeks, monthly through 6 months, then 3-monthly through 24 months, 6-monthly through 5 years, and annually through 15 years

Treatment Details

Interventions

• AProArt
• Busulfan
• CliniMACS® CD34 Reagent System cell sorter device

Trial Overview The study tests a gene therapy method where stem cells are modified with a normal DCLRE1C gene and infused back into the patient after low-dose busulfan conditioning. The goal is to see if this can safely rebuild the immune system in ART-SCID patients.

Participant Groups

Group I: Gene therapy (AProArt) Experimental Treatment 3 Interventions

Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) Using a Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells. The CliniMACS® CD34 Reagent System sorter device will be used to select CD34 cells. Patients will be conditioned with low dose busulfan prior to transplant.

AProArt is already approved in United States for the following indications:

Approved in United States as AProArt for:

• Artemis-deficient Severe Combined Immunodeficiency (ART-SCID)

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Findings from Research

Gene therapy using lentiviral vectors to express the human Artemis gene in hematopoietic stem cells (HSCs) from Artemis knockout mice successfully corrected the severe combined immunodeficiency (RS-SCID), restoring normal B and T cell function in animal models.

The study demonstrated that nonmyeloablative conditioning regimens, such as low-dose Busulfan, can effectively promote the engraftment of genetically modified HSCs, offering a potential alternative to traditional irradiation-based treatments for immunodeficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Mostoslavsky, G., Fabian, AJ., Rooney, S., et al.[2018]

Gene therapy using a self-inactivated lentiviral vector to express the Artemis gene successfully restored T- and B cell function in Artemis knockout mice over a 15-month follow-up period, indicating its potential efficacy for treating radiosensitive severe combined immunodeficiency (RS-SCID).

While one mouse developed a thymoma after treatment, there was no evidence of oncogene activation from the lentivirus, suggesting that the lymphoproliferation observed was likely due to the underlying chromosomal instability from the Artemis deficiency rather than the gene therapy itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells. Benjelloun, F., Garrigue, A., Demerens-de Chappedelaine, C., et al.[2017]

In patients with severe combined immunodeficiency (SCID) due to RAG or ARTEMIS mutations, using myeloablative conditioning during allogeneic hematopoietic stem cell transplantation (HSCT) significantly increases the likelihood of achieving full immunologic recovery.

For ARTEMIS patients, the use of alkylating chemotherapy agents during treatment is linked to a higher risk of nonimmunologic complications, highlighting the need for safer conditioning strategies or gene therapy to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tearing RAGs apart. Gaspar, HB.[2021]

Gene therapy using a lentiviral vector to deliver human ARTEMIS mRNA has shown promising safety and efficacy in preclinical models for treating radiosensitive severe combined immunodeficiency (RS-SCID), with successful long-term engraftment of modified hematopoietic stem cells in irradiated mice.

The treated mice demonstrated normal immune system development, including the production of T and B cells and immunoglobulins, without any signs of transgene toxicity or increased risk of cancer, indicating a safe approach for potential clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biosafety Studies of a Clinically Applicable Lentiviral Vector for the Gene Therapy of Artemis-SCID. Charrier, S., Lagresle-Peyrou, C., Poletti, V., et al.[2020]

A novel gene therapy using a self-inactivating lentivirus vector to deliver normal DCLRE1C cDNA has shown promise in correcting the radiosensitivity and restoring T and B cell development in ART-SCID patients' cells, indicating its potential efficacy.

The AProArt lentivirus demonstrated a favorable safety profile, with no increased risk of oncogene activation in transduced cells, supporting the initiation of clinical trials for this gene addition therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Punwani, D., Kawahara, M., Yu, J., et al.[2019]

Gene therapy using genetically corrected autologous hematopoietic stem cells has shown promise as an effective alternative to traditional stem cell transplants for treating severe combined immunodeficiencies, including Wiskott-Aldrich syndrome (WAS).

Recent preclinical studies indicate that this gene therapy approach is safe and effective in murine models and patient-derived cells, paving the way for potential clinical trials to address the life-threatening complications associated with WAS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current understanding of the Wiskott-Aldrich syndrome and prospects for gene therapy. Trifari, S., Marangoni, F., Scaramuzza, S., et al.[2010]

Gene therapy using autologous gene-modified hematopoietic stem cells has been successfully applied to over 30 ADA-SCID patients since 2000, leading to effective immune reconstitution and long-term engraftment, with excellent survival rates compared to allogeneic transplants.

This approach shows a better safety profile than gene therapy for SCID-X1, as it allows for multilineage engraftment without the need for myeloablative preconditioning, and ongoing developments in safer integrating vectors may enhance its efficacy and safety even further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. Ferrua, F., Brigida, I., Aiuti, A.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

Tearing RAGs apart. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Biosafety Studies of a Clinically Applicable Lentiviral Vector for the Gene Therapy of Artemis-SCID. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Current understanding of the Wiskott-Aldrich syndrome and prospects for gene therapy. [2010]

7. United States pubmed.ncbi.nlm.nih.gov

Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. [2021]