Gene Therapy for Severe Combined Immunodeficiency (SCID)

Overseen By Satiro De Oliveira, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, Los Angeles

Disqualifiers: Anemia, Neutropenia, Thrombocytopenia, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a gene therapy treatment for Severe Combined Immunodeficiency (SCID) caused by ADA deficiency. The goal is to determine if EFS-ADA Lentiviral Vector (also known as OTL-101) can safely and effectively improve immune function in infants and children with this condition by using their own modified stem cells. It targets those with a confirmed diagnosis of ADA-SCID who cannot receive a bone marrow transplant from a matched sibling. Participants must have a severe immune deficiency that affects their daily health. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and assess its effectiveness in an initial, smaller group of patients.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants likely to require treatment with drugs not permitted by the study protocol are excluded, suggesting some medications might not be allowed.

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

Research has shown that the EFS-ADA lentiviral vector treatment appears safe for humans. This gene therapy can successfully deliver the human ADA gene, which is crucial for improving metabolism and immune function in patients with ADA-deficient SCID.

In past studies, patients who received similar gene therapy generally tolerated the treatment well. Some side effects were reported, but they were usually mild and manageable. It is important to note that this treatment is still in the early stages of human testing (Phase 1/2), so more information will be collected to confirm its long-term safety.

Overall, early results suggest the treatment is well-tolerated, and safety is being carefully monitored. Prospective participants should discuss the potential risks and benefits with their healthcare provider. ^{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 EFS-ADA Lentiviral Vector gene therapy offers a groundbreaking approach. This treatment works by using a lentiviral vector to deliver a correct copy of the ADA gene into the patient's own blood cells, aiming to restore immune function from within. Researchers are particularly excited because this method targets the root cause of the disorder rather than just managing symptoms, potentially offering a one-time, long-lasting solution. This approach could transform the lives of patients by reducing the need for ongoing treatments and minimizing associated risks and complications.

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

Research has shown that the EFS-ADA lentiviral vector, which participants in this trial will receive, can successfully insert the human ADA gene into patients' cells, crucial for treating ADA-deficient Severe Combined Immunodeficiency (SCID). Studies have found that this method strengthens the immune system and improves overall health. For those with ADA-SCID, this gene therapy has been associated with better health outcomes, including fewer infections. Early results suggest this treatment could be a promising option for people with ADA deficiency. In short, this approach aims to correct the genetic issue, helping the body fight infections more effectively. ^{1 2 5 6 7}

Who Is on the Research Team?

Satiro De Oliveira, MD

Principal Investigator

Assistant Professor

Are You a Good Fit for This Trial?

This trial is for infants and children with ADA-SCID, a genetic disorder that affects the immune system. Participants must be at least 30 days old, unable to undergo bone marrow transplant from a family donor, and able to follow study procedures. Pregnant individuals or those with certain organ dysfunctions or previous gene therapy are excluded.

Inclusion Criteria

I am older than 30 days.

I am a woman of child-bearing age and can provide a negative pregnancy test.

I don't have a family member who can donate bone marrow to me.

Exclusion Criteria

The subject is pregnant or has a major congenital anomaly

You have a positive test for HIV-1, Hepatitis B, or Parvovirus B19.

My kidney function is not normal, or I have very high levels of sodium, potassium, calcium, magnesium, or phosphate.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive pharmacokinetically-adjusted busulfan reduced intensity conditioning prior to re-infusion of their gene-modified cells

1-2 weeks

Treatment

Autologous CD34+ cells transduced with EFS-ADA lentiviral vector are infused into participants

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment, including immune reconstitution and cessation of PEG-ADA ERT

24 months

Long-term follow-up

Participants may enroll in a long-term follow-up study to reach a total of 15 years post-gene therapy

What Are the Treatments Tested in This Trial?

Interventions

• EFS-ADA Lentiviral Vector

Trial Overview The trial tests a treatment where patients' own blood stem cells are modified outside the body using a special virus that carries a correct copy of the ADA gene. These modified cells are then returned to the patient's body to help restore their immune function.

How Is the Trial Designed?

Group I: Autologous mobilized peripheral blood (mPB) transduced with EFS ADA lentiviral vector Experimental Treatment 1 Intervention

Evaluate safety and efficacy of this autologous gene therapy

EFS-ADA Lentiviral Vector is already approved in United States, European Union for the following indications:

Approved in United States as OTL-101 for:

• Adenosine Deaminase Severe Combined Immunodeficiency (ADA SCID)

Approved in European Union as OTL-101 for:

• Adenosine Deaminase Severe Combined Immunodeficiency (ADA SCID)

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Published Research Related to This Trial

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 shown promising results in treating severe combined immunodeficiency (SCID) by correcting T-cell immunodeficiency, with sustained effects observed in clinical trials over the past decade.

Advancements in vector technology, such as the use of lentiviral vectors and the removal of oncogenic elements from retroviral vectors, aim to enhance the safety and efficacy of gene therapy, reducing the risk of leukemia associated with earlier treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for primary adaptive immune deficiencies. Fischer, A., Hacein-Bey-Abina, S., Cavazzana-Calvo, M.[2013]

Gene therapy has been shown to effectively correct T cell immunodeficiencies in severe combined immunodeficiencies (SCID), specifically for SCID-X1 and adenosine deaminase deficiency.

The shift from first-generation retroviral vectors to self-inactivated (SIN) retroviral or lentiviral vectors aims to maintain efficacy while improving safety, reducing the risk of gene toxicity observed in earlier trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy of primary T cell immunodeficiencies. Fischer, A., Hacein-Bey-Abina, S., Cavazzana-Calvo, M.[2013]

The self-inactivating lentiviral vector (LV EFS ADA) effectively transfers the human ADA gene into hematopoietic stem cells, leading to significant immune and metabolic recovery in ADA-deficient mice, demonstrating its potential as a safer alternative to γ-retroviral vectors.

Compared to traditional γ-retroviral vectors, LV EFS ADA shows a significantly lower risk of insertional mutagenesis, as evidenced by in vitro assays and integration-site analysis, making it a promising option for gene therapy in ADA-deficient severe combined immunodeficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Carbonaro, DA., Zhang, L., Jin, X., et al.[2023]

Gene therapy using retroviral vectors has shown significant efficacy in treating severe combined immunodeficiencies (SCID), with 15 out of 16 patients with X-linked SCID and all 4 patients with ADA deficiency benefiting from the treatment, maintaining correction of immunodeficiency for up to 6 years.

However, there are safety concerns, as three patients developed leukemia-like complications due to the insertion of the viral vector near proto-oncogenes, highlighting the need for modifications to improve safety while preserving the therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene therapy of severe combined immunodeficiency disease: proof of principle of efficiency and safety issues. Gene therapy, primary immunodeficiencies, retrovirus, lentivirus, genome]. Fischer, A., Hacein-Bey-Abina, S., Lagresle, C., et al.[2012]

A clinical trial involving 9 patients with SCID-X1 showed that gene therapy using retroviral-mediated transfer of the gamma c gene into bone marrow cells resulted in the development of functional T-cells without any adverse effects over more than 2 years of follow-up for some patients.

Most patients also developed the ability to produce immunoglobulins, reducing their need for intravenous immunoglobulin therapy, indicating that this gene therapy approach can provide significant clinical benefits in treating SCID conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy of X-linked severe combined immunodeficiency. Hacein-Bey-Abina, S., Fischer, A., Cavazzana-Calvo, M.[2019]

A clinical trial initiated in 1990 demonstrated that retroviral-mediated gene therapy using the ADA gene in T cells of two children with severe combined immunodeficiency (ADA-SCID) resulted in normalized T cell counts and improved immune responses.

The effects of the gene therapy persisted for two years after treatment, indicating that gene therapy can be a safe and effective long-term option for managing this severe immunodeficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Blaese, RM., Culver, KW., Miller, AD., et al.[2022]

Gene therapy has been successfully used to treat severe combined immunodeficiency (SCID) caused by adenosine deaminase deficiency (ADA-), with T cell-directed gene transfer showing positive results in clinical trials involving 11 patients since 1990.

However, retroviral-mediated gene transfer to hematopoietic stem cells has not provided sufficient clinical benefits, highlighting the need for improved retroviral vector systems for future gene therapy approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for severe combined immunodeficiency caused by adenosine deaminase deficiency: improved retroviral vectors for clinical trials. Onodera, M., Nelson, DM., Sakiyama, Y., et al.[2017]

A four-year-old boy with ADA-deficient SCID showed significant immune improvements after receiving gene therapy targeting his peripheral blood lymphocytes, including increased CD8+ T lymphocytes and serum immunoglobulin levels, although the effects were hard to isolate due to concurrent PEG-ADA treatment.

Two additional ADA-SCID patients treated with gene therapy using engineered bone marrow CD34+ cells demonstrated restored ADA activity and improved liver function without adverse effects, remaining clinically well 12 months post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene therapy for adenosine deaminase deficiency]. Sakiyama, Y., Ariga, T., Ohtsu, M.[2012]

Gene therapy using autologous CD34+ cells for treating ADA-SCID showed a 100% survival rate in 18 patients over a median follow-up of 6.9 years, indicating its long-term safety and potential effectiveness.

While adverse events were common, they were mostly mild (grade 1 or 2) and not related to the gene therapy, with serious adverse events reported but not linked to the treatment, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety. Cicalese, MP., Ferrua, F., Castagnaro, L., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05432310

NCT05432310 | Gene Therapy for Adenosine Deaminase ... The EFS-ADA lentiviral vector with the human ADA complementary DNA (cDNA) will be used to transduce autologous CD34+ cells from Granulocyte Colony Stimulating ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8240285/

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine ... Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.

3. ashpublications.org ashpublications.org/blood/article/140/7/685/485484/Outcomes-following-treatment-for-ADA-deficient

Outcomes following treatment for ADA-deficient severe ... Infection was the most common reason to suspect ADA deficiency (57.5%), followed by a positive SCID NBS result (23.6%) and family history (18.9%).

4. sciencedirect.com sciencedirect.com/science/article/pii/S1525001616311856

Preclinical Demonstration of Lentiviral Vector-mediated ... These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery.

5. cirm.ca.gov cirm.ca.gov/clinical-trial/efficacy-and-safety-of-cryopreserved-autologous-cd34-hsc-transduced-with-efs-lentiviral-vector-encoding-for-human-ada-gene-in-ada-scid-subjects/

CIRM Funded Clinical Trials - CA.gov Preliminary data indicates that OTL-101 – a stem cell gene therapy developed by UCLA and Orchard Therapeutics Limited – may significantly improve outcomes ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03765632

Study Details | NCT03765632 | Efficacy and Safety of the ... This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3944341/

Preclinical Demonstration of Lentiviral Vector-mediated ... These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while ...