Genome editing unveils cellular mechanisms at the basis of VEXAS Syndrome

Researchers from IRCCS San Raffaele Hospital, using an innovative technology of genome editing, have developed a preclinical model that enabled the identification of blood cell poisoning as the main mechanism underlying VEXAS syndrome, an inflammatory disease linked to ageing

Moreover, San Raffaele Hospital opens a multidisciplinary clinic dedicated to patients affected by VEXAS syndrome, becoming a reference center in Italy for its diagnosis and clinical management

A research group at San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), in collaboration with the Division of Genetics and Cell Biology, has published a new study in Nature Medicine shedding light on the mechanisms underlying VEXAS syndrome, an inflammatory disease linked to ageing that eventually leads to bone marrow failure. This syndrome affects 1 person in 4000, prevalently males above 50 years old. The study has been coordinated by Doctor Samuele Ferrari, UniSR Alumnus, project leader in the Novel Gene Therapy Strategies Unit, together with Professor Luigi Naldini, SR-Tiget director and full professor of Histology at the Vita-Salute San Raffaele University, and Doctor Giulio Cavalli, immunologist at San Raffaele until 2022.

VEXAS syndrome is a blood stem cell disease caused by a mutation, acquired with ageing, of the UBA1 gene, which encodes for an enzyme involved in protein degradation. In VEXAS syndrome, mutated blood stem cells progressively replace healthy ones – which did not acquire the mutation – through a mechanism called clonal hemopoiesis. Causes and characteristics of clonal hemopoiesis are unknown.

Consequently, the disease results in inflammation of several organs, presenting symptoms such as fever, skin lesions, involvement of lungs and blood vessels, and cartilage inflammation. Eventually, the bone marrow becomes unable to generate new blood cells, leading to anemia and platelet reduction. Currently there is no definitive treatment for VEXAS syndrome, apart from the use of immunosuppressors (like cortisone), to control inflammation, together with drugs that improve specific blood parameters, like erythropoietin and 5-azacitidine. Bone marrow transplantation from healthy donors can be an option only in selected cases. In the long term, unfortunately the disease leads to a fatal outcome.

First, the authors studied the molecular characteristics of blood stem cells derived from patients affected by VEXAS syndrome. They observed that those cells displayed signs of inflammation and early ageing and preferentially generated myeloid cells – that is, monocytes and granulocytes that are associated with inflammation – instead of lymphoid cells – that is, B and T lymphocytes, which mediate immune defense. Then, the researchers developed a preclinical model of the disease using a new technology of genetic editing to introduce the VEXAS mutation in the UBA1 gene of blood stem cells derived from healthy donors. These cells, which resemble diseased ones, were transplanted in mouse bone marrows together with healthy blood stem cells, to study their behavior in vivo. Mutated stem cells recapitulated many features of VEXAS syndrome in the preclinical model, including signs of inflammation, early senescence and preferential generation of myeloid cells instead of lymphocytes.

Above all, and as observed in patients, mutated blood stem cells took over healthy ones, progressively replacing them. The authors showed that clonal hemopoiesis was due to the inability of healthy blood stem cells to survive the inflammatory environment created by diseased stem cells and their progeny, rather than to an increased proliferation of the latter as previously thought. «Clonal hemopoiesis and the pathological manifestations of VEXAS result from the progressive poisoning of the healthy cell fraction by the inflammatory setting created by diseased blood stem cells, which are more resistant to it», say Doctor Raffaella Molteni and Doctor Martina Fiumara, researchers from the Division of Genetics and Cell Biology at IRCCS San Raffaele Hospital and co-first authors of the study.

«The mechanisms of clonal dominance described in this study not only shed light on the cellular characteristics of VEXAS syndrome but also set a starting point to guide research on blood diseases linked to ageing, thus contributing to enhance our understanding of these conditions», says Professor Luigi Naldini.

«This study provides new information on the mechanisms at the basis of the clonal dominance in VEXAS syndrome and its link to other blood diseases connected with ageing. We hope that the new preclinical model that we have set up will allow new treatments for VEXAS and other diseases that present similar gene alterations in blood stem cells»

adds Doctor Ferrari, who is one of three last authors of the paper. In 2024, Doctor Ferrari received the prestigious ERC Starting Grant thanks to a study on VEXAS. 

Regarding his academic journey at UniSR, Ferrari comments: "I can proudly say that I completed my entire academic path at UniSR, where professors and researchers have inspired me with a passion for Science and the mission of research since day one. The opportunity to engage in biotechnology laboratory work from the very first year was crucial in helping me understand the role of a researcher. Moreover, the presence of an international university campus and a hospital of excellence have been essential elements in shaping both my undergraduate and postgraduate education".  Find out more about the Degree Course in Biotechnology Research in Medicine

This year, IRCCS San Raffaele Hospital opened a new clinic specialized in VEXAS syndrome. The clinic stemmed from the collaboration between the Hematology and Bone Marrow Transplantation Unit, directed by Prof. Fabio Ciceri, also director of the Comprehensive Cancer Center, and the Immunology, Rheumatology, Allergology and Rare Diseases, directed by Prof. Lorenzo Dagna, with the aim of guaranteeing patients a personalized and multidisciplinary assistance.

This clinic offers patients a place where to receive early diagnosis, personalized treatments and constant, multidisciplinary support in the disease management. Moreover, the new clinic promotes research through the access to clinical trials by enabling patients to access new therapeutical protocols. Thanks to the synergy between experts in various disciplines, the clinic aims at improving patient quality of life, providing them with tools to better handle the pathology and creating a reference community where they can feel understood and supported.

«The opening of a clinic dedicated to VEXAS syndrome is a crucial step to guarantee patients specialized and personalized assistance», explains Prof. Lorenzo Dagna, «this initiative not only will help to improve the clinical management of the disease, but will also allow us to collect valuable data for research, accelerating the development of new therapies», concludes Prof. Fabio Ciceri.