McKenna, Alexander John; (2023) Towards personalised medicine for STAT1 gain-of-function primary immunodeficiency. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text PhD thesis_Alexander John McKenna_Towards personalised medicine for STAT1 gain-of-function primary immunodeficiency.pdf - Submitted Version Download (5MB) | Preview

Abstract

Germline, monoallelic, gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause an ultra-rare form of primary immunodeficiency (PID) through overactivation of the Janus-associated kinase/STAT1 signalling pathway. The clinical phenotype of this disorder is extremely variable and encompasses chronic mucocutaneous candidiasis, combined immunodeficiency and autoimmunity. To date, the functional validation of STAT1 GOF PID remains a significant challenge due to inconsistent access to specialised testing. Genotype: phenotype correlations have also remained elusive, and the molecular mechanism driving the disease is yet to be described. This, in part, means that the clinical management of STAT1 GOF PID at present is mainly limited to supportive care with antimicrobial prophylaxis and prompt treatment of infections. In this study, a standardised, flow cytometric-based diagnostic assay panel was designed and optimised to facilitate an accurate yet simple, functional diagnosis of STAT1 GOF PID. Secondly, the collation of clinical data from 428 patients with STAT1 GOF mutations worldwide identified that distinct mutations manifest in unique clinical phenotypes, particularly the T385M GOF mutation which induces a significantly greater disease course severity in comparison to all other mutations. Furthermore, through the development of cell line models and the interrogation of patient primary cells, four distinct molecular mechanisms potentially underpinning STAT1 GOF disease that depend upon the dimeric interface the mutation resides at were outlined. Finally, the design, development, and assessment of three gene editing approaches for STAT1 GOF PID is described. This work has opened more avenues for disease interrogation and targeting, has provided proof-of-concept for gene editing as a potentially curative measure for patients with STAT1 GOF PID and could potentially impact clinical decision making and prognostication. But ultimately, it supports the notion of a more personalised approach to treating STAT1 GOF PID.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item