Study of STAT1 gain-of-function pathogenesis and gene therapy

The Allergy and Clinical Immunology Research Group and the Laboratory of Molecular Virology and Gene Therapy at KU Leuven are seeking a talented PhD candidate to join our research on STAT1 gain-of-function (GOF). The position involves studying:
• The pathogenesis of STAT1 GOF via isogenic cell models
• The impact of STAT1 GOF mutations on responsiveness to JAK-inhibitors
• A gene-therapeutic approach for STAT1 GOF

Research Environment
The Allergy and Clinical Immunology Research Group, part of the Department of Microbiology, Immunology, and Transplantation at the Faculty of Medicine, KU Leuven, is engaged in various research areas including anaphylaxis, barrier dysfunction, and inborn errors of immunity. The team comprises 2 postdocs, 10 PhD students, 3 senior technicians, and 1 part-time data manager, supervised by 5 principal investigators (all clinician-researchers).
The Gijsbers’ group within the Laboratory of Molecular Virology and Gene Therapy hosts 5 PhD students and 2 technicians and operates the Leuven viral vector core.
Both groups maintain a productive and collaborative atmosphere, equipped with the necessary facilities for this project, located near the University Hospital and collaborating groups.

Website Links:
• Allergy and Clinical Immunology Research Group
https://www.kuleuven.be/wieiswie/en/unit/regional/50000631
• Laboratory of Molecular Virology and Gene Therapy
https://gbiomed.kuleuven.be/english/research/50000715/50488973/molmed/Molecular-Virology-and-Drug-Discovery/molvirgen-general
Website unit

Project

The project focuses on STAT1 gain-of-function (GOF), a monogenic inborn error of immunity (IEI). IEIs are rare inherited disorders that compromise the immune system, leading to increased susceptibility to pathogens, autoimmunity, autoinflammation, allergies, and sometimes malignancies. These conditions are difficult to diagnose and treat due to their broad phenotype and poor understanding.

STAT1 GOF is characterized by chronic mucocutaneous candidiasis (CMC) due to impaired IL-17 production, bacterial infections, and autoimmunity. Since its discovery in 2011, over 400 patients with around 105 different mutations have been reported. Besides a common phenotype, some patients exhibit distinct presentations including non-malignant lymphoproliferation, combined immunodeficiency without CMC, or autoimmunity-predominant presentations (so called IPEX-like syndromes). The mechanisms underlying these diverse phenotypes remain unexplained. We demonstrated earlier that different routes towards a STAT1 GOF phenotype exist and hypothesize that these could explain (in part) the variable clinical presentation.

Currently there is no cure for STAT1 GOF and treatments are symptomatic (antibiotics, immunosuppressives for autoimmune manifestations). JAK-inhibitors have shown effectiveness in some cases, but their results are inconsistent. We hypothesize that these effects are mutation-specific and propose to study, in isogenic cell models expressing the various mutants, the responsiveness to JAK-inhibitors to guide treatment choices for these patients.

Therefore, we studied in silico (in collaboration with the group of Prof. Voet, KU Leuven) the impact of various mutations and validate these in cellulo by looking at the dynamic behavior (microscopy, flow based STAT1-phosphorylation) of GOF mutants in response to stimuli (type I and type II IFN). In addition we are elaborating  single cell sequencing experiments, studying the effect of JAK-inhibitors on STAT1 GOF.

Finally, allogenic hematopoietic stem cell transplantation (allo-HSCT) could be a curative treatment but is associated with a high mortality. Therefore, our group focusses on improving our understanding of the disease mechanism by studying isogenic cell models expressing different STAT1 GOF mutants. Given the absence of a safe cure, our group is elaborating a gene therapeutic approach using CRISPR gene-editing with a first in vitro proof-of-concept presented at the latest ESGCT meeting (references below).

Your role:

• You will perform the in vitro experiments using various cell models
• You will setup the live cell imaging experiments (as indicated in the reference and in collaboration with Prof. Marquez REGA institute)
• You will (help to) optimize the gene therapeutic approach
• You will closely collaborate with the laboratory staff and senior doctoral fellow (FWO-SB, Drs. Cecilia Iglesias Herrero)
• You will be able to take up additional topics related to your project, depending on the progress of your work and personal initiatives (e.g. applying the cell model to other STAT GOF disorders)
• The project requires careful planning, coordination and dedication
• You will disseminate your results on national and international conferences, publish scientific reports and prepare and defend a doctoral thesis manuscript

References

• Live Cell Imaging Demonstrates Multiple Routes Toward a STAT1 Gain-of-Function Phenotype. Giovannozzi S, Lemmens V, Hendrix J, Gijsbers R, Schrijvers R. Front Immunol. 2020 Jun 9;11:1114. doi: 10.3389/fimmu.2020.01114. eCollection 2020. PMID: 32582194 Free PMC article.
• Transcriptional Profiling of STAT1 Gain-of-Function Reveals Common and Mutation-Specific Fingerprints. Giovannozzi S, Demeulemeester J, Schrijvers R, Gijsbers R. Front Immunol. 2021 Feb 17;12:632997. doi: 10.3389/fimmu.2021.632997. eCollection 2021. PMID: 33679782 Free PMC article.
• Iglesias Herrero, C., Kristoforus, T., Schrijvers, R., Gijsbers, R. (2023). Proof-of-concept for a one-step gene therapy for STAT1 gain-of-function. In: Human Gene Therapy: vol. 35 (3-4), (Abstract No. P393), (A337-A365). Presented at the ESGCT/SFTCG/NVGCT Collaborative Congress, Brussels, 24 Oct 2023-27 Oct 2023.
• Case report: Myocarditis in congenital STAT1 gain-of function. Staels F, Roosens W, Giovannozzi S, Moens L, Bogaert J, Iglesias-Herrero C, Gijsbers R, Bossuyt X, Frans G, Liston A, Humblet-Baron S, Meyts I, Van Aelst L, Schrijvers R. Front Immunol. 2023 Mar 20;14:1095595. doi: 10.3389/fimmu.2023.1095595. eCollection 2023. PMID: 37020552 Free PMC article.

Other (selected) articles from the Allergy and Clinical Immunology research group, PI Prof. Dr. Rik Schrijvers (https://pubmed.ncbi.nlm.nih.gov/?term=schrijvers+r&sort=date)

Other (selected) articles from the Laboratory of Molecular Virology and Gene Therapy, PI Prof. Dr. Ir. Rik Gijsbers (https://pubmed.ncbi.nlm.nih.gov/?

Profile

Offer

Key reference(s)
Key reference(s)
More information on the research project

Interested?

For more information please contact Prof. dr. Rik Schrijvers, mail: [email protected] or Prof. dr. Rik Gijsbers, mail: [email protected].

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