CD4^LVFOXP3 for IPEX Syndrome

Overseen By Rosa Bacchetta, MD

Age: < 65

Sex: Male

Trial Phase: Phase 1

Sponsor: Bacchetta, Rosa, MD

Disqualifiers: Medical instability, Life expectancy <6 months, Cardiac, renal, pulmonary, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 60 days post-infusion

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants may or may not be on immunosuppressive medication when starting the study.

What data supports the effectiveness of the treatment CD4^LVFOXP3 for IPEX Syndrome?

Research by Masiuk et al. (2019) shows that a gene therapy approach targeting the FOXP3 gene can effectively eliminate the symptoms of IPEX syndrome in mouse models, suggesting potential for similar treatments in humans. ^{1 2 3 4 5}

How is the CD4^LVFOXP3 treatment different from other treatments for IPEX Syndrome?

CD4^LVFOXP3 is unique because it involves gene therapy targeting the FOXP3 gene, which is crucial for the function of regulatory T cells that are defective in IPEX Syndrome. This approach aims to correct the underlying genetic cause of the disease, unlike other treatments that may only address symptoms. ^{1 4 6 7 8}

What is the purpose of this trial?

This trial tests if using special immune cells can help patients with a rare immune disorder by replacing their faulty immune cells, aiming to restore immune balance and improve health.

Research Team

Jessie Alexander, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for individuals with IPEX Syndrome who have persistent symptoms despite medication, weigh over 8 kg, and can tolerate leukapheresis. Participants should have a FOXP3 gene mutation and be at least 50% functional on the Lansky/Karnofsky Scale. They cannot join if they have severe unrelated diseases, allergies to study treatments, certain cancer histories, are medically unstable or expected to live less than six months.

Inclusion Criteria

Uncontrolled IPEX disease but unable to tolerate immune suppressive medication

My organ and bone marrow functions are within normal ranges.

I can do most activities but may need help.

Exclusion Criteria

I am eligible and willing to undergo a stem cell transplant from a matched donor.

I cannot take the required dose of steroids.

I have no heart, kidney, lung, liver, or blood diseases unrelated to my cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CD4^LVFOXP3 infusion to replace defective Treg cells and restore immune control

Up to 60 days post-infusion

Daily visits for the first month, followed by monthly visits

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes

Up to 15 years

Monthly visits for the first year, then periodic visits

Treatment Details

Interventions

• CD4^LVFOXP3

Trial Overview The trial is testing CD4^LVFOXP3 in people with IPEX Syndrome to see if it's safe and how it affects their disease. It's a Phase 1 trial focused on evaluating the manufacturing feasibility of this treatment and its administration safety in up to 36 participants.

Participant Groups

Group I: Cohort B (<12 years) Experimental Treatment 1 Intervention

Participants in Cohort B will always follow treatment of participants in Cohort A for the same dose level. Cohort B will start at Dose Level 2 and be administered 3 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants.

Group II: Cohort A (≥12 years) Experimental Treatment 1 Intervention

The first participant in Dose Level 1 will be administered 1.0 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in the first participant, the following participants in Dose Level 1 will be administered the same dose of 1.0 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 1, participants will be enrolled into Dose Level 2 and administered 3 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants.

Who Is Running the Clinical Trial?

Bacchetta, Rosa, MD

Lead Sponsor

Trials

1

Recruited

30+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

Findings from Research

In a study of 173 patients with IPEX syndrome, 44 distinct FOXP3 gene variants were identified, including 9 new variants, highlighting the genetic diversity associated with this disorder.

Among 85 patients with IPEX-like symptoms but normal FOXP3, 19 disease-associated variants in 9 different genes were found, suggesting that a broader genetic analysis can aid in diagnosing similar immune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. Gambineri, E., Ciullini Mannurita, S., Hagin, D., et al.[2019]

IPEX syndrome is a rare and severe disorder that often leads to early death in infants or children, highlighting the importance of clinical awareness for timely diagnosis.

Mutation analysis of the FOXP3 gene can confirm the diagnosis of IPEX syndrome, as demonstrated in two new patients diagnosed retrospectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular findings in IPEX syndrome. Myers, AK., Perroni, L., Costigan, C., et al.[2018]

This study analyzed five Chinese patients with atypical IPEX syndrome caused by FOXP3 mutations, identifying two novel mutations and highlighting the diverse clinical presentations, including one case of immune-related peripheral neuropathy.

Despite three patients having normal Treg cell frequencies, their Treg cell subsets and other immune cell types were imbalanced, suggesting that immune dysregulation in atypical IPEX may not always correlate with Treg cell numbers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and immunological characteristics of five patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China-expanding the atypical phenotypes. Huang, Y., Fang, S., Zeng, T., et al.[2022]

Masiuk et al. (2019) present a promising method to effectively eliminate the symptoms of IPEX, a severe X-linked autoimmune disorder caused by mutations in the FOXP3 gene, in mouse models.

The study suggests that this approach could lead to durable treatment options for IPEX, highlighting its potential for long-term efficacy in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

21st Century FOX: Toward Gene Therapy for the Regulatory T Cell Deficiency Syndrome IPEX. Petty, NE., Gill, SI.[2019]

Hematopoietic cell transplantation using a low-intensity, nonmyeloablative conditioning regimen was successfully performed in two high-risk patients with IPEX syndrome, leading to stable engraftment and correction of immune deficiency.

Both patients showed full immune function and normal FOXP3 protein expression after transplantation, with minimal toxicity from the conditioning regimen, demonstrating a promising alternative to traditional myeloablative approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Burroughs, LM., Torgerson, TR., Storb, R., et al.[2022]

Patients with IPEX syndrome show a consistent increase in Treg-cell-Specific Demethylated Region (TSDR) demethylation in FOXP3, particularly in those with typical IPEX, indicating a potential biomarker for disease progression.

The study identified a unique inflammatory signature in IPEX patients, characterized by elevated cytokines associated with macrophage activation and TH2 polarization, which may help in understanding the disease's clinical variability and guiding treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation. Narula, M., Lakshmanan, U., Borna, S., et al.[2023]

IPEX syndrome is characterized by a range of autoimmune symptoms, including diarrhea, diabetes, thyroid disorders, and eczema, indicating significant immune dysregulation.

The FOXP3 gene, located on the X chromosome, is crucial for the function of regulatory T-cells, and mutations in this gene disrupt immune homeostasis, leading to the symptoms associated with IPEX.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Gambineri, E., Torgerson, TR., Ochs, HD.[2020]

IPEX syndrome is a rare genetic disorder caused by mutations in the FOXP3 gene, leading to a deficiency in CD4+CD25+ regulatory T cells, which are crucial for maintaining immune balance and preventing autoimmunity.

The lack of these regulatory T cells results in severe autoimmune conditions, such as enteropathy and type 1 diabetes, often leading to life-threatening complications within the first two years of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IPEX as a result of mutations in FOXP3. van der Vliet, HJ., Nieuwenhuis, EE.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Clinical and molecular findings in IPEX syndrome. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical and immunological characteristics of five patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China-expanding the atypical phenotypes. [2022]

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

21st Century FOX: Toward Gene Therapy for the Regulatory T Cell Deficiency Syndrome IPEX. [2019]

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

Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. [2022]

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

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation. [2023]

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

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. [2020]

8. Egypt pubmed.ncbi.nlm.nih.gov

IPEX as a result of mutations in FOXP3. [2021]