Analysis And Manipulation Of The Genome-wide Integration Signatures Of Gamma-retroviral And Lentiviral Vectors In Human Haematopoietic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$612,154.00
Summary
Gene therapy has been successful in treating several diseases involving the bone marrow, but has been associated with the development of leukaemia in a number of patients. The cause has been tracked to the gene transfer technology used and associated damage to the genetic blueprint of treated cells. In this study we plan to use high-throughput genetic analysis to better understand the nature of this damage and to develop strategies to improve the safety of the gene repair process.
Improving The Safety Characteristics Of Lentiviral Vectors.
Funder
National Health and Medical Research Council
Funding Amount
$296,250.00
Summary
Gene therapy holds great promise for the treatment of many types of disease including inherited disorders, cancer and cardiovascular disorders. However, the potential of gene therapy has in many cases been limited by the lack of suitable technologies for gene delivery. We have developed a novel gene delivery vehicle from human immunodeficiency virus type 1 (HIV-1). Although this vehicle has many of the characteristics desired of a gene therapy vector its derivation from a retrovirus, particularl ....Gene therapy holds great promise for the treatment of many types of disease including inherited disorders, cancer and cardiovascular disorders. However, the potential of gene therapy has in many cases been limited by the lack of suitable technologies for gene delivery. We have developed a novel gene delivery vehicle from human immunodeficiency virus type 1 (HIV-1). Although this vehicle has many of the characteristics desired of a gene therapy vector its derivation from a retrovirus, particularly one with such an unenviable reputation, raises obvious safety concerns. In order to properly address this issue it is necessary that the vector is carefully designed and properly tested. This project aims to continue our rational, systematic and stepwise approach to the development of our vector with the aim of producing a vector that can be used with a high degree of confidence in its safety, such that it is suitable for clinical usage. Given the highly desirable properties of these vectors, and the wide range of diseases where their use is being considered, the availability of such a vector will have great significance for the widespread practical application of gene therapy. Indeed, several of the projects we are developing with our vector will in all likelihood lead to lead to clinical trials and it is clear that the conduct of these trials will depend on the availability of a suitable vector.Read moreRead less
Correction Of Diabetes In An Autoimmune Model Using Insulin-secreting Liver Cells.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology ....Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology is to deliver the insulin gene directly to a patient's own liver cells which would regulate insulin secretion in response to glucose and other substances that stimulate insulin secretion, controlling blood glucose without the need for immunosuppression. To accomplish this it must be possible to deliver the insulin gene efficiently to primary liver cells (cells derived from an animal's or human's body). Results from our laboratory using a non-pathogenic viral delivery system indicate that we can reverse diabetes in chemically induced diabetic rats by expression of insulin and a beta cell transcription factor NeuroD. The aim of this study is to repeat this in an auto-immune model of diabetes the nonobese diabetic mouse, which mimicks very closely the development of diabetes in humans. We will determine if we can reverse diabetes in these animals and determine if their response to glucose is normal over an extended period of time, with no attack by the factors of the immune system that stimulate the development of diabetes in man. The results from this research proposal should result in the delivery of the insulin gene to large numbers of primary liver cells that will then synthesise, store and secrete insulin in response to glucose. These cells would control blood glucose levels in patients without the need for immunosuppression.Read moreRead less
Transgenic Expression Of The EWS-WT1 Fusion Protein,inducing The Development Of Tumour That Replicates The Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$112,976.00
Summary
A genetic translocation encoding the EWS-WT1 fusion protein is found desmoplastic small round cell tumours. Our aim is to examine the effect of this protein in inducing tumour growth in tissue cell lines. A virus will then be used to introduce the genetic translocation into mice to examine the effect of this protein on tumour growth in a mammal, thereby serving as a 'solid tumour model' to try and identify therapeutic targets.
Development Of Contemporary Surveillance And Control Methodologies For Dengue And Other Mosquito-borne Viral Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$512,290.00
Summary
This research proposal will address the need for better surveillance and control methodologies for mosquito-borne viral diseases and their vectors, including dengue and its global mosquito vector, Ae. aegypti, and a range of other important arboviral diseases throughout Australia. Research will focus in three areas: surveillance and control of Ross River and Barmah Forest viruses; development of contemporary risk management frameworks for dengue; and innovative investigations of insect age to pr ....This research proposal will address the need for better surveillance and control methodologies for mosquito-borne viral diseases and their vectors, including dengue and its global mosquito vector, Ae. aegypti, and a range of other important arboviral diseases throughout Australia. Research will focus in three areas: surveillance and control of Ross River and Barmah Forest viruses; development of contemporary risk management frameworks for dengue; and innovative investigations of insect age to provide evidence based monitoring and novel approaches to arbovirus disease prevention.Read moreRead less
Harnessing RNA Interference In Gene Therapy Vectors For ?-thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$719,188.00
Summary
There is an urgent need to develop safe and effective treatments for ?-thalassaemia. We anticipate that ?-globin-specific RNAi sequences will synergise with ?-globin transgene expression to achieve balanced ?-/?-globin ratio in a clinical setting. Given that one of the major issues with current gene therapy vectors is achieving high levels of expression, we believe this will be a more effective gene therapy strategy than ?-globin transgene expression alone.
The Brain As A Therapeutic Target For Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$923,432.00
Summary
In heart failure there is a large increase in sympathetic nerve activity to the heart that leads to damage to the heart and sudden death. We have shown that lesion of the area postrema, a brain nucleus that senses hormones in the blood, reduces nerve activity to the heart and, importantly, improves cardiac function. We aim to translate these findings into a treatment that can be used clinically, which our findings compellingly indicate should improve cardiac function in heart failure