Idiopathic pulmonary fibrosis (IPF) is a rare and poorly understood lung condition that causes scarring of the lungs. IPF gets worse over time and is often fatal. Symptoms include shortness of breath (even from performing day-to-day activities), which gets worse over time and persistent dry cough.
The disease appears to involve damage to the cells that line the tiny air sacs in the lungs (‘alveoli’) which causes them to die. The underlying causes of this damage is not understood (‘idiopathic’) but is likely to include both genetic and environmental factors such as cigarette smoking. The body tries to repair the damage by releasing another type of cell known as fibroblasts, but the production of the fibroblasts goes out of control and they cause scarring and hardening (fibrosis) of the delicate tissues of the lungs. As this scarring gets worse, the lungs find it more difficult to work properly, compromising the uptake of oxygen from the lungs into the blood, resulting in the symptoms of IPF.
The diagram below shows how fibrosis due to IPF affects the air sacs in your lungs:
The incidence of IPF is thought to be increasing, with evidence showing that incidence more than doubled between 1990 and 2003, even when taking into account ageing and improved diagnosis1. It is estimated that more than 5,000 patients are diagnosed with IPF every year in the UK2. In the US there are approximately 100,000 people with IPF, with 30,000 to 40,000 new cases diagnosed each year3. IPF primarily effects people over the age of 50, with six out of ten new cases being diagnosed in men. The number of people with the disease is expected to grow due to our ageing population.
The median survival time for people diagnosed with IPF is approximately 3 years (worse than many cancers, as shown in the chart below) from the point of diagnosis, however survival time varies from person to person, with approximately 20%-40% of patients surviving for more than 5 years.
5 year survival rates (%) comparing IPF to cancer4
There is currently no cure for IPF so the aim of treatment is to try to relieve symptoms and slow its progression. Patients may be treated with supplemental oxygen or pulmonary rehabilitation (exercise classes aimed at improving the uptake and use of oxygen in the body). In terms of drug treatment two products have been licensed for the treatment of IPF:
- Pirfenidone, whose mechanism is not fully understood, is licensed in Europe and the US.
- Nintedanib, which targets biological pathways linked to fibrosis, is licensed in the US and Europe.
There is still a need for new therapies above and beyond pirfenidone and nintedanib because many patients still suffer a loss of lung function over time, despite the benefits of these therapies.
LOXL2 as a target in IPF
Inhibition of Lysyl Oxidase-like protein 2 (LOXL2) is an attractive target in treatment of IPF.
Scar tissue is made up of collagen fibres, which are produced by a type of cell called a fibroblast. LOXL2 is an enzyme released from fibroblasts that links collagen fibres together to stiffen scar tissue. Excessive production and linking of collagen fibres results in fibrosis. LOXL2 levels are increased in the lungs of patients with IPF5, and higher levels are associated with more rapid disease progression6
- Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. J Gribbin, RB Hubbard, I Le Jeune, CJP Smith, J West, LJ Tata. Thorax 2006;61:980–985
- The rising incidence of idiopathic pulmonary fibrosis in the UK. V Navaratnam, KM Fleming, J West, CJP Smith, RG Jenkins, A Fogarty, RB Hubbard. Thorax 2011;66:462-467
- United States National Library of Medicine website (http://ghr.nlm.nih.gov/condition/idiopathic-pulmonary-fibrosis. Accessed 31 July 2015)
- Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. C Vancheri, M Failla, N Crimi and G Raghu. Eur Respir J 2010; 35: 496-504
- Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment. V Barry-Hamilton, R Spangler, D Marshall, S McCauley, HM Rodriguez, M Oyasu, A Mikels, M Vaysberg, H Ghermazien, C Wai, CA Garcia, AC Velayo, B Jorgensen, D Biermann, D Tsai, J Green, S Zaffryar-Eilot, A Holzer, S Ogg, D Thai, G Neufeld, P Van Vlasselaer & V Smith. Nature Medicine 2010; 16, 9: 1009-1018
- Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. JW Chien, TJ Richards, KF Gibson, Y Zhang, KO Lindell, L Shao, SK Lyman, JI. Adamkewicz, V Smith, N Kaminski, and T O’Riordan. Eur Respir J 2014; 43: 1430–1438