Chronic respiratory disease: towards better treatments

Alaina J. Ammit PhD

Alaina.Ammit@uts.edu.au

Professor of Respiratory Pharmacology, UTS Director, Woolcock Emphysema Centre, Woolcock Institute of Medical Research

Chronic respiratory disease • Asthma

– 1 in 10 Australians have asthma – More common in males aged 0–14, but among those aged 15

and over, asthma is more common in females • Chronic Obstructive Pulmonary Disease (COPD)

– In Australia, COPD ranks third behind ischaemic heart disease and stroke as a major cause of disability and early death

– 1 in 7 Australians over the age of 40 are affected by COPD – By 2020, COPD is projected to become the third most important

chronic illness in the world Asthma Australia; Australian Institute of Health and Welfare

Asthma and airway remodelling • Acute asthma – bronchoconstriction and difficulty

breathing • Asthma is a chronic inflammatory condition of the lung

associated with structural remodelling, or thickening, of the airway wall – Mucus hypersecretion – Neovascularization – Airway fibrosis – Increased airway smooth muscle mass

Asthmatic airway Non-asthmatic airway

COPD • Chronic inflammatory disease characterised by progressive lung

function decline • Main symptoms are breathlessness, cough and sputum production • Major public health problem worldwide • Globally, the burden of COPD is projected to increase due to

continued exposure to COPD risk factors: – tobacco smoke, outdoor air pollution and indoor noxious particles and gases

from cooking and heating fires

• Prevalence, morbidity and mortality of COPD are increasing in many westernised countries and cigarette smoking is the main cause

Chronic inflammation in the lungs of people with COPD drives damage and long-term decline in lung function (breathlessness). Current COPD medications don’t slow the accelerated rate of decline

COPD: lung function decline

But wait… don’t we have drugs for that already?

Target molecular mechanisms to treat chronic respiratory diseases

YES

GOAL

BUT… they are not always effective…

• Anti-inflammatory corticosteroids and bronchodilatory β2-agonists are first line therapy

• Although these medicines have proven clinical efficacy, many respiratory conditions are not responsive: – severe asthma, COPD, infectious exacerbation

• We urgently require improved and novel ways to treat chronic respiratory disease when current medicines are ineffective

• Need greater understanding of molecular mechanisms • This is what my research team does...

What are the current issues limiting treatment today? β2-adrenergic receptor desensitization

>5 recent publications in the top respiratory journals (in collaboration with Brian Oliver)

What are the current issues limiting treatment today? Cannot repress inflammation in severe asthma and COPD

Current project as an example of our capabilities for potential funding and collaboration with industry partners

Harness the power of endogenous anti-inflammatory proteins in COPD

TTP (tristetraprolin) A molecular switch

IL-6, IL-8, IL-2, GM-CSF, GRO-α, TNFα

TTP Tristetraprolin (TTP), a destabilising RNA binding protein,

is a critical anti-inflammatory protein that induces the decay of mRNAs encoding several cytokines, including those that drive

COPD pathogenesis

Inflammation in COPD TTP is a molecular switch and is likely turned off

under respiratory disease conditions

TTP

GOAL Switch TTP on to turn off inflammatory in COPD

HOW?

We can switch TTP on by activating PP2A

We can repress inflammation when current medicines (corticosteroids) cannot

Target inflammatory mechanisms to treat inflammation and reduce lung function

decline in COPD

GOAL

The development of novel

pharmacotherapeutic anti-inflammatory

strategies

more effectively ^

PP2A activators