Hunting gremlins: GREM1 as a new therapeutic target for multiple diseases including glaucoma

The transforming growth factor-β (TGF-β) superfamily of signaling molecules is involved in normal development and homeostasis. However, aberrant signaling among members of the TGF-β superfamily plays an important pathogenic role in numerous diseases. Increased expression of the pleiotropic cytokine and growth factor TGF-β leads to aberrant signaling associated with numerous diseases, including fibrosis of multiple tissues, a wide variety of cancers, obesity and diabetes, and glaucoma, among others. Normally, the profibrotic effects of TGF-β are regulated by concurrent signaling through bone morphogenetic proteins (BMPs). Unfortunately, many disease states exhibit increased expression of the BMP antagonist Gremlin-1 (GREM1), which suppresses this protective effect of BMPs. Targeting TGF-β is challenging as a therapeutic target because TGF-β is still needed for basal signaling required for normal tissue/cell functions. GREM1 is a more attractive therapeutic target because its expression in most tissues is limited after development. However, targeting GREM1 has been very challenging and long considered an "undruggable" target. Fortunately, several new approaches, including the discovery of GREM1-directed aptamers, proteolysis targeting chimera small molecules, and neutralizing antibodies, as well as the design of protein-protein interaction inhibitors, are being explored to directly target and inhibit GREM1 pathogenic functions and activities, thereby restoring homeostasis. SIGNIFICANCE STATEMENT: Gremlin-1 (GREM1) is a secreted bone morphogenetic protein antagonist re-expressed in numerous diseases fibrosis, glaucoma, and cancer. Once deemed "undruggable," GREM1 has recently become a validated therapeutic target, exemplified by the current clinical development of GREM1-neutralizing antibodies. Additional experimental strategies represent promising, although still preclinical, approaches to suppress GREM1 activity or enhance its degradation, offering new avenues to restore transforming growth factor-β/bone morphogenetic protein signaling balance in disease.