A path towards personalized medicine for autoinflammatory and related diseases

The human stories behind rare rheumatic diseases illustrate how genetic information can benefit patients. In 1988, a team of physicians met a patient with a unique disease of multiple organs, including the kidneys, liver, brain and eyes7. No immunosuppressive therapy was effective, and the patient and several of his family members passed away with severe multi-organ damage. The histological assessment at autopsy revealed vasculopathy involving multiple organs, including the brain and eye, as well as brain lesions that resemble radiation necrosis8,9. A careful family history revealed that about half of the patients’ family members suffered from a similar condition, although the family had previously received other diagnoses, including multiple sclerosis and SLE. Two decades later, an international team of scientists reported that this disease, now known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL; also known as RVCL-S or HERNS), is caused by autosomal-dominant C-terminal frameshift mutations in the gene TREX1 (ref. 10). One hundred percent of patients with RVCL have similar, autosomal-dominant mutations in the carboxy (C)-terminal region of TREX1, and all of these patients develop multi-organ damage beginning around the age of 40 years8. Furthermore, all patients with RVCL die prematurely from the disease, often within 5–10 years of the onset of symptoms8. RVCL is clinically distinct from an autosomal-recessive autoinflammatory disease known as Aicardi–Goutières syndrome (AGS), although both RVCL and AGS are characterized by mutations in TREX1. Whereas AGS can also be caused by mutations in other genes11, RVCL is only caused by mutations in TREX1. Unlike RVCL, which is caused by a single truncation in one TREX1 allele, AGS can result from the complete loss of TREX1 function12,13. TREX1 encodes a DNA exonuclease14 and loss of TREX1 function in AGS leads to accrual of dsDNA in the cytosol and unabated activation of the cGAS-STING pathway, as TREX1 negatively regulates the expression of type I interferon and interferon-stimulated genes12,13,15 (Fig. 2). The amino terminal domain of the TREX1 enzyme contains all of the structural elements for full exonuclease activity, whereas the C-terminal region controls localization of TREX1 at the perinuclear space. The precise immunological and molecular mechanism by which TREX1 frameshift mutations cause RVCL is less well understood, although it might be related to mislocalization of a functional TREX1 enzyme10 or, alternatively, dysregulation of cGAS–STING signalling16.

Fig. 2: Rare rheumatic diseases and the TREX1–cGAS–STING pathway.figure 2

Different single-gene mutations in the same pathway can cause unique clinical phenotypes, including organ pathology resembling that of common rheumatic diseases. TREX1 is a DNase that degrades cytosolic DNA to prevent activation of the cGAS–STING pathway, which induces production of cytokines, including type I interferon. Mutations in different regions of TREX1 cause entirely distinct clinical phenotypes. Loss of TREX1 function causes disease of the central nervous system, whereas mutations in STING or mutations in COPA that result in STING activation trigger lung disease in patients with SAVI or COPA syndrome. These pathways are increasingly being studied in common rheumatic diseases. The original version of this figure was created with BioRender.com. ANCA, anti-neutrophil cytoplasmic antibody; CNS, central nervous system; ER, endoplasmic reticulum.

What is most concerning for patients with RVCL and their families is the fact that no effective treatment is yet available for this disease. As a consequence, these patients undergo relentless disease progression leading to blindness, chronic renal insufficiency, liver damage, as well as dementia, strokes, osteonecrosis, thyroid disease, gastrointestinal disease, chronic pain, disability and premature death8. Nevertheless, despite our incomplete understanding of the molecular mechanisms that underlie RVCL, the discovery of disease-causing TREX1 mutations has transformed the lives of these patients and their families (Fig. 3). Now, patients with RVCL have the option to undergo genetic testing in early adulthood—long before disease onset. This testing enables patients and their families to prepare and plan for the future. Patients with RVCL can now consider in vitro fertilization combined with genetic testing, which prevents transmission of the mutant TREX1 allele to the next generation. Furthermore, the patients also have the option of participating in longitudinal studies and clinical trials17,18. Most importantly, patients with RVCL and their families now feel more hopeful, as mutations in TREX1 pinpoint this protein as a key therapeutic target. Physicians and scientists are now working to define molecular mechanisms of RVCL pathogenesis, and to develop gene therapies to correct the disease-causing mutation, as well as small molecule drugs that preferentially correct defects elicited by the mutant TREX1 protein.

Fig. 3: The discovery of RVCL and subsequent search for a cure.figure 3

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) was discovered more than three decades ago, in 1988. The identification of disease-causing mutations in the gene TREX1 has enabled patients to plan ahead, to participate in research studies, and to choose in vitro fertilization with genetic testing to prevent the next generation from inheriting the dominant disease-causing mutation, which results in premature death in 100% of cases. Now researchers are developing personalized medicines for RVCL, including gene therapies and small molecules that target the mutant TREX1 protein. *J.J.M., unpublished work. SLE, systemic lupus erythematosus.

In 2014, another rare disease known as STING-associated vasculopathy with onset in infancy (SAVI) was discovered and reported by the laboratory of Raphaela Goldbach-Mansky at the National Institutes of Health19. Patients with SAVI develop severe Raynaud syndrome, vasculopathy with autoamputation of digits, skin rash and pulmonary fibrosis, often within the first year of life19. The disease-causing mutation renders STING constitutively active. STING is an important player in the cell-intrinsic innate immune response against viruses and other pathogens20. Introduction of the SAVI mutation into animal models using CRISPR/Cas9 technology has confirmed that these STING gain-of-function mutations are indeed pathogenic21,22,23. The peripheral blood mononuclear cells of patients with SAVI exhibit constitutive upregulation of type I interferon-stimulated genes, which are one of the most prominent pathways activated downstream of STING19. These findings led to the use of JAK inhibitors as a treatment for patients with SAVI, which can reduce signalling downstream of the type I interferon receptor24. Unfortunately, JAK inhibition does not always control the progression of this disease19,24,25,26. Studies in mouse models of SAVI have shown that disease progresses normally even in animals lacking the receptor for type I interferons, suggesting that the disease-causing mutations also have type I interferon-independent effects that contribute to disease21,22,23,27. Ongoing efforts in the field are aimed at further defining the molecular mechanisms of SAVI pathogenesis as well as the cell types involved in disease initiation, which might eventually lead to even better treatments for SAVI.

In 2015, researchers described another disease called COPA syndrome28. Patients with COPA syndrome have mutations in the COPA gene that encodes the α-COP component of the coatomer (a macromolecular complex involved in membrane trafficking), and deficiency of coatomer complex I (COPI) components causes activation of the STING pathway29. α-COP has a role in COPI vesicle biogenesis and retrograde transport of proteins from the Golgi to the endoplasmic reticulum (ER); hence, COPA mutations are thought to dysregulate the transit of proteins from the Golgi to the ER, or to other subcellular compartments30,31,32. In some ways, COPA syndrome clinically resembles SAVI, although the two diseases have some distinguishing features. For example, unlike SAVI, COPA syndrome does not typically cause severe peripheral vasculopathy or autoamputation of digits. Additionally, COPA syndrome can cause pulmonary haemorrhage as well as glomerulonephritis, and can elicit the formation of anti-neutrophil cytoplasmic antibodies (ANCA)33,34, similar to what occurs in patients with ANCA-associated vasculitis35. In 2020, multiple groups reported that COPA mutations lead to trapping of STING in the Golgi, which results in constitutive STING signalling30,31,32. Additionally, a SAVI-associated mutation in an adult also caused ANCA-associated vasculitis36, further suggesting potential phenotypic overlap resulting from mutations in the genes encoding STING and α-COP proteins. Thus, constitutive STING signalling is now implicated in the pathogenesis of multiple autoinflammatory and autoimmune diseases.

What might be most remarkable about these stories is that all of these rare diseases, which are generally quite heterogeneous in clinical phenotype, converge at the molecular level on a single pathway (Fig. 1). This convergence underscores the probable importance of the TREX1–cGAS–STING signalling pathway in the pathogenesis of various rheumatic diseases, in addition to its role in a variety of non-rheumatic diseases37,38. Even more mutations that dysregulate this pathway and the related signalling pathways will undoubtedly be uncovered in the future. More importantly, the discovery of these mutations, as well as of other rare mutations, will probably lead to novel therapies and therapeutic targets of pathways involved in more common types of autoimmune and autoinflammatory diseases.

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