A Disease-Modifying Protein Therapeutic for the Treatment of COPD

Project Summary Abstract COPD is projected to become the third most common cause of death worldwideand we currently lack any medical therapies that significantly alter the course of this diseaseOur recent work identifies ADAMa disintegin and metalloproteinase domainas the first proteinase that promotes the three key COPD pulmonary pathologiesemphysemasmall airway fibrosisand airway mucus cell metaplasiain cigarette smoke exposed miceMoreoverADAMexpression is robustly increased in lung epithelial cells and macrophages in the lungs of COPD patientseven in early stage diseaseAdditionallyAdammediates its activitiesin partby increasing lung inflammationdegrading lung elastinand shedding epidermal growth factor receptorEGFRand vascular endothelial growth factor receptorVEGFRto reduce the survival of alveolar septal cellsand increase the number of activated small airway myofibroblastsWe have developed a protein therapeutic based on a domain of ADAMthat specifically targets this enzymeandapos s activity to reduce shedding of a number of substrates for ADAMWe have promising results using this protein in mice acutely exposed to smokeIn Aimwe will establish the pharmacokineticsmaximum tolerated dose and dosing regimen for use in the efficacy studyAimwill focus on performing a proof of concept six month cigarette smoke exposure experiment that will serve to demonstrate satisfactory efficacy of our inhibitorSuccessful completion of the aims will advance this protein therapeutic towards the clinic as the first disease modifying therapy for COPDwith potential to slow the progression of key COPD phenotypes associated with lung function impairmentmorbidity and mortality Narrative Overmillion people have chronic obstructive pulmonary diseaseCOPDand it is projected to become the third most common cause of death word wide byWe have developed a potentially disease modifying therapeutic agent to treat COPDIt is expected to reduce inflammationsmall airway fibrosis and mucus cell metaplasia in a safe and effective manner