Reducing the burden of COPD by targeting skeletal muscle mass and function. Targets and endpoints for drug development

Lead Research Organisation: Royal Brompton & Harefield NHS Fdn Trust
Department Name: Respiratory Medicine

Abstract

Chronic Obstructive Pulmonary disease (or emphysema and chronic bronchitis) is a family of lung diseases usually but not always caused by cigarette smoking. There is an urgent need to develop new drugs to treat this condition since existing therapies are insufficiently effective. Importantly in more advanced disease complications outside the lung become as important as the lung disease itself and in fact one of the most effective treatments, pulmonary rehabilitation (supervised exercise training) is thought to work in large part by improving the strength and function of the walking muscles; thus we believe a drug which could magnify or extend the benefit of this treatment would be every useful. Thus the aim of this work package is to bring together the groups interested this field in Great Britain with selected drug companies. Three stages of the WP are described. In the first we will assess what material is available and whether, by sharing, the consortium can achieve some ?quick wins? which will facilitate the development of drugs or ideas already known to the participants. In the second we will do some detailed studies which will relate actual rates of protein synthesis in the leg muscles to more readily accessible measures that can be obtained from blood or muscle since this will allow the latter measures to guide drug development more reliably. As part of this work we will also build the largest ever cohort of COPD patients from whom a muscle biopsy and clinical data are available. Lastly we will study patients around the time of rehabilitation (which improves muscle function) and acute exacerbation (which worsens it) to try to identify further targets for new drugs

Technical Summary

The overall aim of this work package is to gain new information regarding the aetiology underlying loss of skeletal muscle function, since this has a clinically relevant impact on morbidity, mortality and healthcare utilisation in Chronic Obstructive Pulmonary Disease (COPD). Key components of the program include (a) quick wins by screening material from available cohorts to assist with development decisions for available products and the development of regulatory endpoints relevant to the non-pulmonary effects of the disease, (b) direct measurement of protein synthesis using labelled amino acids and (c) extension of existing cohorts both when stable and at times of changing muscle bulk (after rehabilitation and exacerbation). Novel clinical features of the cohort will be the assessment of quadriceps strength, bulk, field test of walking performance and the obtaining of paired muscle and blood samples.

Signalling pathways to be evaluated by the consortium will include (i) Muscle cell phenotype (MHC gene expression and fibre-type, mitochondrial function, myogenic transcription factors, such as myf5, myoD, myogenin, SRF, MRTFA/B and MASTR, and mechano-sensitive regulators of transcription factor activity specifically FHL1 and FHL3 (ii) Anabolic and insulin signalling (Akt,mTOR, P70s6 kinase, 4EBP1, FOXO1, IRS-1, IRS-2 and phospho-IRS-2 and GLUT-1/GLUT-4 expression (iii) Myostatin signalling (myostatin and extracellular regulators of myostatin (follistatin, FLRG and GASP-1) by ELISA (iv)Protein degradation (MAFbx, cathepsin-L and PDK2 (mRNA by qPCR, total and phospho, protein by Western blotting), (v) metabolism; Muscle metabolites (ATP, PCr, glycogen, lactate by fluorescence), muscle pyruvate dehydrogenase complex activity pyruvate dehydrogenase kinase 2 and 4 mRNA and (vi) cellular markers of ageing. Importantly material will be made available to pharma who have offered to share the cost of these analyses as an ?in-kind contribution.

Within the workpacakge a responsive management style will allow movement of funds so that the consortium as a whole can focus its funds to obtain maximum productivity and will have a steering committee co-chaired by academia and pharma. Externally the WP will interdigitate with WP 1,2 & 3 for maximum ?added-value? and more widely with the PRO-active and COPD Foundation initiatives with the aim of supporting regulatory approval for outcomes relevant to antisarcopenic drugs
 
Description ATS/ARS statement on skeletal muscle dysfunction in COPD
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description COPD Foundation exercise CBQC
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Based on expertise gathered by this and other consortia, Professor Polkey is a representative on the COPD foundation CBQC working group seeking to qualify exercise as an FDA acceptable outcome
 
Description ERS taskforce on Nutrition in COPD
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description National Clinical COPD audit
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Pulmonary Rehabilitation Quality Standards
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact I co-chair the British Thoracic Society Quality Standards Committee with responsibility for drafting and agreeing the publication of the standards. These standards will provide guidance for commissioners and providers on improving quality in pulmonary rehabilitation provision
 
Description MRC NIRG
Amount £249,815 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2011 
End 09/2014
 
Description MRC/ARUK Centre for Musculoskeletal Ageing Research
Amount £2,000,000 (GBP)
Organisation Versus Arthritis 
Start 08/2017 
End 07/2022
 
Description Novartis affymetrix analysis 
Organisation Novartis Institutes for BioMedical Research (NIBR)
Country United States 
Sector Private 
PI Contribution Under the collaboration created by COPD MAP, Novartis agreed to undertake affymetrix analysis of archive specimens held by the universities of Leicester and Nottingham Exact cost unknown and commercially sensitive
Collaborator Contribution Leicester and Nottingham provided clinical data and biopsies
Impact paper in prepartaion
Start Year 2011
 
Description Stratified Exercise Interventions in Chronic Obstructive Pulmonary Disease: optimal delivery of exercise and anabolic therapies to meet individual health needs 
Organisation University of Leicester
Department Department of Physics & Astronomy
Country United Kingdom 
Sector Academic/University 
PI Contribution This was a collaborative application submitted by Prof Steiner but including many of the partners from COPD MAP; rejected by MRC
Collaborator Contribution Workup of proposal
Impact Plan is to use same core for an MRC Cohort application
Start Year 2016
 
Description TSB ERICA 
Organisation GlaxoSmithKline (GSK)
Department GlaxoSmithKline Medicines Research Centre
Country United Kingdom 
Sector Private 
PI Contribution Co PI on new grant award
Impact Project started October 2011. no tangible outcome at time of writing
Start Year 2011
 
Description affymatrix analysis of MATCH samples 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution COPD MAP provided clinical data and biopsies, from the Leicester site
Collaborator Contribution they have undertaken affymetric analysis
Impact paper in preparation
Start Year 2015
 
Description Cafe Scientifique 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact 30 members of the public attended a presentation which sparked questions and discussion afterwards

Good positive feedback and future events to be arranged
Year(s) Of Engagement Activity 2011