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

Trial Summary

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 G2SCID vector for SCID?

Gene therapy using similar vectors has shown success in treating SCID, with many patients experiencing restored immune function. However, past trials have faced challenges like the development of leukemia, leading to improved safety designs in newer trials. ^{1 2 3 4 5}

Is gene therapy for SCID generally safe in humans?

Gene therapy for SCID has shown success in many patients, but there have been safety concerns, such as some patients developing leukemia due to the therapy. Newer versions of the therapy have been designed to improve safety, and studies in mice suggest these newer versions are safer, though ongoing research is needed to fully understand and minimize risks. ^{1 2 6 7 8}

How is the G2SCID vector treatment different from other treatments for SCID?

The G2SCID vector treatment is unique because it uses a self-inactivating gamma-retroviral vector, which is designed to improve safety by reducing the risk of leukemia that was seen in previous gene therapies for SCID. This approach focuses on directly correcting the genetic defect in patients' cells, offering a potentially safer and more effective alternative to traditional treatments like bone marrow transplants. ^{1 2 9 10 11}

What is the purpose of this trial?

This is a phase I/II open label multi-center study in which patients will receive low dose targeted busulfan followed by infusion of autologous CD34+ selected bone marrow or mobilized peripheral blood cells transduced with the G2SCID vector. Subjects will be enrolled over 3 years and be followed for 2 years post-infusion on this protocol, then followed long-term on a separate long-term follow-up protocol. Enrollment of subjects will be agreed upon by representatives of both sites. Data will be collected uniformly from both sites through an electronic capture system and key laboratory studies will be centralized. Harvest, cellular manufacturing and infusion will occur at each site using the same SOPs. Key aspects of cellular product characterization will be centralized

Research Team

Sung-Yun Pai, MD

Principal Investigator

National Institutes of Health (NIH)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Gene therapy for primary immunodeficiencies: Part 1. [2021]

2. England 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. [2022]

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

Evolving Gene Therapy in Primary Immunodeficiency. [2019]

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

Eliminating SCID row: new approaches to SCID. [2016]

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

A tale of two SCIDs. [2013]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening. [2020]

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

Stem cell clonality and genotoxicity in hematopoietic cells: gene activation side effects should be avoidable. [2019]

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

Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector. [2021]

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

In Vivo Gene Therapy for Canine SCID-X1 Using Cocal-Pseudotyped Lentiviral Vector. [2022]

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

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy. [2023]

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

Gene therapy techniques in the treatment of adenosine deaminase--deficiency severe combined immune deficiency syndrome. [2019]