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
Development Of An Intracellular Tau-specific Antibody Therapeutic For The Treatment Of Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$410,378.00
Summary
The protein, tau, is a promising therapeutic target for the treatment of Alzheimer's disease and related dementia's. Targeting tau is a challenge, however, as it is mostly localised within brain cells and a therapeutic must therefore be able to cross multiple barriers to engage and neutralise tau. This project overcomes this hurdle by using virus' to deliver a tau-specific antibody gene across the multiple barriers where it can be produced by brain cells and target intracellular tau.
Dissecting The Central Organisation Of Cough Neural Networks
Funder
National Health and Medical Research Council
Funding Amount
$880,928.00
Summary
Cough is the most prevalent symptom of lung disease and the most common reason for people to seek medical advice. However, cough neural processes are poorly defined and as a result current cough therapies are largely ineffective making cough a significant unmet clinical problem. This project will novel viral strategies to dissect and manipulate cough neural pathways in the brain, providing insights into the neural processing of airway sensations and coughing.
Development Of Lentiviral Vectors For The Treatment Of X-linked Severe Combined Immunodeficiency (SCID-X1)
Funder
National Health and Medical Research Council
Funding Amount
$71,434.00
Summary
The first successful gene therapy clinical trial was reported in 2000 with the treatment of X-linked severe combined immunodeficiency (SCID-X1), commonly known as “bubble-boy” disease. The subsequent development of leukaemia in 3 of 11 patients has prompted the need to develop alternative vectors for gene delivery, such as HIV-1-based lentiviral vectors. This project will evaluate the efficacy and safety of lentiviral vectors in vivo, and hence their therapeutic potential for treating SCID-X1.
Hepatocellular Carcinoma: Understanding The Genotoxic Risks Of Liver-targeted Gene Therapy Using Recombinant AAV Vectors
Funder
National Health and Medical Research Council
Funding Amount
$891,639.00
Summary
Advances in gene transfer technology using an engineered virus known as AAV underpin success in the treatment of haemophila B, and offer the exciting prospect of treating many other liver diseases. While continued improvement of gene transfer efficiency is essential there is an equal need to focus on safety. We have discovered a genetic element in AAV that we believe is a key to unlocking accurate analysis of the safety of AAV-based gene transfer technology. Here we propose to turn the key.
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
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.
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.
Regeneration And Repair In The Rodent Visual System: An In Vivo Gene Therapy And Neural Transplantation Study
Funder
National Health and Medical Research Council
Funding Amount
$426,000.00
Summary
In the adult human central nervous system (CNS), traumatic injury, stroke, or loss of nerve cells due to degenerative disease all result in long-term and severe functional impairments. The personal, social and economic costs associated with these neurological problems are massive. In the proposed work, gene therapy and transplant techniques will be used to develop new cooperative strategies for neural repair. The aims are to protect and-or replace damaged nerve cells (neurons) and promote the lo ....In the adult human central nervous system (CNS), traumatic injury, stroke, or loss of nerve cells due to degenerative disease all result in long-term and severe functional impairments. The personal, social and economic costs associated with these neurological problems are massive. In the proposed work, gene therapy and transplant techniques will be used to develop new cooperative strategies for neural repair. The aims are to protect and-or replace damaged nerve cells (neurons) and promote the long-distance regrowth of their processes (axons). The ultimate goal is to improve the treatment of human CNS injury and disease, leading to better functional recovery. We will use the visual system as our experimental CNS model. Viruses are novel tools that can be used for the introduction of foreign genes into cells. We will use modifed, non-harmful viral vectors to genetically alter retinal neurons. We will incorporate extra copies of known neuroprotective and-or growth-promting genes into retinal cells and analyze whether these genetically engineered neurons possess a greater ability to survive and regenerate their axons after injury. We will combine this approach with the transplantation of peripheral nerve bridges which are known to boost the regrowth of CNS axons. We will also test the effects of viral transfer of genes into retinal neurons in transgenic mice that have already been given an 'extra dose' of a neuroprotective gene. We will determine if different genes cooperate together to produce a synergistic therapeutic effect after CNS injury. The above studies focus on regeneration in what are essentially acute injury models. We are also interested in the restoration of circuitry in chronic situations, where the damage occured some time previously and neurons have already been lost. We will therefore graft neural precursor cells into the rat eye in an attempt to replace endogenous retinal neurons that are dying or have been lost due to injury.Read moreRead less