Gene Therapy for Hyper IgM Syndrome

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Disqualifiers: Allergies, Febrile illness, Alemtuzumab consent, others

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

Compensation: Varies

Number of Visits: 1

Duration: 5 weeks or more

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you will need to take certain drugs to prepare your body for the stem cell treatment, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment for Hyper IgM Syndrome?

Research shows that gene editing in hematopoietic stem cells (cells that can develop into different types of blood cells) can correct genetic mutations and restore normal immune function in conditions similar to Hyper IgM Syndrome. This suggests that the treatment could potentially be effective for Hyper IgM Syndrome as well. ^{1 2 3 4 5}

Is gene therapy for Hyper IgM Syndrome safe?

Research suggests that gene therapy using edited T cells and hematopoietic stem cells (HSPCs) for Hyper IgM Syndrome shows a reassuring safety profile, with studies indicating preserved cell function and successful integration in animal models, which is promising for human application. ^{1 2 3 6 7}

How is the gene therapy treatment for Hyper IgM Syndrome different from other treatments?

This gene therapy for Hyper IgM Syndrome is unique because it uses base-edited hematopoietic stem and progenitor cells to correct the CD40LG gene, which is crucial for immune function. Unlike traditional treatments, this approach aims to provide a long-term solution by directly fixing the genetic cause of the disease, potentially offering a permanent cure. ^{1 2 3 6 8}

What is the purpose of this trial?

Background: X-linked Hyper IgM (HIGM) syndrome is caused by a mutation in the CD40L gene. People with this disease have white blood cells that do not work properly. These people are at risk of severe infections and autoimmune diseases. Stem cell transplant can cure this disease. However, transplanting stem cells donated by other people can have serious complications. Another approach is gene therapy; this treatment repairs the mutation in a person's own stem cells by base editing. Researchers want to know if these base-edited stem cells can help people with CD40L-HIGM syndrome. Objective: To test base-edited stem cell transplant in 1 person with CD40L-HIGM syndrome. Eligibility: A male with CD40L-HIGM syndrome. Design: Participant will be screened. Tests will include medically indicated imaging scans, blood tests, and a sample of tissue and fluid (biopsy) may be taken from the bone marrow. Participant may undergo apheresis to collect stem cells. The collected stem cells will undergo base editing to repair the mutation. For treatment, participant will be admitted to the hospital for 5 weeks or more. For 2 weeks he will receive drugs to prepare his body for receiving the stem cells. After receiving the edited stem cells, he will remain in the hospital until his cell counts recover. Participant will have follow-up visits every few months in the first 2 years after treatment. The bone marrow biopsy will be repeated after 2 years. Long-term visits will continue annually for 15 years.

Research Team

Suk S De Ravin, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

This trial is specifically for a male with CD40L-Hyper IgM Syndrome, which affects white blood cells and increases the risk of infections and autoimmune diseases. The participant will undergo extensive screening including imaging scans, blood tests, and possibly a bone marrow biopsy.

Inclusion Criteria

Provision of signed and dated informed consent form

Use of condoms or other methods to ensure effective contraception with partner

Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

Unwillingness to submit information as part of the alemtuzumab (Campath(R)) Distribution Program application or deemed unqualified by the Distribution Program committee

Known allergic reactions to components of the BE HSPC study product

I have not had a fever or illness in the last two weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Apheresis and Base Editing

Participant may undergo apheresis to collect stem cells, which will then undergo base editing to repair the mutation.

2-3 weeks

Treatment

Participant will be admitted to the hospital for 5 weeks or more. For 2 weeks, he will receive drugs to prepare his body for receiving the stem cells. After receiving the edited stem cells, he will remain in the hospital until his cell counts recover.

5 weeks or more

Inpatient stay

Follow-up

Participant will have follow-up visits every few months in the first 2 years after treatment. The bone marrow biopsy will be repeated after 2 years.

24 months

Visits every few months

Long-term Follow-up

Long-term visits will continue annually for 15 years.

15 years

Annual visits

Treatment Details

Interventions

• Base-edited hematopoietic stem and progenitor cells

Trial Overview The study is testing gene therapy using base-edited stem cells to treat one patient with CD40L-HIGM syndrome. It involves collecting the patient's stem cells, editing them to repair the genetic mutation, then transplanting them back after pre-treatment with drugs in hospital.

Participant Groups

Group I: Single Arm Study Experimental Treatment 5 Interventions

The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan and serotherapy.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

References

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

Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome. [2021]

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

Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Targeted genome editing in human repopulating haematopoietic stem cells. [2022]

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

Optimizing Integration and Expression of Transgenic Bruton's Tyrosine Kinase for CRISPR-Cas9-Mediated Gene Editing of X-Linked Agammaglobulinemia. [2023]

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

Vector Strategies to Actualize B Cell-Based Gene Therapies. [2022]

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

Scalable GMP-compliant gene correction of CD4+ T cells with IDLV template functionally validated in vitro and in vivo. [2023]

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

CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells. [2022]

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

Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. [2018]