Targeting NAD metabolism to treat systemic sclerosis

The unique and defining feature of systemic sclerosis (SSc) is synchronously occurring fibrosis in the skin, lungs, heart and muscles. Transformation of tissue progenitor cells into activated myofibroblasts defines all forms of fibrosis; however the metabolic alterations driving this transformation remain largely unknown. We uncovered striking biological parallels between mechanisms driving cellular aging and SSc fibrosis, including altered nutrient sensing and reduced activity of anti-aging sirtuin (SIRT) deacetylases. SIRT activity is tightly controlled by bioavailability of NAD+, the cellular sensor linking metabolic states to signaling. We had shown that chronological aging is associated with decline in NAD+ levels and SIRT activity that are explained by elevated activity of the NAD+ hydrolase CD38. Remarkably, tissues from SSc patients and mice with experimental scleroderma demonstrate elevated CD38 and reduced SIRT activity similar to aging. CD38 directly stimulated fibrotic responses in fibroblasts, while blocking CD38 NADase activity, or supplementing mice with the unique NAD+ precursor nicotinamide riboside (NR) attenuated both spontaneous (age- dependent) and inducible (bleomycin) fibrosis. Based on these Preliminary Results, we propose the novel hypothesis that similar to chronological aging, in SSc up-regulation of CD38 causes organismic NAD+ depletion and impaired SIRT function, which account for persistent myofibroblast activation and organ fibrosis. Thus our premise is that genetic and/or pharmacological approaches to boost NAD+ bioavailability will restore SIRT activity and limit fibrosis in both inflammation-dependent and inflammation-independent scleroderma models, and represents a novel treatment strategy for SSc. We will test our hypothesis in two independent Specific Aims: determine if mice with deletion of CD38 or expressing catalytically-inactive mutant CD38 are protected from NAD+ decline and fibrosis in complementary scleroderma models (Aim 1); and directly evaluate the pathogenic role of NAD+ depletion by increasing its bioavailability using a highly selective CD38 NADase inhibitor, alone or combined with NAD+ repletion (Aim 2). Based on a sound premise amply supported by genomic, biochemical and cellular data and using novel mouse strains, robust assays and experimental tools, this multi-PI R21 will definitively identify the contribution and mechanism of CD38 and NAD+ metabolism in SSc, and the viability of selective CD38 inhibition as therapy. These studies introduce the innovative paradigm of SSc as an accelerated aging phenotype, and carry significant clinical implications.