Project Summary Systemic sclerosis (SSc) is a systemic autoimmune disease that results in widespread fibrosis of the skin and internal organs, vascular dropout and autoantibody formation. SSc has the highest case fatality rate of any systemic autoimmune disease and there remain for FDA approved therapies. Analysis of gene expression data on samples collected from SSc patients strongly indicates that alternatively activated macrophages are the key drivers of SSc pathogenesis. Our goal is to develop a cellular therapy that will target alternatively activated macrophages through the use of a chimeric antigen receptor (CAR). In addition to activated macrophage elimination, we will design constructs that will be capable of secreting antifibrotic molecules to revert or even ameliorate the fibrotic process locally and potentially systemically. At the end of Phase I, we will have selected a lead construct (based on in vivo readouts) for IND-enabling studies in Phase II.

Project Narrative Systemic Sclerosis (SSc) is a fibrotic autoimmune disease that results in fibrosis of the skin and multiple internal organs, and it currently lacks options of treatment. We have made significant impact understanding disease heterogeneity and the molecular mechanisms that underlie the pathology across end organs in SSc and have identified targets that can be used for the development of new therapeutics for this disease. A novel approach based on the development of a cellular immunotherapy is described in this proposal.