Correction And Measurement Of The Basic Defects In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$929,335.00
Summary
Airway disease caused by the genetic disease cystic fibrosis (CF) cannot currently be prevented or cured. Current treatments (other than lung transplant) can only slow the inevitable decline in lung health. Early death from lung failure occurs for many with CF. We have developed a gene transfer technique to introduce the corrective gene (CFTR) into CF-diseased airway cells. We have used airways in mice to test and develop this method, to determine if long-lasting genetic correction of the airway ....Airway disease caused by the genetic disease cystic fibrosis (CF) cannot currently be prevented or cured. Current treatments (other than lung transplant) can only slow the inevitable decline in lung health. Early death from lung failure occurs for many with CF. We have developed a gene transfer technique to introduce the corrective gene (CFTR) into CF-diseased airway cells. We have used airways in mice to test and develop this method, to determine if long-lasting genetic correction of the airway cells can be achieved. The gene is introduced into the airway as a single small dose of special delivery-particles (vector) that have been built using highly-modified components of the HIV-1 virus. If ultimately successful in humans with CF, the disease should be halted, or even cured. Our recent work indicates that we have been able to insert the gene into airway progenitor cells, confirming our hypothesis that long-lasting gene expression can be achieved this way. To know if the method would be safe and effective in humans, we must now test the technique in sheep (as a human-size lung) and in marmosets (as a human-like lung) before clinical trials could be considered. We will monitor animals for up to 3 years to be sure the effect of the gene is truly long-lasting, and we will document how the gene-transfer vector disappears from the body. We have also discovered a new way to examine the detail of the very thin fluid layer on the airway surface. This fluid is too shallow in CF airway (allowing bacteria to stick and start disease) and so a successful gene therapy should return the fluid to it's proper depth. This method uses X-ray light from a synchrotron, and we expect it will work without the need to sacrifice animals to measure the airway surface. If successful it also has potential to be used much like a normal X-ray in humans with CF, to test if a gene therapy has worked.Read moreRead less
Cell-targeted Gene Delivery Into Human Haematopoietic Stem Cells For The Treatment Of Thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$171,208.00
Summary
Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various ot ....Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various other abnormalities of haemoglobin synthesis. If untreated, most thalassaemia patients will die within the first few years of life. The vast majority of thalassaemia patients depend on regular blood transfusions every two to three weeks, and on nightly infusions of an iron chelator (a drug for removing excess iron from the blood). These procedures place considerable burden on thalassaemia patients, their families and society, and expose them to blood transmitted infections. The only curative treatment for thalassaemia is bone marrow transplantation from a matching donor. However, the vast majority of patients do not have matching donors and thus the only prospect for them to receive such therapy is to replace in their bone marrow cells a copy of the normal set of genes for the synthesis of haemoglobin. The studies in this proposal are therefore designed to test gene therapy protocols on bone marrow stem cells derived from thalassaemia patients. A normal set of globin genes will be delivered to the bone marrow stem cells via non-viral delivery systems and examined for function in an immunodeficient mouse strain that can accept human bone marrow. This research may enable bone marrow transplantation to be applied for the therapy of most patients with thalassaemia, while it may also have a major impact on therapeutic approaches for other haematological anomalies.Read moreRead less
SiRNA Induced TGS Of Retroviruses: Elucidation Of Underlying Mechanisms And Their Application In Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$371,502.00
Summary
AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechani ....AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechanisms underlying this effect. BACKGROUND These RNA molecules can suppress a range of pathogenic human viruses including HIV-1 in the test tube. Our novel approach appears to induce changes that are long lasting and are less susceptible to mutations by the virus that allow it to become resistant to other therapeutic strategies. RESEARCH PLAN Initially more work will be done in tissue culture to determine the optimal design of these molecules and the best way to administer them. The most promising of these designs will be tested in small groups of infected animals as a preliminary demonstration of efficacy. In parallel experiments will be performed to elucidate the mechanisms undelying the suppressive effects of these molecules. OUTCOMES AND SIGNIFICANCE This work will lead to a significant increase in our understanding of the way replication of HIV is regulated and will develop a promising new therapeutic strategy for this virus that may be applicable to other conditions.Read moreRead less
Site-specific Integration Of Functional Genomic Loci: Applications In Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$442,664.00
Summary
Gene therapy strategies have traditionally focused on the delivery of therapeutic genes by viral vectors. Mindful of the limitations and potential problems of viral gene delivery, non-specific viral integration and limited transgene expression, this investigation will explore the delivery and site-specific integration of large genomic fragments into human stem cells. It is anticipated this approach will avoid some of the problems associated with poor gene expression and insertional oncogenesis.
Molecular Markers Of The Progression Of Intestinal Metaplasia To Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$556,618.00
Summary
Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characteri ....Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characterised by genetic events that are largely unknown and occur over a period that can take years. It is also evident, especially in countries where GC is not as prevalent, that only a proportion of individuals will eventually develop GC. The long latency from the develpoment of IM and diagnosis of GC offers an opportunity to intervene and study the changes that lead to GC as well as find genes that may predict which individuals will progress. IM is the stage in which intervention is obvious. It is very easily diagnosed, is present for a long time and, for certain individuals, will eventually accumulate enough genetic events that will mandate progression to GC. Targeted screening of these individuals will enable a feasible strategy to find early GC, and avoid costly non-targeted screening. This proposal seeks to find key genetic events responsible for the transition of IM to GC. The first step utilises Affymetrix arrays to detect genes expressed in IM and specifically linked to GC. These candidates will be validated and used to study their role in the progression to GC using a mouse model of GC. This study is designed to find genes responsible for GC that can be used as: 1) a marker of progression in humans that will be used as a tool to stratify individuals into a screening protocol; 2) candidates to be tested in animal studies to study the pathogenesis of GC and potentially used as preventative or therapeutic targets.Read moreRead less
Inherited Muscle Disorders - Gene Discovery, Pathobiology And Therapy.
Funder
National Health and Medical Research Council
Funding Amount
$1,750,277.00
Summary
The project proposed by Professors Nigel Laing and Kathryn North and Dr Kristen Nowak is based upon the results of their successful identification of disease genes for genetic muscle diseases. The project is divided into three parts. In the first part of the project, the research team will identify further novel disease genes, some of which they are already close to finding. In the second part of the project the team will determine how the mutations they have identified in the disease genes actu ....The project proposed by Professors Nigel Laing and Kathryn North and Dr Kristen Nowak is based upon the results of their successful identification of disease genes for genetic muscle diseases. The project is divided into three parts. In the first part of the project, the research team will identify further novel disease genes, some of which they are already close to finding. In the second part of the project the team will determine how the mutations they have identified in the disease genes actually cause the diseases. The aim of this work is to discover targets that may ultimately lead to new therapies for these muscle diseases. In the third and final part of the project, the team will pursue one possible therapeutic approach, which is based upon the understanding of the diseases the researchers have gained from their previous studies. There are currently no cures for these muscle diseases, though symptoms can be treated. The team will determine whether heart actin can replace muscle actin in skeletal muscle and thus might treat the muscle disease.Read moreRead less
Manipulating Cardiac-selective PI3K Targets To Reverse Heart Failure Progression
Funder
National Health and Medical Research Council
Funding Amount
$532,921.00
Summary
Heart failure is a major clinical problem which is becoming worse as our population ages. New therapeutic strategies with the capability of improving function of the failing heart are greatly needed. We have identified novel targets of a gene with protective properties in the heart. This proposal will examine whether these new targets can reverse heart failure progression. Technologies that target these genes may lead to innovative pharmacotherapies in the clinical management of heart failure.
GENETIC MANIPULATION OF TUMOURS TO INDUCE IMMUNE REJECTION
Funder
National Health and Medical Research Council
Funding Amount
$396,342.00
Summary
The ability to be able to modify tumour growth and bring about tumour rejection by activating the host immune system is a prime objective in many laboratories throughout the world. Our aim is to take advantage of the considerable advances in molecular technology of recent years to develop effective approaches to the modification of tumour cells so that their growth can be inhibited in vivo. The project has three main aims: (i) to identify combinations of genes which, when administered to or expr ....The ability to be able to modify tumour growth and bring about tumour rejection by activating the host immune system is a prime objective in many laboratories throughout the world. Our aim is to take advantage of the considerable advances in molecular technology of recent years to develop effective approaches to the modification of tumour cells so that their growth can be inhibited in vivo. The project has three main aims: (i) to identify combinations of genes which, when administered to or expressed in tumour cells will induce protective immune responses against the tumour (ii) to investigate the effectiveness of combination approaches to gene therapy whereby genetic manipulations which cause destruction of tumour cells, or inhibition of blood vessel growth in tumours can be combined with administration of immunologically relevant genes to enhance tumour destruction (iii) to identify molecules which can act as target tumour antigens for the immune response or which are involved in promoting tumour survival so that these genes may be manipulated to enhance the development of anti-tumour immunity. The model we will use to investigate these issues will be malignant mesothelioma (MM). This tumour type is currently untreatable and is resistant to all available forms of therapy. Achievement of the aims described above would lead to the capacity for early treatment of MM. The identification of suitable target antigens has the potential to lead to vaccination protocols for therapy or as a preventative measure. Furthermore, the principles defined in this project will be applicable to the treatment of a variety of other solid tumours which are currently resistant to conventional therapy.Read moreRead less