Good news!
"Yale School of Medicine (YSM) researchers have made key breakthroughs in understanding how to treat fibrotic diseases such as scleroderma and graft-versus-host disease.
Fibrotic diseases are a group of conditions—often autoimmune—characterized by excessive tissue scarring. They can drastically hinder patients’ quality of life, and in some cases, they can be life-threatening—fibrosis contributes to approximately 45% of all deaths in developed nations. However, there are no effective treatments.
Now, in a study ... researchers have developed a monoclonal antibody that is showing promise as a new therapy for patients. And in a [second] ... study, the same team discovered a signaling pathway that may be mediating fibrosis and could be a target for future therapies. ...
Then, the team tested their anti-EREG antibody in humanized mouse models and skin biopsies from patients and found that inhibiting epiregulin reduced biomarkers associated with fibrosis. These findings suggest that the therapeutic antibody could be a promising new therapy for patients with various types of fibrotic conditions. ...
In a second recent study, the researchers aimed to further understand mechanisms that differentiate fibrotic and non-fibrotic skin diseases. The team compared single-cell RNA sequencing data from seven different inflammatory skin diseases. Some of the diseases, like atopic dermatitis and psoriasis, were associated with redness and scaling, but not fibrosis. They also analyzed data from patients with fibrotic diseases such as scleroderma, graft-versus-host disease, and lupus.
Their analyses revealed that fibrotic diseases were associated with greater activity of a protein called STAT1 in fibroblasts, the key cell type that’s hyperactivated in fibrotic diseases. To better understand how STAT1 interacts with the EGFR signaling pathway to drive fibrosis, the researchers developed mouse models that lacked STAT1. When the team activated EGFR, they found that mice without STAT1 showed less fibrosis compared to regular animal models.
“If we activate EGFR by inducing injury when there’s no STAT1 present, none of the fibrotic genes are activated,” ...
The researchers conducted further experiments on cultured fibroblasts in vitro which confirmed that STAT1 was required for the onset of fibrosis. ...
Importantly, the upregulation of epiregulin activation of EGFR-STAT1 pathway isn’t always active—it’s only switched on under specific conditions such as the presence of injury or inflammation. ..."
"Key Points
- New fully human anti-EREG therapeutic antibody is highly developable and demonstrates antifibrotic capabilities in vivo.
- Sclerotic GvHD and SSc share EREG-TNC-TLR4 signaling axis that is reduced by anti-EREG treatment in patient skin explants.
..."
From the abstract:
"Chronic inflammatory skin diseases affect the health of millions of people worldwide, and those that feature fibrosis are refractory to treatments. The signals that determine whether fibrosis occurs during chronic skin inflammation are poorly understood.
We generated a scRNA-seq atlas of seven inflammatory skin diseases and their healthy controls.
Diseases with fibrosis demonstrate higher expression and activity of STAT1 in fibroblasts.
Fibroblast STAT1 is required for skin fibrosis development in mice. STAT1 activation promotes a fibrotic gene expression profile which can be activated directly by EGFR in a JAK-independent manner and abrogated by genetic and pharmacologic STAT1 inhibition.
The EGFR-STAT1 pathway is stimulated by high affinity EGFR ligands expressed by activated keratinocytes, suggesting keratinocyte-derived signals as triggers of skin fibrosis.
In sum, fibroinflammatory skin diseases are characterized by fibroblast EGFR-STAT1 signaling that controls expression of fibrotic genes, elucidating an interferon independent function of STAT1 to mediate fibrotic skin diseases."
Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody (no public access)
Fig. 1: Integrated inflammatory skin disease atlas shows upregulated STAT1 expression in SFRP2+ fibroblasts.
Fig. 2: SCENIC analysis of fibroblasts identifies STAT1 as a central regulon in fibrotic skin.
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