Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less
Agonists And Antagonists Of The Human Complement C3a Receptor
Funder
National Health and Medical Research Council
Funding Amount
$473,250.00
Summary
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. One of the most important complement proteins is known as C3a. It is called an anaphyla ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. One of the most important complement proteins is known as C3a. It is called an anaphylatoxin and is thought to be a pivotal component of the complement system synthesized by the human body early on in the development of inflammatory and immune diseases. New compounds that could stimulate or block the activity of C3a are expected : (a) To lead us to a better understanding of how C3a binds to its receptors on immune cells and its role in the immune response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available. It is not yet possible to examine detailed structures of the receptors on cells that interact with complement proteins. However it is possible to determine and analyse three dimensional structures of small molecules that can bind to human immune cells, and mimic or block effects of human C3a on cells, rat tissues, and in whole rats. We will identify and improve such small molecules by optimising their binding to immune cells, by tailoring them to selectively block or mimic just the effects of C3a, and by making them pharmacologically stable for administration (preferably by mouth) to rats (and humans). We will then test them in rats for potential future development into a completely new type of anti-inflammatory drug, one that treats inflammatory disease processes rather than just the symptoms like most current antiinflammatory drugs.Read moreRead less
Complement C5a Receptors , Placental Inflammation And Reproductive Impairment.
Funder
National Health and Medical Research Council
Funding Amount
$1,025,229.00
Summary
We are investigating how mothers may have health difficulties during pregnancy, such as high blood pressure, and how this can affect their fetuses' health. There is emerging evidence that an unhealthy placenta during pregnancy can greatly affect fetal development, and it seems that inflammation in the placenta during pregnancy may be a key factor in reducing fetal growth, resulting in low birth weight infants. Our studies are aimed at developing new treatments for this.
The Therapeutic Role Of Complement Inhibition In ANCA Associated Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$600,964.00
Summary
ANCA associated vasculitis is an inflammatory disease involving the kidney filters which is a major cause of chronic kidney failure. Current drugs to treat it are toxic. Less toxic treatments are required. In this study we will explore the potential for new treatments targeting complement (a normal blood protein involved in inflammation) to attenuate this disease in mice. We hope to define the role of complement in this disease and the benefits of inhibiting it before we use it in humans.
Contribution Of Complement C5a To Neuronal Cell Death During Ischemic Stroke
Funder
National Health and Medical Research Council
Funding Amount
$455,263.00
Summary
Ischemic stroke remains the second leading cause of death in Australia. This project aims to understand the role the innate immune system plays in neuronal cell death following ischemic stroke. We will use cellular and animal models of ischemic stroke, as well as examine patients affected by stroke, to explore and inhibit potential damaging immune factors generated by stroke tissue. By exploring these immune pathways, we aim to identify novel therapeutic targets to treat ischemic stroke.
Targeting Neuroinflammatory Pathways As Novel Treatments For Dementia
Funder
National Health and Medical Research Council
Funding Amount
$600,116.00
Summary
Australia has a rapid increase in its ageing population, and consequently an increase in detrimental age-related dementia and neurodegenerative diseases which are a major healthcare burden. Current treatments for diseases such as Alzheimer’s, Parkinson’s and Huntington’s are inadequate and there is a desperate need for new treatments. I have unique access to molecules that target two novel mechanisms for neurodegenerative diseases. This fellowship will explore their therapeutic potential.
Therapeutic Targeting Of Complement C5a Receptors In HuntingtonÍs Disease
Funder
National Health and Medical Research Council
Funding Amount
$468,312.00
Summary
HuntingtonÍs disease is a genetic neurodegenerative condition leading to progressive cognitive and motor deficits and eventual death. This research aims to explore the role of immune and inflammatory pathways in the progression of disease in patients suffering HuntingtonÍs disease, as well as in an animal model of this condition. By exploring these immune and inflammatory pathways, we aim to identify novel therapeutic targets to treat HuntingtonÍs disease.
Preclinical Development Of A Humanised Antibody To C5aR.
Funder
National Health and Medical Research Council
Funding Amount
$124,875.00
Summary
Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) ....Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models of inflammation (rheumatoid arthritis, sepsis and colitis) to determine the efficacy of the antibody, safety, the most effective dose, timing and route of administration. These studies are a necessary prelude to human clinical trials, which we hope to perform in approximately 24 months.Read moreRead less