New and Superior Treatments

New therapeutic strategies for asthma and other airways diseases are urgently required. The current treatments for asthma provide effective symptomatic relief for most mild asthmatics, but the options available for those with moderate or severe asthma are, in most cases, inadequate. The mainstay for these patients is high dose corticosteroids, a relatively nonselective treatment associated with major side effects. Although there is scope for improvements to existing drugs, it is generally considered that the identification of new and selective therapeutic targets will be required to facilitate major improvements in treatment of asthma. Similarly, treatments for other airways diseases are equally inadequate and require the identification of new targets and new therapeutics. This is the largest program and is focussing on the identification and validation of targets for new therapeutics, and the development of immunotherapies for asthma and allergic disease. It comprises of five integrated sub-programs (research leaders, main participant organisations and user linkages are given in brackets):

Novel Asthma Drug Targets

	Professor Charles Mackay Garvan Institute

Target identification is only the first stage in the long-term process leading to the development of new drugs. The initial gene profiling and discovery program within the CRCAA has involved extensive use of Affymetrix microarray technology to probe the asthmatic inflammatory response. We believe we have one of the most extensive and diverse inflammatory microarray datasets worldwide (the “immune transcriptome”), and this resource will be of ongoing value for directing further gene discovery efforts. In the CRCAA, we will continue to mine the “immune transcriptome” to identify gene targets, and to validate a number of targets currently under investigation. A particular focus of the program will be utilisation of the immune transcriptome to direct the development of monoclonal antibody-based strategies for depletion of mast cells. The research program has validated two genes as asthma therapeutic targets, and as a priority these will be taken into commercial development, starting with discovery and testing of small molecule inhibitors. Patents have been taken out to protect our validated target genes. A number of other gene targets are currently being validated and we anticipate that several of these will also be brought into clinical/commercial development during the course of the CRCAA.

Drug Targets from New Animal Models

	Professor Paul Foster University of Newcastle

Current approaches to drug therapy and the identification of new therapeutic targets in the field of asthma and chronic obstructive pulmonary disease (COPD) have had limited success. New insights into pathogenesis of these life threatening respiratory diseases are urgently required in dynamic living systems. The aim of this research program is to utilize established and new models of asthma and COPD that accurately reflect the pathophysiology of the human condition, providing reliable predictive models for the dissection and identification of new therapeutic targets and approaches to treat disease. These models would also serve as the benchmark for the validation of new target molecules and therapeutic agents designed elsewhere in the CRCAA. We are developing unique models of defined aspects of asthma (acute exacerbations, chronic disease, occupational asthma, infection-induced asthma and cell mediated models) and COPD (tissue destruction of the peripheral airways) pathogenesis. We are profiling the molecular and cellular events that regulate the development and progression of disease in these models. By identifying the key pathogenic pathways in our models we will identify unique sets of genes, inflammatory molecules and proteins that will formulate a rational commercial approach to target discovery, validation and the formulation of novel therapeutic strategies to treat various aspects of disease. This knowledge will then be used in collaboration with our industry partners as a platform to advance the development of novel modalities to treat disease worldwide.

Genetics of Asthma

	Professor Phil Thompson University of Western Australia

Better understanding of the genetic determinants of disease and drug action will allow

a) better screening for risk with appropriate risk avoidance measures to follow,

b) better understanding of disease pathways and drug targeting and

c) better prescribing of medications to patients.

Our broad aims are

a) to develop new drug targets – both at the gene, gene regulation and protein level;

b) to define individuals at risk of developing different forms of asthma and differing severities of asthma by using genetic screening techniques and

c) to improve the way current and newly emerging drugs can be utilised using clinical genetic assessment.

The CRCAA has established a significant databank of 1,600 patients who have been carefully phenotyped with matched DNA and serum stored. Extensive knowledge of the genotyping of the arachidonic pathway has also been generated. We are looking more extensively at genes that may be relevant to drug responsiveness, airway remodelling and susceptibility to air pollutant airway damage.
A novel aspect of this work includes evaluating in detail splice variants of the arachidonic acid pathways and the potential for polymorphisms to be influencing their expression. This research program involves applying both traditional and novel genetic techniques to real clinical problems with the potential to lead to real changes in both our understanding and management of airways diseases.

Mechanisms of Airway Remodelling

	Professor Judy Black University of Sydney

The function of the lung is to allow oxygen from the air we breathe to diffuse into red blood cells to oxygenate the tissues and organs of the body, and to remove carbon dioxide (the waste product of respiration) which is expelled when we breathe out.  The way in which this process happens can be altered if the physical structure of the airways is altered.  In the asthmatic lung structural changes or remodelling occur, which makes the process of gas exchange more difficult.  These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix proteins), and an increased mass of bronchial smooth muscle cells. It is these muscle cells that cause the airways to narrow and make breathing difficult. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Today, the airway smooth muscle cell is regarded as an important cell which is responsible for the altered structure of the asthmatic airways.  Our group is only one of a handful of groups worldwide which is able to grow smooth muscle cells from asthmatic and non-asthmatic volunteers, and this valuable research tool has led to the discovery of  number of important differences between these two cell types.  We have discovered that a transcription factor (a small intracellular messenger molecule which controls the production of messenger RNA) known as C/EBP-alpha is missing in bronchial smooth muscle cells in people with asthma. The lack of C/EBP-alpha rendered the cells obtained from asthma patients less sensitive to the anti-proliferative effect of steroids, while the anti-inflammatory action of steroids was not affected. The lack of C/EBP-alpha may also help to explain the greater proliferation which is observed in smooth muscle cells from asthmatic volunteers.  We have also shown that the secretion of extracellular matrix proteins, and the enzymes which break down this matrix, is altered in cells from asthmatic volunteers leading to an increased deposition of extracellular matrix.  The smooth muscle cell is also actively involved in the regulation of the local inflammatory process.  We have shown that the release of anti-inflammatory factors is reduced and the release of pro-inflammatory factors is increased in smooth muscle cells from asthmatic volunteers.

In our studies with the CRCAA we will examine the intracellular mechanisms which control airway remodelling and inflammation in asthma, and clarify the role of the smooth muscle cell in these processes.  We will identify genes which are differentially regulated in the asthmatic airway in order to establish new therapeutic targets for the treatment of asthma.  One of the characteristics of the remodelling which takes place in the asthmatic lung is the formation of new blood vessels or angiogenesis.  As a part of our investigation into the mechanisms of airway remodelling we will look for the presence of factors which control angiogenesis.  From our preliminary studies we have identified that one of the extracellular matrix proteins which acts as an anti-angiogenic factor is missing from the lungs of subjects with asthma.  We will investigate both the reason why this factor is missing from the lungs of asthmatic subjects, and the potential effects that this absence may cause.  In order to show the relevance of any given gene in the progression and impaired respiratory function which is observed in the asthmatic airway, in collaboration with Prof Paul Foster’s group within the CRCAA, we will examine these processes in animal models of asthma. We will investigate the effect of existing and new anti-asthma drugs on the signalling mechanism(s) and on airway remodelling, and test new ways to deliver drugs. Finally we will analyse polymorphisms of the identified genes as a possible basis for asthma in a well characterised population of asthmatics in collaboration with Prof Phil Thompson’s group within the CRCAA.

Immunomodulation

	Professor Robyn O’Hehir Monash University

Allergen immunotherapy or “allergy shots” are suitable and effective treatments for some patients with asthma and hayfever. Commonly used drug treatments in allergy provide relief from symptoms but must be taken long term and some have side-effects. Allergy shots on the other hand are able to stop the long-term progress of the disease. Nevertheless the currently available commercial shots are generally not given to patients with asthma because there is a risk that the allergens shots will cause a more severe episode of symptoms. The immune system of the body has white blood cells that react with allergen and release substances (cytokines) that drive the symptoms of allergy. With effective allergy shots the body of an allergic person behaves like a non-allergic person and changes its pattern of cytokine production. Special white blood cells that dampen allergic responses are also increased with this type of treatment. Thus we are developing allergen preparations which enhance the safety and effectiveness of this type of therapy. Natural rubber latex allergy is a major cause of occupational asthma among latex glove users, associated with significant risk of asthma and severe allergic reactions and currently allergy shots are not available. In the CRCAA we are progressing new allergy shots for the treatment of latex allergy and for patients with hayfever due to grass pollen allergy. We are exploring safer and better ways of giving allergy shots to patients to avoid injections. New ways of identifying types of allergy and success of the shots are also being examined.