Targeted Corrective Gene Conversion (TCGC): Application In DMD Mutations And Delivery To Dystrophic (mdx) Muscle
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
The muscular dystrophies are inherited diseases that lead to muscle wastage and severe disabilities. The most severe forms result in the early death of newborns, but a large number are diagnosed in children showing early mild symptoms and progress steadily to severe disabling forms in the juvenile and young adult. Perhaps the most devastating of these dystrophies is Duchenne Muscular Dystrophy (DMD). This condition affects 1 in 3,300 boys, who show symptoms at around 5 years of age until wheelch ....The muscular dystrophies are inherited diseases that lead to muscle wastage and severe disabilities. The most severe forms result in the early death of newborns, but a large number are diagnosed in children showing early mild symptoms and progress steadily to severe disabling forms in the juvenile and young adult. Perhaps the most devastating of these dystrophies is Duchenne Muscular Dystrophy (DMD). This condition affects 1 in 3,300 boys, who show symptoms at around 5 years of age until wheelchair confinement by early teens. DMD boys undergo major clinical and surgical treatments which at present only provide small but significant improvements to their lives. The median age at death for Duchenne boys is 22 years. The cause of DMD has been known for almost 2 decades and is a defect in just a single component of muscle, Dystrophin which is produced by muscle cells. In general, boys with DMD possess Dystrophin which is missing an important part that prevents the breakdown of muscles during activity. As a consequence, all the muscles in DMD boys slowly break down over their lifetime until they die because the muscle which helps in drawing breath (Diaphragm) is no longer capable of helping them to breathe. The muscle component Dystrophin is produced by a gene (the dys gene) and the defect of Dystrophin is caused by a defect in the dys gene. If the dys gene defect was able to be corrected in boys with DMD, their Dystrophin may also be corrected and the breakdown of their muscle prevented. We have been able to correct the dys gene in muscle cells from a mouse with DMD. We wish to improve this technology and allow muscle to be corrected with genetically corrected fibres to form a basis for treatment of human DMD. In this way we hope to significantly improve and lengthen these boys' lives and even lead to a cure for DMD and other genetic muscle diseaseRead moreRead less
RNA Interference And Retigabine Therapy Protect Against Hereditary Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$370,522.00
Summary
The preservation of hearing function is central to the treatment of individuals who are genetically predisposed to hearing loss. At present only synthetic hearing aids and cochlear implants can provide functional improvement, albeit sub-optimal. The studies described here will seek to prevent hearing loss by reducing the damaging effects of defective genes. Gene therapies that reduce the effect of these defective genes and a drug that enhances the activity of functional genes will be developed.
Mammalian chitinases and gene therapy: new weapons to combat fungal and insect attack in mammals. Plants combat fungal and insect attack by producing chitin degrading enzymes. Related, chitinolytic enzymes have been identified in mammals, but their functions are unclear. We found that chitinases from human macrophages inhibited fungal growth. We hypothesise that, like plants, mammalian chitinases are produced to fight chitin containing pathogens. We will transform cells with a chitotriosidase ge ....Mammalian chitinases and gene therapy: new weapons to combat fungal and insect attack in mammals. Plants combat fungal and insect attack by producing chitin degrading enzymes. Related, chitinolytic enzymes have been identified in mammals, but their functions are unclear. We found that chitinases from human macrophages inhibited fungal growth. We hypothesise that, like plants, mammalian chitinases are produced to fight chitin containing pathogens. We will transform cells with a chitotriosidase gene and encapsulate them, creating bioreactors secreting chitinases. Therapeutic effects will be tested by grafting bioreactors to mice inoculated with Aspergillus. The research is a new approach to fighting chitin containing pathogens, with potential applications from parasite infestations in livestock to fungal infections in humans.Read moreRead less
THE ROLE OF SMALL NON CODING RNAS IN BONE MARROW MEDIATED TUMOR ANGIOGENESIS. Despite advances in treatment and diagnosis cancer remains the leading underlying cause of deaths, representing about a third of all deaths each year in Australia (ABS stats. www.abs.gov.au). The ability to understand the process of tumour vascularisation and spread has enormous economic and social outcomes. Indeed, the most effective anti-angiogenic therapy developed to date Avastin (aka Bevacizumab), although providi ....THE ROLE OF SMALL NON CODING RNAS IN BONE MARROW MEDIATED TUMOR ANGIOGENESIS. Despite advances in treatment and diagnosis cancer remains the leading underlying cause of deaths, representing about a third of all deaths each year in Australia (ABS stats. www.abs.gov.au). The ability to understand the process of tumour vascularisation and spread has enormous economic and social outcomes. Indeed, the most effective anti-angiogenic therapy developed to date Avastin (aka Bevacizumab), although providing only a modest survival advantage (4-6 months) has annual sales of several billion dollars. microRNA represent a relatively newly discovered form of gene activity regulation. Taking a key leadership role in this area will put Australian science at the forefront of international research initiatives.Read moreRead less
Zonal Expression And Persistence Of RAAV Vectors Within The Hepatic Lobule: Towards Gene Therapy For Metabolic Disease.
Funder
National Health and Medical Research Council
Funding Amount
$84,173.00
Summary
In its most severe form the urea cycle disorder OTC deficiency has a high risk of death. Current therapy is liver transplantation which has significant shortcomings including lack of donor organs. Therefore, a need to provide a safer and more effective alternative treatment exists. Liver directed gene therapy with adeno-associated virus (AAV) can potentially provide this treatment. This project aims to optimise AAV2-8 vectors for liver gene therapy in the treatment of metabolic liver disease.
The Role Of Bone Morphogenetic Proteins In The Pathogenesis Of Pulmonary Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$236,540.00
Summary
Many people develop problems with the blood vessels in the lungs, which then leads to a narrowing of these vessels and consequently a back-pressure strain on the heart. These disorders can arise from inherited diseases of the blood vessels themselves, or from accquired lung disease (for example due to smoking or chronic infections). At present there are few treatments which have any benefits for these patients and many must undergo lung or heart-lung transplantation. This project is desigened bo ....Many people develop problems with the blood vessels in the lungs, which then leads to a narrowing of these vessels and consequently a back-pressure strain on the heart. These disorders can arise from inherited diseases of the blood vessels themselves, or from accquired lung disease (for example due to smoking or chronic infections). At present there are few treatments which have any benefits for these patients and many must undergo lung or heart-lung transplantation. This project is desigened both to find out new information about the disease process that affects the lung blood vessels and to offer a strategy for new treatments. The project will use a crippled form of the cold virus to deliver genes to the lining of the lung blood vessels, then see what impact that has on the pressure within the vessels and the ways in which they respond to certain stresses. These studies will be carried out using laboratory animals. If successful, it may be possible to eventually design such viruses to deliver genes which have a helpful therapeutic impact on the disease in patients.Read moreRead less
Induction Of Antigen-specific Humoral Tolerance By RAAV-mediated Delivery Of CTLA4-Ig-antigen Fusion Molecules
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
There are many medical situations where immune suppression is required. Available methods lack specificity and risk infection, drug-related side-effects and cancer. We have discovered a novel way of suppressing immunity such that only unwanted responses are eliminated. This involves virus-mediated delivery of antigen fused to CTLA4-Ig. We plan to test this strategy in the context of gene therapy, to work out how it works and to optimise the approach. Success will have broad health implications.
Cell-targeted Gene Delivery Into Human Haematopoietic Stem Cells For The Treatment Of Thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$171,208.00
Summary
Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various ot ....Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various other abnormalities of haemoglobin synthesis. If untreated, most thalassaemia patients will die within the first few years of life. The vast majority of thalassaemia patients depend on regular blood transfusions every two to three weeks, and on nightly infusions of an iron chelator (a drug for removing excess iron from the blood). These procedures place considerable burden on thalassaemia patients, their families and society, and expose them to blood transmitted infections. The only curative treatment for thalassaemia is bone marrow transplantation from a matching donor. However, the vast majority of patients do not have matching donors and thus the only prospect for them to receive such therapy is to replace in their bone marrow cells a copy of the normal set of genes for the synthesis of haemoglobin. The studies in this proposal are therefore designed to test gene therapy protocols on bone marrow stem cells derived from thalassaemia patients. A normal set of globin genes will be delivered to the bone marrow stem cells via non-viral delivery systems and examined for function in an immunodeficient mouse strain that can accept human bone marrow. This research may enable bone marrow transplantation to be applied for the therapy of most patients with thalassaemia, while it may also have a major impact on therapeutic approaches for other haematological anomalies.Read moreRead less
Antisense Oligonucleotide Induced Exon Skipping As A Treatment For Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$363,055.00
Summary
Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to ....Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to dystrophin gene replacement therapies, due to the nature of the target (muscle fibres) and the size and complexity of the gene. This project will investigate an alternative genetic approach in cells expressing dystrophin (this gene is transcribed and processed differently in a variety cell types), whereby antisense oligonucleotides are used to redirect the processing of dystrophin pre-mRNA in the region of the DMD mutation. Although the DMD mutation would still be present at the gene level, the disease-causing mutation would be removed during the processing of the dystrophin pre-mRNA. Once a nonsense mutation has been removed or the reading frame restored from a DMD transcript, the resultant engineered dystrophin mRNA could be translated into a functional Becker-like protein.Read moreRead less