Gene/Cell Therapy Approaches for Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome

Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare autoimmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of devastating autoimmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here.

• Publication year

  2014

• Venue

  Current Gene Therapy

• Publication date

  2014-11-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.2174/1566523214666141001123828PMID 25274247PMCID 4443799
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies

  2015cited by this paper
• Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells

  2015cited by this paper
• Forkhead box P3: The Peacekeeper of the Immune System

  2014cited by this paper
• Selective expansion of donor‐derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome

  2014cited by this paper
• A guide to genome engineering with programmable nucleases

  2014cited by this paper
• Targeted Genome Editing in Human Repopulating Hematopoietic Stem Cells

  2014cited by this paper
• Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.

  2014cited by this paper
• Development and applications of CRISPR-Cas9 for genome engineering.

  2014cited by this paper
• Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells

  2013cited by this paper
• Nuclease-mediated gene editing by homologous recombination of the human globin locus

  2013cited by this paper
• Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

  2013influential reference
• CD4+ T Cells from IPEX Patients Convert into Functional and Stable Regulatory T Cells by FOXP3 Gene Transfer

  2013influential reference
• Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections.

  2013cited by this paper
• A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells.

  2013cited by this paper
• Gene therapy on the move

  2013cited by this paper
• Reading Frame Correction by Targeted Genome Editing Restores Dystrophin Expression in Cells From Duchenne Muscular Dystrophy Patients

  2013cited by this paper
• Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases.

  2013cited by this paper
• Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

  2013cited by this paper
• TALEN-based gene correction for epidermolysis bullosa.

  2013cited by this paper
• Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells.

  2013cited by this paper
• Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity

  2013influential reference
• Autoantibodies to Harmonin and Villin Are Diagnostic Markers in Children with IPEX Syndrome

  2013influential reference
• The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome

  2012cited by this paper
• Naturally occurring regulatory T cells: markers, mechanisms, and manipulation

  2012cited by this paper
• Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A Paradigm of Immunodeficiency with Autoimmunity

  2012cited by this paper
• Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome

  2012cited by this paper
• Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease.

  2012cited by this paper
• Flow Cytometric Analysis of TCR Vβ Repertoire in Patients with 22q11.2 Deletion Syndrome

  2011cited by this paper
• Regulatory T cells in stem cell transplantation: strategies and first clinical experiences.

  2011cited by this paper
• Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.

  2011cited by this paper
• Immunology. Regulatory T cells get their chance to shine.

  2011cited by this paper
• Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX.

  2011cited by this paper
• Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation.

  2011cited by this paper
• Bet v 1-specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1-specific T-cell effector function in an activation-dependent manner.

  2011cited by this paper
• Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability.

  2011cited by this paper
• Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

  2011cited by this paper
• Autoantibodies to villin occur frequently in IPEX, a severe immune dysregulation, syndrome caused by mutation of FOXP3.

  2011influential reference
• Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy.

  2010cited by this paper
• Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease.

  2010cited by this paper
• The Immune Tolerance Network at 10 years: tolerance research at the bedside

  2010cited by this paper
• Human Antigen-Specific Regulatory T Cells Generated by T Cell Receptor Gene Transfer

  2010cited by this paper
• Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity

  2009cited by this paper
• How I treat ADA deficiency.

  2009influential reference
• First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells.

  2009cited by this paper
• Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations.

  2009cited by this paper
• Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation.

  2009cited by this paper
• In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates.

  2009cited by this paper
• Gene therapy for immunodeficiency due to adenosine deaminase deficiency.

  2009influential reference
• FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome.

  2009cited by this paper
• Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3.

  2008cited by this paper
• Use of Sirolimus in IPEX and IPEX-Like Children

  2008cited by this paper
• Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity.

  2008cited by this paper
• Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

  2008cited by this paper
• The Wiskott-Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells

  2007cited by this paper
• WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells

  2007cited by this paper
• IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity

  2007cited by this paper
• CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.

  2007cited by this paper
• Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development.

  2006cited by this paper
• Defective regulatory and effector T cell functions in patients with FOXP3 mutations.

  2006cited by this paper
• Characterization of Immunodeficiency in a Patient With Growth Hormone Insensitivity Secondary to a Novel STAT5b Gene Mutation

  2006cited by this paper
• Cutting Edge: Decreased Accumulation and Regulatory Function of CD4+CD25high T Cells in Human STAT5b Deficiency1

  2006cited by this paper
• Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b.

  2005cited by this paper
• Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome).

  2005cited by this paper
• HIV Infection of Naturally Occurring and Genetically Reprogrammed Human Regulatory T-cells

  2004cited by this paper
• Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.

  2004cited by this paper
• Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

  2004cited by this paper
• Rescue of the autoimmune scurfy mouse by partial bone marrow transplantation or by injection with T‐enriched splenocytes

  2003cited by this paper
• Growth hormone insensitivity associated with a STAT5b mutation.

  2003cited by this paper
• Specific transgene expression in human and mouse CD4+ cells using lentiviral vectors with regulatory sequences from the CD4 gene.

  2003cited by this paper
• X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

  2001cited by this paper
• JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.

  2000cited by this paper
• A 75‐kD autoantigen recognized by sera from patients with X‐linked autoimmune enteropathy associated with nephropathy

  1998cited by this paper
• An interleukin-2 receptor gamma chain mutation with normal thymus morphology.

  1997cited by this paper

• A hemizygous mutation in the FOXP3 gene (IPEX syndrome) resulting in recurrent X-linked fetal hydrops: a case report

  2021cites this paper
• IPEX Syndrome: Genetics and Treatment Options

  2021cites this paper
• A Review of Autoimmune Enteropathy and Its Associated Syndromes

  2020cites this paper
• IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with Intractable Diarrhea as a Single Symptom

  2020cites this paper
• T cell gene therapy to treat immunodeficiency

  2020cites this paper
• Molecular feature and therapeutic perspectives of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

  2020cites this paper
• Idiopathic Thrombocytopenic Purpura

  2019cites this paper
• Advances in site-specific gene editing for primary immune deficiencies

  2018cites this paper
• ALLERGIC MANIFESTATIONS OF PRIMARY IMMUNODEFICIENCY DISEASES AND ITS TREATMENT APPROACHES

  2018influential citation
• Thymus

  2018cites this paper
• Engineered Tolerance: Tailoring Development, Function, and Antigen-Specificity of Regulatory T Cells

  2017cites this paper
• Is Stem Cell Therapy Ready for Prime Time in Treatment of Inflammatory Bowel Diseases?

  2017cites this paper
• New Insights and Perspectives in Congenital Diarrheal Disorders

  2017cites this paper
• Type 1 Diabetes Mellitus in Monogenic Autoimmune Diseases

  2017cites this paper
• Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome

  2016cites this paper
• Primary immunodeficiency update: Part I. Syndromes associated with eczematous dermatitis.

  2015cites this paper
• Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies

  2015cites this paper
• Congenital Immunodeficiency Diseases

  2015cites this paper
• Preface. Genes don't care.

  2015cites this paper