RARE DISEASE
Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
Synonyms: Autoimmune enteropathy type 1, IPEX
Synonyms: Autoimmune enteropathy type 1, IPEX
Synonyms: Autoimmune enteropathy type 1, IPEX
Drug discovery
2
drugs
With orphan designations
Overview
Immune Dysregulation-Polyendocrinopathy-Enteropathy-X-Linked (IPEX) Syndrome: A rare X-linked recessive disorder caused by FOXP3 gene mutations, impairing regulatory T-cell function and causing severe multiorgan autoimmunity. Core features include autoimmune enteropathy (90-100% cases), type 1 diabetes (60-80%), and dermatitis (60-70%). Untreated mortality exceeds 90% by age 2 [1][6][13]. Diagnosis combines clinical triad, genetic testing, and low FOXP3+ Treg cells [1][4][6].
Therapies
Immediate: Immunosuppression (tacrolimus/sirolimus ± corticosteroids) for symptom control [6][13]
Curative: Allogeneic HSCT achieves 75-85% survival if performed pre-organ damage [7][10][13]
Emerging: Autologous Treg engineering [3][10] and FOXP3 gene editing in HSPCs [3][10] show preclinical efficacy
Categories: rare endocrine diseases, rare gastroenterological diseases, rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
514 drug discovery papers related to Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, with 5 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
514 drug discovery papers related to Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, with 5 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-01 | Peripheral Expression of FOXP3 in Brazilian Patients with IPEX Syndrome: From FOXP3 Biomarker to Targeted FOXP3 Therapy Within the CNE3I
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder caused by loss-of-function mutations in the FOXP3 gene, which is critical for the development of functional regulatory T cells (Tregs). In IPEX patients, Tregs are unable to inhibit effector T cell proliferation and cytokine production, leading to a loss of peripheral immune tolerance. The disease presents with heterogeneous clinical manifestations, severe early-onset autoimmunity, the classic triad (enteropathy, eczema, and type 1 diabetes), as well as atypical or late-onset symptoms. A clear genotype–phenotype correlation has not been established for IPEX, and immunological assessments that could contribute to the diagnosis are scarce. Therefore, we aim to characterize the peripheral Treg cells in IPEX patients in Brazil through combined quantitative and qualitative flow cytometry analysis. We enrolled 6 male patients with a confirmed IPEX diagnosis (clinical, genetic, and immunological). All patients exhibited autoimmunity (enteropathy: 5/6; arthritis: 3/6; hemolytic anemia: 2/6; type 1 diabetes: 2/6), and allergic manifestations (rhinitis: 6/6; asthma: 4/6), eczema (4/6), and recurrent sinusitis (4/6) were also observed. Up to the last follow-up, two patients were alive after bone marrow transplantation and one after gene therapy (Figure 1). Peripheral FOXP3 expression was assessed in peripheral blood mononuclear cells (PBMCs) by flow cytometry (CD3, CD4, CD25, CD127, and FOXP3). Quantitative analysis determined the frequency of Tregs (CD4+CD25+CD127-FOXP3+), while qualitative analysis measured FOXP3 protein expression via median fluorescence intensity (MFI). The frequency of circulating Tregs in IPEX patients from our cohort was highly variable (14.6%–81.2%; mean: 58.5%) and overlapped with the control range (59.6%–84.1%; mean: 72.4%). In contrast, FOXP3 MFI was significantly lower in patient Tregs (mean: 986, range: 863–1,276) compared to controls (mean: 1,937, range: 1,089–4,132; p<0.05), another indication of quantitative Treg defects. Different patterns of FOXP3 expression have been reported, depending on the type and location of the mutation. While Treg numbers can be preserved in IPEX syndrome, FOXP3 protein expression per cell is consistently and significantly reduced. This defect in the expression level of FOXP3 likely underlies Treg dysfunction and disease pathogenesis. Assessment of FOXP3 MFI emerges as an additional valuable complementary diagnostic tool, providing functional insight beyond genetic sequencing alone. Figure 1. Clinical, immunologic, genetic, and therapeutic findings for IPEX syndrome within the CNE3i (Centro Nacional de Erros Inatos da Imunidade e Imunodesregulação) in Brazil. (1) Demonstrates the main clinical and geographical findings of the six IPEX patients; (2) general and advanced laboratory findings; and (3) genetics and therapeutics. SP, São Paulo; MG, Minas Gerais; PE, Pernambuco; DF, Distrito Federal; ES, Espírito Santo; IgE, immunoglobulin E; IgG immunoglobulin G; DNT, double negative T cells; IFN-SG, interferon-stimulated genes; MFI, median fluorescence intensity; BMT, bone marrow transplantation; GT, gene therapy; LFW, last follow-up. FINEP funding: 0956/24; FAPESP funding: 2023/09965-0; Instituto de Investigação em Imunologia funding CNPQ/MCTI: 408685/2024-7.
2026-03-15 | Preclinical efficacy and safety assessment of engineered regulatory T cells for treatment of IPEX and other autoimmune disorders.
FOXP3 is an essential transcription factor driving lineage commitment and function of regulatory T cells (Tregs). We previously reported a proof-of-concept study describing engineered Tregs (EngTregs) generated using homology-directed repair-based editing of the FOXP3 gene in CD4+ T cells, resulting in constitutive, high-level endogenous FOXP3 expression leading to acquisition of a Treg phenotype and robust in vitro and in vivo suppressive function. Here, we expand this gene-editing strategy to integrate a functional FOXP3 cDNA to enable EngTreg therapy for immune dysregulation, poly-endocrinopathy, enteropathy, X-linked syndrome (IPEX), a devastating multiorgan autoimmune disorder mediated by mutations within the FOXP3 gene. We provide a detailed characterization of preclinical EngTreg generation, including gene targeting efficiencies, cell enrichment and expansion, analyses of potential off-target editing, and phenotypic and functional characterization, including in vitro suppression of effector T cells and in vivo reversal of graft-versus-host disease. Importantly, in parallel, we utilize syngeneic and humanized mouse models to demonstrate the safety of EngTregs in primary and secondary humoral responses and viral infection control, respectively. Our combined preclinical dataset strongly supports the efficacy and safety of EngTregs as a promising potential cellular therapeutic approach for IPEX and possibly other autoimmune disorders.
2026-02-09 | Regulatory T Cells from Concept to Clinic: The 2025 Nobel Prize and Its Implications for Immune-Mediated Diseases and Cancer.
The 2025 Nobel Prize in Physiology or Medicine, awarded to Shimon Sakaguchi, Mary E. Brunkow, and Fred Ramsdell, recognizes the discovery and molecular definition of regulatory T cells (Tregs) as the cornerstone of peripheral immune tolerance. This recognition honors a transformative journey marked by Sakaguchi's identification of CD4+CD25+ T cells as a regulatory population (1995), followed by Brunkow and Ramsdell's discovery that mutations in the FOXP3 gene cause both the scurfy mouse phenotype and human IPEX syndrome (2001), and culminating in the demonstration that FOXP3 governs Treg development and function (2003). This achievement crowns a turbulent half-century arc. The suppressor T-cell (Ts) hypothesis of the 1970s proposed an active T-cell brake on immunity but collapsed in the 1980s due to phenotypic ambiguity and reproducibility failures. Following this "dark age," the concept of active suppression was kept alive through functional studies in organ-specific autoimmunity (Parish, Kong, Rose) and transplantation tolerance (Waldmann). However, it was Sakaguchi's discovery of CD25 as a specific marker that finally provided the physical identity of these cells, bridging the gap between functional observation and cellular definition. The subsequent identification of FOXP3 as the lineage-defining transcription factor transformed a disputed concept into a reproducible, engineerable immune module. Today, this molecular precision drives broad clinical translation, ranging from Treg-based therapies in autoimmunity and transplantation to targeted Treg modulation in cancer immunotherapy. This Short Review traces the trajectory-from controversy to molecular definition-and frames a forward path for context-dependent modulation of Tregs in clinical medicine.
2026-05-01 | Peripheral Expression of FOXP3 in Brazilian Patients with IPEX Syndrome: From FOXP3 Biomarker to Targeted FOXP3 Therapy Within the CNE3I
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder caused by loss-of-function mutations in the FOXP3 gene, which is critical for the development of functional regulatory T cells (Tregs). In IPEX patients, Tregs are unable to inhibit effector T cell proliferation and cytokine production, leading to a loss of peripheral immune tolerance. The disease presents with heterogeneous clinical manifestations, severe early-onset autoimmunity, the classic triad (enteropathy, eczema, and type 1 diabetes), as well as atypical or late-onset symptoms. A clear genotype–phenotype correlation has not been established for IPEX, and immunological assessments that could contribute to the diagnosis are scarce. Therefore, we aim to characterize the peripheral Treg cells in IPEX patients in Brazil through combined quantitative and qualitative flow cytometry analysis. We enrolled 6 male patients with a confirmed IPEX diagnosis (clinical, genetic, and immunological). All patients exhibited autoimmunity (enteropathy: 5/6; arthritis: 3/6; hemolytic anemia: 2/6; type 1 diabetes: 2/6), and allergic manifestations (rhinitis: 6/6; asthma: 4/6), eczema (4/6), and recurrent sinusitis (4/6) were also observed. Up to the last follow-up, two patients were alive after bone marrow transplantation and one after gene therapy (Figure 1). Peripheral FOXP3 expression was assessed in peripheral blood mononuclear cells (PBMCs) by flow cytometry (CD3, CD4, CD25, CD127, and FOXP3). Quantitative analysis determined the frequency of Tregs (CD4+CD25+CD127-FOXP3+), while qualitative analysis measured FOXP3 protein expression via median fluorescence intensity (MFI). The frequency of circulating Tregs in IPEX patients from our cohort was highly variable (14.6%–81.2%; mean: 58.5%) and overlapped with the control range (59.6%–84.1%; mean: 72.4%). In contrast, FOXP3 MFI was significantly lower in patient Tregs (mean: 986, range: 863–1,276) compared to controls (mean: 1,937, range: 1,089–4,132; p<0.05), another indication of quantitative Treg defects. Different patterns of FOXP3 expression have been reported, depending on the type and location of the mutation. While Treg numbers can be preserved in IPEX syndrome, FOXP3 protein expression per cell is consistently and significantly reduced. This defect in the expression level of FOXP3 likely underlies Treg dysfunction and disease pathogenesis. Assessment of FOXP3 MFI emerges as an additional valuable complementary diagnostic tool, providing functional insight beyond genetic sequencing alone. Figure 1. Clinical, immunologic, genetic, and therapeutic findings for IPEX syndrome within the CNE3i (Centro Nacional de Erros Inatos da Imunidade e Imunodesregulação) in Brazil. (1) Demonstrates the main clinical and geographical findings of the six IPEX patients; (2) general and advanced laboratory findings; and (3) genetics and therapeutics. SP, São Paulo; MG, Minas Gerais; PE, Pernambuco; DF, Distrito Federal; ES, Espírito Santo; IgE, immunoglobulin E; IgG immunoglobulin G; DNT, double negative T cells; IFN-SG, interferon-stimulated genes; MFI, median fluorescence intensity; BMT, bone marrow transplantation; GT, gene therapy; LFW, last follow-up. FINEP funding: 0956/24; FAPESP funding: 2023/09965-0; Instituto de Investigação em Imunologia funding CNPQ/MCTI: 408685/2024-7.
2026-03-15 | Preclinical efficacy and safety assessment of engineered regulatory T cells for treatment of IPEX and other autoimmune disorders.
FOXP3 is an essential transcription factor driving lineage commitment and function of regulatory T cells (Tregs). We previously reported a proof-of-concept study describing engineered Tregs (EngTregs) generated using homology-directed repair-based editing of the FOXP3 gene in CD4+ T cells, resulting in constitutive, high-level endogenous FOXP3 expression leading to acquisition of a Treg phenotype and robust in vitro and in vivo suppressive function. Here, we expand this gene-editing strategy to integrate a functional FOXP3 cDNA to enable EngTreg therapy for immune dysregulation, poly-endocrinopathy, enteropathy, X-linked syndrome (IPEX), a devastating multiorgan autoimmune disorder mediated by mutations within the FOXP3 gene. We provide a detailed characterization of preclinical EngTreg generation, including gene targeting efficiencies, cell enrichment and expansion, analyses of potential off-target editing, and phenotypic and functional characterization, including in vitro suppression of effector T cells and in vivo reversal of graft-versus-host disease. Importantly, in parallel, we utilize syngeneic and humanized mouse models to demonstrate the safety of EngTregs in primary and secondary humoral responses and viral infection control, respectively. Our combined preclinical dataset strongly supports the efficacy and safety of EngTregs as a promising potential cellular therapeutic approach for IPEX and possibly other autoimmune disorders.
2026-02-09 | Regulatory T Cells from Concept to Clinic: The 2025 Nobel Prize and Its Implications for Immune-Mediated Diseases and Cancer.
The 2025 Nobel Prize in Physiology or Medicine, awarded to Shimon Sakaguchi, Mary E. Brunkow, and Fred Ramsdell, recognizes the discovery and molecular definition of regulatory T cells (Tregs) as the cornerstone of peripheral immune tolerance. This recognition honors a transformative journey marked by Sakaguchi's identification of CD4+CD25+ T cells as a regulatory population (1995), followed by Brunkow and Ramsdell's discovery that mutations in the FOXP3 gene cause both the scurfy mouse phenotype and human IPEX syndrome (2001), and culminating in the demonstration that FOXP3 governs Treg development and function (2003). This achievement crowns a turbulent half-century arc. The suppressor T-cell (Ts) hypothesis of the 1970s proposed an active T-cell brake on immunity but collapsed in the 1980s due to phenotypic ambiguity and reproducibility failures. Following this "dark age," the concept of active suppression was kept alive through functional studies in organ-specific autoimmunity (Parish, Kong, Rose) and transplantation tolerance (Waldmann). However, it was Sakaguchi's discovery of CD25 as a specific marker that finally provided the physical identity of these cells, bridging the gap between functional observation and cellular definition. The subsequent identification of FOXP3 as the lineage-defining transcription factor transformed a disputed concept into a reproducible, engineerable immune module. Today, this molecular precision drives broad clinical translation, ranging from Treg-based therapies in autoimmunity and transplantation to targeted Treg modulation in cancer immunotherapy. This Short Review traces the trajectory-from controversy to molecular definition-and frames a forward path for context-dependent modulation of Tregs in clinical medicine.
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Drug Discovery Landscape
2 orphan drug designations for Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.
2 orphan drug designations for Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous CD34+ hematopoietic stem and progenitor cells modified ex-vivo with a lentiviral vector which restores endogenously regulated expression of FOXP3 | cell therapies | FDA | 2021-04-27 | — | ImmunoVec |
autologous patients¿ CD4+ T cells that have been subjected to lentivirus mediated gene transfer of healthy FOXP3 | gene therapies | FDA | 2020-10-26 | — | Stanford University |
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