Targeting TGFβ superfamily ligand accessory proteins as novel therapeutics for chronic lung disorders.
Dysregulation of the transforming growth factor β (TGFβ) pathway has been implicated to underlie a number of disease indications including chronic lung disorders such as asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonias, and pulmonary arterial hypertension (PAH). Consequently, the pharmaceutical industry has devoted significant resources in the pursuit of TGFβ pathway inhibitors that target the cognate type I and II receptors and respective ligands. The progress of these approaches has been painfully slow, due in part to dose-limiting safety issues that result from the antagonism of a pathway that is responsible for regulating many fundamental biological processes including immune surveillance and cardiovascular responses. These disappointments have led many in the field to conclude that modulating the TGFβ pathway for chronic indications with a sufficient safety window using conventional approaches may be extremely difficult to achieve. Here we review the rationale and limitations of the use of TGFβ pathway inhibitors in chronic lung disorders and the possibility of targeting TGFβ superfamily ligand accessory proteins to allow rheostatic regulation of signaling to achieve efficacy while maintaining a sufficient therapeutic index.
Respiratory Drug Discovery, Inflammation, Hoffmann-La Roche Inc., Nutley, NJ, USA. david.budd@roche.com
David C
DC
Budd
Alan M
AM
Holmes
D000818:Animals; D002908:Chronic Disease; D055513:Connective Tissue Growth Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D008171:Lung Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D018125:Receptors, Transforming Growth Factor beta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D055411:TGF-beta Superfamily Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology
C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D055411:TGF-beta Superfamily Proteins; D055513:Connective Tissue Growth Factor