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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.
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
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.
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.