VLA-4 inhibition for treatment of Scleroderma

Systemic sclerosis (Scleroderma) is a multisystem, autoimmune disorder defined by progressive vascular, inflammatory, and fibrotic dysfunction. It is characterised by an early inflammatory phase, which is followed by progressive fibrosis of varying extent and distribution, resulting in severe dysfunction of involved organs. Interaction of vascular cell adhesion molecule 1 (VCAM-1) with its ligand, very late antigen 4 (VLA-4), is a key process in inflammatory disease. There is an established genetic and clinical link for VCAM-1 in Scleroderma, with VCAM-1 having a genome-wide association with Scleroderma, and Scleroderma patients having elevated VCAM-1 serum levels. VLA-4, an α1β4 integrin, plays a pivotal role in controlling immune cell migration into inflamed tissue as it directly participates in cell arrest under flow. The VCAM-1:VLA-4 interaction therefore makes an attractive target for therapeutic intervention in Scleroderma. A lead series of small molecule inhibitors has been developed to disrupt the VCAM-1:VLA-4 interaction. Proof of concept has been demonstrated with VLA-4 inhibition in the Tsk1/+ mouse model of Scleroderma. Further preclinical assessment is underway for the selection of a lead compound for entry into the clinic in 2023.