Treatment Of Genetic Liver Disease By Homologous Recombination In Vivo, Coupled With A Pharmoco-genetic Strategy For Selective Expansion Of Genetically Repaired Hepatocytes
Funder
National Health and Medical Research Council
Funding Amount
$920,836.00
Summary
This project seeks to exploit recent advancements in our ability to precisely “edit” and correct mutations underlying human genetic diseases. To improve therapeutic efficiencies of the system, we will deliver the technology using highly efficient virus-based systems and apply a novel post-repair selection process to preferentially repopulate the liver with gene-repaired cells. Demonstration of the strategy in a humanised mouse model will provide important preclinical data for human applications.
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.
Applying Gene Therapy Towards Limb Girdle Muscular Dystrophy 2I And Other Human Muscle Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$347,264.00
Summary
Therapeutic replacement of small, normal sections of the dystrophin gene can prevent muscle wasting in young dystrophic mice with mutations in dystrophin. This project attempts to apply the same principle to treat another inherited muscle disorder, caused by mutations in the FKRP gene. This approach can also potentially be used to enhance muscle regeneration and treat age related muscle atrophy, or synergistically applied with other therapies that target specific genetic mutations.
Self-destructing CRISPR-constructs For Targeted Genome Editing In The Retina.
Funder
National Health and Medical Research Council
Funding Amount
$679,926.00
Summary
Despite the identification of specific mutations causing many inherited retinal dystrophies, all of these conditions are currently untreatable. We have established gene-editing techniques and have developed a novel mouse model, which will serve as a robust platform for testing different techniques of gene editing in the retina. No other group in the world is known to be using this platform for gene editing and our work will expedite the clinical translation of this technology.
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.
Development Of A Novel Hybrid RAAV/transposon Gene Delivery System For Life-long Correction Of Metabolic Liver Disease In Infants And Children
Funder
National Health and Medical Research Council
Funding Amount
$505,897.00
Summary
The immense potential of gene therapy for the treatment of genetic liver disease has been confirmed by recent success in a clinical trial for Haemophilia in adult males, and therapeutic benefit in other adult trials is imminent using the same technology. In the young, however, ongoing growth of the liver causes the therapeutic benefit to be short-lived. To address this problem we are developing a powerful new hybrid technology capable of conferring life-long benefit on infants and children.
Directed Evolution Of AAV Capsid Variants For Enhanced Targeted Genome Editing In The Human Liver
Funder
National Health and Medical Research Council
Funding Amount
$386,012.00
Summary
Liver transplantation is often the only treatment option available for patients with severe liver disease, and is complicated by a shortage of donor organs and the need for life-long drug therapy to prevent rejection. Repair of a patient’s own liver by gene therapy is a promising alternative. This project focuses on developing the technology required to undertake precise correction of genetic spelling errors in diseased liver cells without the need to first remove them from the body.
Mechanically-restricted Percutaneous Gene Therapeutic Solutions For Heart Failure.
Funder
National Health and Medical Research Council
Funding Amount
$187,000.00
Summary
We have developed a novel system for the localized delivery of specialised genes to the heart in order to improve contractility and function of a failing heart. Many genes, for reasons of toxicity, clearance, or uptake, require direct delivery to the target region without spillover to the systemic circulation. Our system addresses these issues by isolating the local circulation of the target organ and directly delivering the agent with minimal systemic loss and improved delivery and uptake effic ....We have developed a novel system for the localized delivery of specialised genes to the heart in order to improve contractility and function of a failing heart. Many genes, for reasons of toxicity, clearance, or uptake, require direct delivery to the target region without spillover to the systemic circulation. Our system addresses these issues by isolating the local circulation of the target organ and directly delivering the agent with minimal systemic loss and improved delivery and uptake efficiency, while minimizing potentially dangerous and toxic systemic effects.Read moreRead less
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.