Gene Therapy for SCID

Recruiting at 5 trial locations

Overseen By Colleen Dansereau

Age: < 18

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: David Williams

Disqualifiers: Active infection, Seizure disorder, Encephalopathy, DNA repair disorder, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy treatment for Severe Combined Immunodeficiency (SCID), a condition where the immune system malfunctions. The treatment uses a special vector, G2SCID, infused into the patient's own modified cells to enhance immune function. The trial seeks participants with SCID-X1 who lack a matching donor for a bone marrow transplant and are 5 years old or younger. Participants should not have severe infections resistant to treatment or other major health issues. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that gene therapy for Severe Combined Immunodeficiency (SCID) has helped many patients, though past safety concerns exist. For instance, some patients developed leukemia, a type of blood cancer, after receiving the therapy. While the treatment can be effective, monitoring for serious side effects is crucial.

Previous studies using treatments like the G2SCID vector have focused on overall safety and survival rates. These studies remain in the early stages, still determining how well patients respond to the treatments. Early-stage studies often assess the safety of a new treatment and identify possible side effects.

This type of gene therapy continues to undergo testing to ensure its safety and effectiveness for everyone. Those considering joining a clinical trial should discuss the benefits and risks with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Severe Combined Immunodeficiency (SCID), which often involve bone marrow transplants or enzyme replacement therapies, the G2SCID vector offers a new approach through gene therapy. This treatment is unique because it involves a single infusion of the patient's own stem cells that have been genetically modified with a self-inactivating lentiviral vector, specifically targeting and correcting the genetic defect causing SCID. Researchers are excited about this therapy because it has the potential to provide a long-term, possibly permanent solution by directly addressing the root cause of the disease, rather than just mitigating symptoms. Additionally, using the patient's own cells reduces the risk of rejection and complications associated with donor transplants.

What evidence suggests that this treatment might be an effective treatment for SCID?

Research has shown that a new gene therapy, called the G2SCID vector, may help treat Severe Combined Immunodeficiency (SCID). In earlier studies, most patients who received this gene therapy experienced improved immune function. Specifically, many patients saw a return of important immune cells, known as T cells, without serious side effects. The therapy successfully altered a large number of necessary cells to help rebuild a functioning immune system. These results suggest that the G2SCID vector could enhance immune function in people with SCID. ^{2 3 4 6 7}

Who Is on the Research Team?

Sung-Yun Pai, MD

Principal Investigator

National Institutes of Health (NIH)

Are You a Good Fit for This Trial?

This trial is for children aged 5 or younger with SCID-X1, a severe immune deficiency known as 'Bubble Boy Disease'. They must lack T cell function and have a specific genetic mutation. Kids without an identical donor match and who haven't had successful previous transplants can join. Participants need to be at least 8 weeks old by busulfan treatment time and commit to long-term follow-up.

Inclusion Criteria

Signed informed consent

I am 5 years old or younger.

I had an allogeneic transplant and it's confirmed that the donor T cells did not engraft.

Exclusion Criteria

I am on a mechanical ventilator or use CPAP.

I have an infection that hasn't improved after 2 weeks of treatment.

My liver tests are much higher than normal.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-conditioning

Participants receive low dose targeted busulfan pre-conditioning

1-2 weeks

Treatment

Single infusion of autologous CD34+ cells transduced with the SIN lentiviral vector G2SCID

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Long-term follow-up

Required long-term monitoring for a total of 15 years after infusion

15 years

What Are the Treatments Tested in This Trial?

Interventions

• G2SCID vector

Trial Overview The study tests gene therapy for SCID-X1 using the patient's own cells modified with G2SCID vector after low dose busulfan conditioning. It's an open-label, multi-center trial where patients are followed for two years post-infusion, then on a separate long-term protocol.

How Is the Trial Designed?

Group I: Treatment arm Experimental Treatment 1 Intervention

single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID

Who Is Running the Clinical Trial?

David Williams

Lead Sponsor

Trials

5

Recruited

60+

Published Research Related to This Trial

A new gene therapy using a self-inactivating gamma-retroviral vector (SIN gRV) for treating X-linked severe combined immunodeficiency (SCID-X1) has been developed to enhance safety by reducing the risk of leukemia, which affected 5 out of 20 patients in previous trials.

The clinical-grade SIN gRV successfully transduced 68-70% of normal human CD34(+) cells and produced T cells in vitro, demonstrating its efficacy and paving the way for a multi-center international phase I/II trial for SCID-X1 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency. van der Loo, JC., Swaney, WP., Grassman, E., et al.[2022]

In vivo gene therapy using a cocal envelope-pseudotyped lentiviral vector successfully treated two neonatal canines with SCID-X1, achieving long-term immune reconstitution without the need for prior conditioning, demonstrating a safer alternative to traditional ex vivo methods.

The treated canines maintained therapeutic levels of gene-corrected T cells for at least 16 months, indicating durable efficacy, and the manufacturing process for the cocal lentiviral vector is similar to existing methods, making it a promising option for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Gene Therapy for Canine SCID-X1 Using Cocal-Pseudotyped Lentiviral Vector. Rajawat, YS., Humbert, O., Cook, SM., et al.[2022]

Gene therapy has been successfully used to treat severe combined immune deficiency syndrome (SCIDS), particularly in infants with adenosine deaminase (ADA) deficiency, by inserting the ADA gene into their hematopoietic stem cells.

The first human trials for this gene therapy began in 1990, and recent treatments have shown promise in restoring immune function in affected infants, highlighting the potential of gene therapy in addressing genetic immunodeficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy techniques in the treatment of adenosine deaminase--deficiency severe combined immune deficiency syndrome. Noonan, NA., Senner, AM.[2019]

Over 60 patients with severe combined immunodeficiency (SCID) due to IL2RG deficiency or adenosine deaminase deficiency have benefited from hematopoietic stem cell gene therapy using gammaretroviral vectors, leading to immune reconstitution in most cases.

Concerns about insertional oncogenesis in SCID-X1 trials have prompted the development of safer gene therapy approaches and new technologies for precise gene editing, highlighting the ongoing evolution of treatment strategies for SCID.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for primary immunodeficiencies: Part 1. Cavazzana-Calvo, M., Fischer, A., Hacein-Bey-Abina, S., et al.[2021]

In a study involving 386 mice over 28 months, the self-inactivating lentiviral vector designed for X-linked severe combined immunodeficiency (XSCID) gene therapy showed no clear cases of hematopoietic malignancies, indicating a promising safety profile.

In contrast, a different retroviral vector led to clonal transformations and T cell leukemias in multiple recipients, underscoring the importance of vector choice in gene therapy and the need for thorough pre-clinical safety evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector. Zhou, S., Ma, Z., Lu, T., et al.[2021]

In newborns suspected of having X-linked severe combined immunodeficiency (SCID), initial genetic testing may not always identify pathogenic variants in the IL2RG gene, which is crucial for treatment eligibility, especially for gene therapy.

Functional assays and maternal X-inactivation studies can help confirm pathogenic IL2RG variants when standard genetic tests are inconclusive, ensuring timely and accurate diagnosis for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening. Purswani, P., Meehan, CA., Kuehn, HS., et al.[2020]

Direct intravenous administration of foamy virus (FV) vectors for gene therapy in a canine model of X-linked severe combined immunodeficiency (SCID-X1) showed improved efficacy without the need for extensive cell manipulation or conditioning, making it a simpler treatment option.

The use of granulocyte colony-stimulating factor (G-CSF) and AMD3100 before FV vector delivery enhanced immune recovery, resulting in normal T lymphocyte function and robust antibody responses, indicating both safety and effectiveness of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy. Humbert, O., Chan, F., Rajawat, YS., et al.[2023]

Significant advancements in newborn screening and gene therapy have transformed the prognosis for children with severe combined immunodeficiency (SCID), allowing for early identification and potential cures.

The development of hematopoietic stem and progenitor cell (HSC/P) gene therapy has become a promising treatment option for SCID and other primary immunodeficiencies, marking a major shift in clinical approaches since the first successful bone marrow transplant in 1968.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving Gene Therapy in Primary Immunodeficiency. Thrasher, AJ., Williams, DA.[2019]

Hematopoietic stem cell transplantation (HSCT) has significantly improved the prognosis for patients with Severe Combined Immunodeficiency (SCID), transforming it from a lethal condition to one with better outcomes through various donor types and transplantation methods.

Gene therapy, particularly through autologous transplantation with ex vivo gene correction, shows promise in treating specific SCID types while minimizing risks like graft-versus-host disease (GVHD), and advancements in gene correction techniques are being developed to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eliminating SCID row: new approaches to SCID. Kohn, DB.[2016]

Gene-modified autologous hematopoietic stem cell (HSC) transplantation has emerged as a promising alternative treatment for severe combined immunodeficiency (SCID), particularly for X-linked SCID and ADA-deficient SCID, addressing the challenge of finding suitable donors.

Recent trials in Italy, France, and the United States demonstrate significant clinical benefits from this gene therapy approach, highlighting its potential to overcome complications associated with traditional allogeneic HSC transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A tale of two SCIDs. Shaw, KL., Kohn, DB.[2013]

Despite two serious adverse events linked to gene therapy for X-linked severe combined immunodeficiency type 1 (SCID-X1), 12 out of 15 treated patients are benefiting from the therapy, showing an 80% treatment success rate and 100% survival.

There is a strong consensus on the need for further research to understand the mechanisms behind adverse events like LMO2 oncogene activation, which will help develop safer gene therapy strategies in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stem cell clonality and genotoxicity in hematopoietic cells: gene activation side effects should be avoidable. von Kalle, C., Fehse, B., Layh-Schmitt, G., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2957288/

Efficacy of Gene Therapy for X-Linked Severe Combined ... Our study showed substantial improvement of immune function in seven of nine patients treated with gene therapy; however, a potentially fatal treatment-related ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03601286

NCT03601286 | Lentiviral Gene Therapy for X-linked ... This study will investigate whether patients with SCID-X1 without a fully matched related donor may benefit from gene therapy.

3. withpower.com withpower.com/trial/phase-2-severe-combined-immunodeficiency-2018-4da02

Gene Therapy for SCID The clinical-grade SIN gRV successfully transduced 68-70% of normal human CD34(+) cells and produced T cells in vitro, demonstrating its efficacy and paving the ...

4. jacionline.org jacionline.org/article/S0091-6749(23)00229-4/fulltext

Gene therapy for SCID, now up to 3! No adverse events linked to the procedure have been observed. Immune reconstitution of T cells occurred in 9 of the 10 patients (and in all 10 ...

5. clinicaltrials.ucbraid.org clinicaltrials.ucbraid.org/trial/NCT03311503

Lentiviral Gene Transfer for SCID-X1 with Low Dose Targeted ... This Immunodeficiency and Severe Combined Immunodeficiency study at University of California Health is now recruiting males ages 0-5.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6019104/

Long term outcomes of severe combined immunodeficiency Five-year survival is 80–95% for patients who are transplanted prior to onset of infection and under 3.5 months of age regardless of donor or conditioning [7,8, ...

7. trialx.com trialx.com/clinical-trials/listings/322195/phase-iii-trial-of-lentiviral-gene-transfer-for-scid-x1-with-low-dose-targeted-busulfan-conditioning/

Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 with Low ... Secondary objectives are to measure overall survival, event-free survival, safety related to the procedure, and clinical and laboratory measures of efficacy ...