Study Evaluating a Gene Therapy for IPEX Syndrome Through the Expression of FOXP3 on Deficient T Cells to Produce Tregs-like. (THERIPEX)

A Phase I/II Open-label, Non-randomized, Monocentric, Single-arm Study Evaluating the Safety and Efficacy of Induced CD4+ Treg by LV Vector Transduction Expressing the FOXP3 cDNA (FOXP3-T4) in Patients With IPEX Syndrome

The purpose of this study is to evaluate the safety and efficacy of FOXP3-T4 (an autologous gene therapy) alone or in combination with low-dose IL-2 for the treatment of IPEX syndrome. The therapy involves the transplantation of autologous CD4+ T-cells transduced ex vivo with the LV-EF1a-FOXP3-LNGFR lentiviral vector. The study follows a staggered approach: the first two patients will receive FOXP3-T4 monotherapy. Subsequent patients will receive FOXP3-T4 followed if needed by low-dose IL-2 treatment consisting of a daily dose for 5 days, then weekly administrations for 3 months.

The study aims to stabilize autoimmune manifestations and potentially cure the underlying disease, ultimately allowing for the discontinuation of ongoing immunosuppressive treatments.

Study Overview

• Status: Not yet recruiting
• Conditions: The Immune Dysregulation Polyendocrinopathy Enteropathy X-linked Syndrome is a Primary Immunodeficiency Caused by Pathogenic Variants in Forkhead Box Protein 3
• Intervention / Treatment: Genetic: FOXP3-T4 drug product; Drug: ILT-101

Detailed Description

IPEX syndrome is a primary immunodeficiency caused by hemizygous mutations in the gene FOXP3, which encodes an essential transcription factor required to maintain immunological tolerance by thymus-derived regulatory T (Treg) cells. The most common presentation suggestive of the diagnosis of IPEX syndrome is the classical triad of enteropathy, type I diabetes (TID), and eczema in neonatal onset. Still, it is now well established that IPEX syndrome comprises a broad spectrum of clinical manifestations with different degrees of severity and evolution.

Currently, the only curative treatment for the severe form is allogeneic hematopoietic stem cell transplantation (HSCT). However, because of its significant toxicity, it can be proposed only for more severe presentations and when an HLA identical donor is available. Moreover, the post-HSCT prognosis is also linked to prior disease activity and organ failures.

This clinical study aims to assess a new therapeutical strategy consisting of the conversion of the IPEX patient's CD4+T-cells into functional Treg-like cells by transducing them with an optimized bidirectional lentivirus vector expressing human FOXP3 and a truncated form of the low-affinity nerve growth factor receptor (ΔLNGFR) allowing the selection of the transduced cells. To favour Treg-like cells engraftment and expansion, the FOXP3-T4 infusion may be combined with subcutaneous injection of low-dose IL-2, if needed. Injecting FOXP3-T4 T-reg-like cells into IPEX patients is expected to stably improve the autoimmune manifestations and even cure the underlying disease, allowing the ongoing immunosuppressive treatments to be stopped.

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marina CAVAZZANA, MD, PhD; Phone Number: + 33 01 44 49 50 68; Email: m.cavazzana@aphp.fr
• Study Contact Backup: Name: Aline DECHANET, Project Manager; Phone Number: +33 01 44 38 17 11; Email: aline.dechanet@aphp.fr

Study Locations

• France
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Department of Biotherapy, Hopital Necker Enfants malades
      • Contact: Marina CAVAZZANA, MD, PHD; Phone Number: +33 01 44 49 50 68; Email: m.cavazzana@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male patients only
• Patients aged from 1 - 45 years of age (the first three patients will be aged between 10 - 45 years of age)
• Patient with IPEX syndrome caused by mutation of the FOXP3 gene
• Patients are eligible from the second line of treatment onward, even those under controlled disease
• Patient with recurrent IPEX symptoms, under immune suppressive medications
• Patient for whom HSCT is not feasible or when no suitable compatible donor is available
• Patients who have had prior allogeneic blood stem cell transplantation (HSCT) with engraftment failure defined as no intake of donor cells
• Patient or parental, guardian's patient signed informed consent
• Male participants of reproductive potential with a partner of childbearing potential (WOCBP): willing to use an effective method of contraception during the trial and for at least 12 months post-infusion
• Affiliation to a French or European social security scheme

Exclusion Criteria:

• Unwillingness to return for follow-up during the 2-year study and during the 15 years of long term follow up study.
• Patient with short life expectancy
• Patient on AME (state medical aid) (unless exemption from affiliation).
• Diagnosis of a significant psychiatric disorder of the patient that could seriously impede the ability to participate in the study.
• Eligible for an HLA matched sibling or matched unrelated donor blood stem cell transplant (HLA 10/10) and be willing to undergo transplant.
• Patients with uncontrolled or ongoing active infections.
• HIV-1 or 2 or HTLV-1 infections.
• Patients with severe IPEX clinical presentation needing a rapid allogeneic HSCT treatment within 3 months.
• Patients with known history of hypersensitivity to IL-2 or any component of the formulation (mannitol, sodium lauryl sulfate, monosodium phosphate dehydrate, disodium phosphate dehydrate, glucose.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FOXP3-T4 drug product; FOXP3-T4 is a genetically modified cell therapy product consisting of autologous CD4+ T-cells transduced ex vivo with a self-inactivating bidirectional lentiviral vector (LV-EF1a-FOXP3-LNGFR) expressing the FOXP3 and LNGFR cDNAs.

Genetic: FOXP3-T4 drug product; Each patient will receive a single IV infusion of FOXP3-T4, autologous gene-modified CD4+ T-transduced ex vivo with a self-inactivating lentiviral vector (LV-EF1a.FOXP3-LNGFR); Drug: ILT-101; The first two patients included in the study will not receive IL-2 treatment. The others will receive the first injection the FOXP3-T4 treatment and if needed IL2-treatment. For IL2 treatment, patients will receive a daily dose for 5 days, followed by an administration per week for 3 months (ILT-101); Other Names: Adeleuskin or IL2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of clinical AEs and pathological variations of laboratory parameters	Number of clinical AEs	Up to 24 months post-infusion
Severity of clinical AEs and pathological variations of laboratory parameters	Grading will be performed according to the CTCAE (Common Terminology Criteria for Adverse Events) current version. Severity is rated on a scale of Grade 1 (Mild) to Grade 5 (Death).	Up to 24 months post-infusion
Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance	This is measured via Vector Insertion Site Analysis (VISA)	Up to 24 months post-infusion
Incidence of clinically detectable lymphoproliferation and abnormal clonal dominance	This is measured by proliferation of LNGFR+ cells	Beyond 3 months to 24 months post-infusion
Detection of Replication-Competent Lentivirus (RCL)		Up to 24 months post-infusion
Persistence of recirculating LNGFR+among CD4+ T cells	Percentage of LNGFR+ among CD4+ T cells	at 3 months post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistence of FOXP3-T4 Cells	Persistence of recirculating LNGFR among CD4+ T cells	Up to 24 months post-infusion
Phenotyping	Deeper phenotyping of FOXP3-T4 (CD4+LNGFR+ CD25+ FOXP3+ CD127low)	Up to 24 months post-infusion
Vector Copy Number (VCN) Analysis	Quantification of the transgene copy number (VCN) on drug product and on sorted T-CD4+	Up to 24 months post-infusion
Immunophenotyping T and B cells if no change is detected from the baseline (e.g. before treatment), the immunological phenotype		Beyond 3 months to 24 months post-infusion
TCR repertoire	Evaluated by NGS before and after the treatment with FOXP3-T4	At 3 months, 12 months and 24 months, post-infusion
Autoantibodies dosage		At 3 months, 6 months, 12 months and 24 months post-infusion
Organ-Specific Remission: Skin disease	Diminution of the skin lesions severity	Up to 24 months post-infusion
Organ-Specific Remission: Skin disease	Diminution of inflammation in the skin biopsy	Up to 24 months post-infusion
Organ-Specific Remission: Endocrine System Function	Evaluation of the functions of endocrine glands	Up to 24 months post-infusion
Organ-Specific Remission: Endocrine System Function	Reduction of insulin dose administrered	Up to 24 months post-infusion
Organ-Specific Remission: Endocrine System Function	Reduction of HBA1C	Up to 24 months post-infusion
Organ-Specific Remission: Renal function	Improvement of creatine and creatine clearance	Up to 24 months post-infusion months
Organ-Specific Remission: Renal function	Improvement of proteinuria	Up to 24 months post-infusion months
Organ-Specific Remission: Renal function	Improvement of tubular effect	Up to 24 months post-infusion months
Organ-Specific Remission: Digestive System	Change in the weight curve	Up to 24 months post-infusion months
Organ-Specific Remission: Digestive System	Change in diarrhea incidence	Up to 24 months post-infusion months
Organ-Specific Remission: Digestive System	Decrease of fecal calprotectin	Up to 24 months post-infusion months
Organ-Specific Remission: Musculoskeletal System	Improvement of arthritis evaluated by physical examination	Up to 24 months post-infusion months
Organ-Specific Remission: Respiratory Function	Improvement of asthma evaluated by physical examination	Up to 24 months post-infusion months
Organ-Specific Remission: General status	Improvement of performance status : Lansky and Karnofsky scores range from 100 to 10	Up to 24 months post-infusion months
Organ-Specific Remission: Blood count	Presence of autoimmune hemolytic anemia	Up to 24 months post-infusion months
Organ-Specific Remission: Blood count	Presence of thrombocytopenia	Up to 24 months post-infusion months
Organ-Specific Remission: Eye	Improvement of blepheratis evaluated by physical examination.	Up to 24 months post-infusion months
Reduction of Concomitant Therapy	Reduction of corticosteroid therapy or immunosuppressive treatment	Up to 24 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Study Chair: Emmanuelle SIX, MD, PhD, Institut Imagine

Publications and helpful links

General Publications

• Delville M, Bellier F, Leon J, Klifa R, Lizot S, Vincon H, Sobrino S, Thouenon R, Marchal A, Garrigue A, Olivre J, Charbonnier S, Lagresle-Peyrou C, Amendola M, Schambach A, Gross D, Lamarthee B, Benoist C, Zuber J, Andre I, Cavazzana M, Six E. A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome. Blood. 2021 Apr 29;137(17):2326-2336. doi: 10.1182/blood.2020009187.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: April 20, 2026
• First Submitted That Met QC Criteria: July 6, 2026
• First Posted (Actual): July 13, 2026

Study Record Updates

• Last Update Posted (Actual): July 13, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Gene therapy; Genetic diseases; Autoimmune diseases; Lentiviral vector; Immune dysregulation Polyendocrinopathy Enteropathy X-linked; Autoimmunity-Immunodeficiency Syndrome; Forkhead Box Protein 3; Low-dose IL-2
• Additional Relevant MeSH Terms: Immune System Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Autoimmune Diseases; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukins; Lymphokines; Interleukin-2
• Other Study ID Numbers: APHP251137; 2025-523305-15-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No