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.
Genetic And Phenotype Studies Of Partial Epilepsy In Gypsies
Funder
National Health and Medical Research Council
Funding Amount
$646,136.00
Summary
Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies ....Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies have proved particularly difficult to understand and the numerous genetic studies conducted so far have failed to produce important and replicable results. It is becoming increasingly clear that enormous genetic heterogeneity, with many rare mutations occurring in different affected subjects, will be a major obstacle to understanding the molecular basis of complex epilepsies. In this context, genetically isolated populations, which stem from a small number of ancestors, can be particularly helpful and revealing, since their limited genetic diversity means that the number of genes involved in causing complex epilepsies may be smaller and shared between individuals and families. In this study, we will analyze affected families, as well as non-familial cases of epilepsy, from a genetically isolated population - the European Roma-Gypsies. We will determine the number of potential susceptibility genes involved in familial forms, the overlap and differences between families, as well as the contribution of the genes identified in families to the development of sporadic epilepsy.Read moreRead less
STUDIES OF NF-E4, A NOVEL FETAL/ERYTHROID SPECIFIC FACTOR INVOLVED IN FETAL GLOBIN GENE REGULATION
Funder
National Health and Medical Research Council
Funding Amount
$753,810.00
Summary
Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated ....Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated clinical course. Therefore, treatment strategies which could reactivate fetal globin gene expression after birth should be explored for these diseases. To achieve this goal we must further our understanding of the normal mechanisms of developmental regulation of globin gene expression. To this end we have recently identified a novel gene which is critical for fetal globin expression. The studies we propose here will further define the function of this gene and assess its potential for gene therapy for sickle cell disease and thalassemia.Read moreRead less
Dystrophin Gene Repair In Mdx Mouse Myoblasts And Bone Marrow Cells As A Basis For Autologous Transplant In Human DMD
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
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 repopulated with genetically corrected cells 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 diseases.Read moreRead less
The Role Of Aire In Immunological Tolerance And Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$434,134.00
Summary
The immune system is designed to protect us from foreign pathogens such as bacteria, viruses and parasites. This is achieved through lymphocytes which recognise foreign pathogens. However in 5-6% of the population the immune system attacks the host and induces autoimmunity. We aim to understand the mechanisms which control the production of self-reacting lymphocytes and how we may reduce the incidence of autoimmunity.
A Structural And Functional Basis For The Regulation Of Gene Expression By Nuclear Retention Of RNA
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
The nuclear retention mechanism is a novel way used by cells to control which genes are made into proteins - a fundamental process for all diseases, particularly cancers. This project will employ cutting edge structural and proteomic techniques to determine the molecular details underpinning nuclear retention. These insights will be important for the development of new tissue-restricted gene therapy applications and drugs targeting the cancers that rely on this mechanism.