Research goal: to develop CaSR antagonists, calcilytics, as novel therapeutics for pulmonary diseases such as asthma, COPD and pulmonary fibrosis

Asthma remains incurable, a major and increasing cause of global suffering and premature death and affects 340 million people worldwide. Current standard asthma therapy is palliative and 5-10% of asthma sufferers do not respond to any treatment at all. What is needed is a new approach to asthma therapy which is safe, that targets the underlying cause of the disease and that prevents environmentally-induced asthma exacerbations. During asthma, the expression of certain polycations such as eosinophil cationic protein, major basic protein, spermine and spermidine) and of polyamines such as poly-L-arginine is increased. We have made the discovery that the CaSR is expressed in the airways, where activation of this receptor by polycations and polyamines drives airways hyperreactivity, bronchoconstriction and inflammation in allergic asthma (Figure 1). Excitingly, blocking the CaSR using calcilytics, we could prevent all of these effects (Yarova et al, 2015). Recently we have also shown that inhaled calcilytics suppress inflammation as well as the current standard-of-care, inhaled corticosteroids, but they also suppress airway hyperresponsiveness and remodelling while corticosteroids do not (Yarova et al, JPET 2020)(Figure 2).

Recently my laboratory has also made the discovery that the CaSR can also be activated by chemicals contained in cigarette smoke and car fumes, and by urban particulate matter (Mansfield et al, 2019)(Figure 3), strongly implicating the CaSR in the development of currently untreatable diseases such as COPD (smoker’s cough) and idiopathic pulmonary fibrosis (Wolffs et al, 2020).

Oral calcilytics were initially developed as an anti-osteoporosis drug. While they were safe and well-tolerated in patients, their development was terminated due to lack of efficacy for this indication. Our goal is repurpose existing calcilytics, delivered topically to the lung, as novel therapeutics to treat inflammatory lung disorders in people.  In addition, in collaboration with Prof Andrea Brancale (Cardiff School of Pharmacy), we are also developing entirely novel calcilytics with an optimal lung delivery profile for the treatment of lung disease.

Patent: WO2014049351 Calcium/cation-sensing receptor (casr) antagonist like nps89636 for use in treating inflammatory lung disorders (asthma or copd)

References:

• Yarova et al. Sci Trans Med 284, ra60, 2015 (doi: 10.1126/scitranslmed.aaa0282)
• Yarova et al., JPET 2020 (DOI: https://doi.org/10.1124/jpet.120.000281
• Mansfield et al.,Eur Resp J 2019; 54: Suppl. 63, PA2401
• Wolffs et al: https://www.medrxiv.org/content/10.1101/2020.03.12.20034751v1
• https://patents.google.com/patent/WO2014049351A1/en

Collaborators

National

• Profs A Brancale, K Broadley, B Hope-Gill, G Taylor, Drs EJ Kidd, WR Ford, B Kariuki, (Cardiff);
• Prof K Lewis (Swansea University and Respiratory Innovation Wales);
• Prof L Mur (Aberystwyth University);
• Profs CJ Corrigan, JPT Ward, C Page and C Hawrylowicz (King's College London)
• Prof D Thickett (Birmingham University)
• Dr DT Ward (Manchester University)

International

• Prof E Kallay, Dr M Schepelmann (Vienna University)
• Dr I Ellinger, R Ecker (TissueGnostics, Vienna)
• Dr W Chang (UCSF, USA)
• Prof G Gamba, Mexico City (UNAM)
• Prof YS Prakash and C Pabelick (Mayo Clinic, Rochester, USA)
• Dr M Ranieri, Prof G Valenti (University of Bari, Italy)
• Prof S Ying (CMU, China)

Work funded by

Asthma UK, King's Commercialisation Institute, The Live Sciences Research Network, Marie Curie ITN “Multifaceted CaSR” and Marie Curie ETN “CaSR Biomedicine", KESS2 studentship, the Saunders Legacy Research Fund

Active research grants

• Marie Curie ETN "Biomedicine"
• KESS2 studentship