An Innovative Therapy for Systemic Sclerosis Using FDA-approved Immune-modifying Nanoparticles

Systemic sclerosis (SSc) is a life-threatening orphan disease, mostly affecting young women. Patients with SSc develop progressive and often disabling skin induration accompanied by visceral organ involvement, including lung fibrosis. There are no FDA-approved therapies, and SSc mortality rates have remained unchanged for four decades. SSc represents a major unmet medical need (1). The Northwestern Scleroderma Program, a national Center of Excellence, serves as a major referral site for patients from around the world. The pathogenesis of SSc involves persistent activation of tissue myofibroblasts, but the triggers initiating and driving the process remain incompletely defined. Recent studies from our groups and others have indicated marked accumulation of inflammatory monocytes (IMs) and macrophages, and presence of a prominent “activated macrophage signature”, in the lesional skin from patients with SSc, as well as in mouse models of disease (2-4) (5). Additionally, levels of circulating CD163, a monocyte/macrophage-specific scavenger receptor, are markedly elevated in SSc patients (6). Genetic studies indicate that variant alleles for seven genes involved in macrophage-mediated innate immunity (STAT4 IRF5, IRF8, TNFAIP3, TLR2, TNFB and TNIP1), confer increased risk in SSc, or modify disease outcomes (7). We recently demonstrated, for the first time, that a specific subset of inflammatory monocytes (MARCO+) is elevated in skin and lung biopsies from SSc patients (see below). Based on these findings, we now propose the innovative hypothesis that IM are key players in organ fibrosis, and their selective targeting could attenuate the process, and improve outcomes for SSc patients.