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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy method to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a serious condition where the immune system malfunctions. The treatment adds a normal gene to the patient's stem cells to help build a healthy immune system. Participants will receive a special infusion after taking Busulfan, a chemotherapy drug, to prepare their bodies. This trial targets patients diagnosed with ART-SCID, particularly those without a suitable family member for a bone marrow transplant or whose previous transplants failed. As a Phase 1/Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative therapy.

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 prior data suggests that this method is safe for treating ART-SCID?

Research has shown that the AProArt treatment for Artemis-deficient SCID, which uses lentiviral gene transfer, has mostly caused only minor side effects in past studies. This indicates that the side effects reported so far have generally been mild. Similar gene therapies for other types of SCID (Severe Combined Immunodeficiency) have demonstrated similar results.

Participants will receive a low dose of busulfan, a type of chemotherapy, to help prepare the body for the new cells. Although busulfan can have side effects, using a low dose aims to reduce these risks.

Overall, while any treatment can have side effects, current data suggests that AProArt and the low-dose busulfan are generally well-tolerated based on past studies. Participants should still discuss potential risks with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for Severe Combined Immunodeficiency (SCID), which often involve bone marrow transplants or enzyme replacement therapy, AProArt gene therapy offers a novel approach by directly targeting the genetic root of the condition. AProArt utilizes a self-inactivating lentiviral vector to deliver a corrected gene into the patient's own CD34 hematopoietic cells, potentially providing a more targeted and long-lasting solution. This method is exciting because it could reduce the need for ongoing treatments and lower the risk of complications associated with traditional therapies. Researchers are hopeful this could bring about more durable and effective results for patients with ART-SCID.

What evidence suggests that this gene therapy could be effective for ART-SCID?

Research has shown that gene therapy using a lentiviral vector offers a promising treatment for Artemis-deficient Severe Combined Immunodeficiency (ART-SCID). In this trial, participants will receive the AProArt gene therapy, which uses a lentivirus to insert a healthy version of the DCLRE1C gene into a patient's stem cells to correct the genetic issue. In similar cases, this method has helped patients develop a functioning immune system. Early results suggest that this technique might cause fewer serious side effects than older treatments. This therapy aims to provide patients with a normal immune system, potentially transforming the lives of those without a suitable stem cell donor. ^{1 2 3 4 6}

Who Is on the Research Team?

Morton Cowan, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

Pregnancy

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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]

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 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]

Citations

1. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT03538899

Autologous Gene Therapy for Artemis-Deficient SCID 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5278830/

Lentivirus Mediated Correction of Artemis-Deficient Severe ... Adverse events from lentiviral gene transfer for ADA deficient and X-linked SCID have been mostly minimal to date, in contrast to the insertional ...

3. clinicaltrial.be clinicaltrial.be/en/details/68534?only_active=0&only_eligible=0&only_recruiting=0&per_page=100

Autologous Gene Therapy for Artemis-Deficient SCID - Clin... Gene therapy (AProArt). Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) Using a Self-Inactivating Lentiviral ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2206575

Lentiviral Gene Therapy for Artemis-Deficient SCID Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to ...

5. clinicaltrials.ucbraid.org clinicaltrials.ucbraid.org/trial/NCT03538899

Autologous Gene Therapy for Artemis-Deficient SCID This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05071222?term=AREA%5BConditionSearch%5D(SCID)%20AND%20AREA%5BBasicSearch%5D(DCLRE1C)&rank=1

NCT05071222 | Safety and Efficacy Study of ... ... Artemis ( DCLRE1C ) Deficient Severe Combined Immunodeficiency Patients (ARTEGENE) (ARTEGENE) ... The purpose of this study is to evaluate the Safety and Efficacy ...