In Vivo Gene Transfer And Phenotype Correction Of Normal And Urea-cycle Deficient Primary Human Hepatocytes In Chimeric Mouse-human Livers: Towards Gene Therapy For Metabolic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$493,747.00
Summary
Genetic liver disease imposes a major health and economic burden. Existing medical treatments are frequently inadequate, often necessitating liver transplantation which carries its own limitations and risks. Using a gene therapy approach we have achieved life-long cure of mice with OTC-deficiency, a condition with a high risk of disability and death in affected infants. This application focuses on translating this success in mice through to human therapy.
Functional Restoration Of OTC Deficient Primary Human Hepatocytes In A Xenograft Model Using An AAV Vector Uniquely Configured For Impending Clinical Trial Use.
Funder
National Health and Medical Research Council
Funding Amount
$235,525.00
Summary
The aim of this project is to acquire preclinical data which will underpin an international gene therapy trial for severe ornithine transcarbamylase (OTC) deficiency, the most prevalent urea cycle defect in infants and children. In most severe cases, liver transplantation is required for long term survival. We, with colleagues at Stanford University, have recently developed a novel gene therapy tool for optimal targeting of human liver cells which will be tested in a humanised mouse model.
Repair Of Urea Cycle Defects In Mice By RAAV-mediated Gene Transfer: Towards Gene Therapy For Genetic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$445,578.00
Summary
Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the ....Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the development of improved AAV vectors with dramatically higher gene transfer efficiencies (up to two orders of magnitude in the liver). This places successful liver-directed gene therapy within reach. Initial human studies will only be possible in the context of severe diseases where existing therapies are high risk or inadequate. Accordingly, we have chosen the most common urea cycle defect, OTC deficiency, as a disease model. In its severe form neonatal hyperammonaemia is associated with a high risk of death and significant disability in those who survive the newborn period. Using the spf(ash) mouse model of OTC deficiency we propose to develop gene therapy strategies capable of achieving life-long disease cure. Preliminary data has confirmed feasibility, and suggests that the greater number of cells in the human liver requiring genetic repair will not prove insurmountable. The proposal focuses on issues critical to success in humans. These include strategies to minimise the number of repaired liver cells required for clinical benefit, overcoming the effects of liver growth, investigating the potential impact of OTC mutations on gene therapy, and establishing the likely efficiency of gene transfer in human liver cells and large animal livers equivalent in size to the human neonate. These studies are part of a long-term commitment to progress through to human clinical trials of gene therapy for urea cycle defects. The potential health and economic benefits are immense.Read moreRead less
Non-invasive Gene Delivery For Expression Of Therapeutic Genes In Oligodendrocytes: A New Strategy To Treat Myelin Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$594,393.00
Summary
White matter diseases are debilitating childhood disorders caused by defects in the insulating myelin sheath normally covering and protecting the nerve fibres from damage. There is currently no effective treatment but the delivery of a genetic medicine to the diseased myelin forming cells in the brain could be curative. This project aims at establishing the safe, efficient and non-invasive delivery of therapeutic genes to myelin forming cells as a gene therapy for white matter disorders.
Evaluation And Comparison Of Lentiviral And AAV Vector Mediated Gene Therapy For The Mucopolysaccharidoses
Funder
National Health and Medical Research Council
Funding Amount
$521,320.00
Summary
The mucopolysaccharidoses are a group of inherited diseases that have profound consequences for affected individuals. They have pleiotropic effects and usually result in premature death. Although intravenous enzyme replacement therapy has been developed for a number of these disorders, this approach to therapy is invasive, very expensive, of limited efficacy, and is completely ineffective in treating brain pathology. The principal reason for this is the protected nature of the brain which preven ....The mucopolysaccharidoses are a group of inherited diseases that have profound consequences for affected individuals. They have pleiotropic effects and usually result in premature death. Although intravenous enzyme replacement therapy has been developed for a number of these disorders, this approach to therapy is invasive, very expensive, of limited efficacy, and is completely ineffective in treating brain pathology. The principal reason for this is the protected nature of the brain which prevents enzymes that are administered intravenously from entering. Therefore, alternative therapies must be considered in order to provide more effective therapy for the mucopolysaccharidoses, especially those that have significant brain pathology. Gene therapy is one such alternative therapy but this still faces the problem of introducing the therapeutic agent (in this case the gene encoding the requisite enzyme) into the brain. This project aims to provide a comparitive evaluation of two gene therapy vectors for their efficacy in treating all aspects of the pathology found in the mucopolysaccharidoses. Both vectors have the properties of being able to efficiently deliver genes to different cell types and result in the stable genetic modification of the target cell, making them ideal for long-term treatment. However, for effective gene therapy, significant and widely distributed gene delivery to the brain, as well as to other tissues, will be required. This project aims to compare the efficacy of these vectors in two different animal models of the mucopolysaccharidoses that exhibit a wide range of the clinical problems associated with these diseases, importantly including brain pathology.Read moreRead less