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Project

Analysis of JAK-inhibitor treatment for STAT1 gain-of-function and development of a CRISPR-based gene therapy approach

Primary immunodeficiencies (PIDs) are rare inherited disorders affecting the immune system presenting with increased susceptibility to pathogens and often associated with severe non-infectious comorbidities. The poor understanding of PIDs makes them difficult to diagnose and thus, challenging to treat or cure. The monogenic nature of several PIDs converts them in the perfect target for precision medicine. In this project, I focus in autosomal dominant (AD) signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) as a PID prototype due to a range of mutations and with a broad, mostly unexplained phenotype. STAT1 is a pivotal transcription factor in the immune response. In follow-up of our recent proof-of-concept publications I propose to (i) assess the underlying molecular routes driving to the distinct phenotypes using biochemistry tools, live-cell imaging and transcriptomics; (ii) study the effect of ruxolitinib, a JAK-inhibitor, treatment in the different mutations at the molecular level and in patient cells, in order to improve its use in the clinical practice; and ultimately (iii) develop a proof-of-concept of a safer curative gene therapeutical approach for most, if not all, STAT1 GOFs using the last advances in viral vector technology. Altogether, I aim to improve the quality of life of these patients providing tools for earlier diagnosis and more stratified treatment, optimize use of existing drugs and hopefully a cure to the disorder.

Date:1 Aug 2021 →  Today
Keywords:Primary immunodeficiency, Transcriptomics, Gain-of-function disorder
Disciplines:Molecular and cell biology not elsewhere classified
Project type:PhD project