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
Studies Of A Novel Manganese Transporter In Lysosomes And Its Implications In Niemann-Pick Type-C Disease
Funder
National Health and Medical Research Council
Funding Amount
$527,036.00
Summary
Niemann-Pick type-C disease is a devastating disease affecting child central nervous system. It is due to too much build up of cholesterol in the lysosomal compartment of cells. Recent studies indicate that bivalent cations are involved in the development of the disease. We recently discovered a manganese transporter in the lysosomal compartment and its interaction of the a protein that causing the disease. We will elucidate how manganese transporter controls trace metal balance and may prevent ....Niemann-Pick type-C disease is a devastating disease affecting child central nervous system. It is due to too much build up of cholesterol in the lysosomal compartment of cells. Recent studies indicate that bivalent cations are involved in the development of the disease. We recently discovered a manganese transporter in the lysosomal compartment and its interaction of the a protein that causing the disease. We will elucidate how manganese transporter controls trace metal balance and may prevent the disease.Read moreRead less
Canine Adenovirus-mediated Gene Therapy For CNS Pathology In LSD
Funder
National Health and Medical Research Council
Funding Amount
$490,029.00
Summary
Lysosomal storage disorders (LSD) are inherited diseases that affect about 1 in 7700 Australian children; all share common physical symptoms include heart and breathing difficulties, stiff joints, skeletal deformities, enlarged head, and a characteristic facial appearance. Two-thirds of patients will also develop brain disease. The lysosome is a component of each cell in the human body; its role it is to break down and remove waste from the cell. This involves a series of proteins (enzymes) that ....Lysosomal storage disorders (LSD) are inherited diseases that affect about 1 in 7700 Australian children; all share common physical symptoms include heart and breathing difficulties, stiff joints, skeletal deformities, enlarged head, and a characteristic facial appearance. Two-thirds of patients will also develop brain disease. The lysosome is a component of each cell in the human body; its role it is to break down and remove waste from the cell. This involves a series of proteins (enzymes) that act in sequence. A LSD arises when the lysosome lacks the activity of one protein in this chain. This loss of protein activity means that the waste removal process is impaired. Waste begins to 'store' in the lysosome, clogging the cell and interfering with its usual functions. This gives rise to devastating symptoms that worsen over time as storage increases. Brain disease in LSD has profound effects on the child: mental capacity declines, they become hyperactive and aggressive and progressively lose learned skills (e.g. walking, talking) and control of bodily functions. Artifically made protein is being successfully used to treat some LSD via intravenous injection. However, it cannot access the brain because of a protective barrier that surrounds it. Gene therapy is a method by which we are attempting to overcome this problem. By using a virus called canine adenovirus (or CAV), we plan to produce and insert the missing protein into mice who are deficient in it. CAV will be the protein carrier. CAV is safe in humans and does not have many of the problems associated with some other viruses being tested in gene therapy. We have diagnosed mice who are naturally affected by a LSD with brain disease called MPS IIIA. Their symptoms are similar to that seen in humans, making them ideal for study. CAV vectors are being considered as a long-term treatment for patients who suffer from MPS IIIA and other degenerative brain diseases.Read moreRead less
Cisterna Magna Delivery Of Therapeutic Lysosomal Enzyme To Correct CNS Pathology In Lysosomal Storage Disorders
Funder
National Health and Medical Research Council
Funding Amount
$760,282.00
Summary
Lysosomal storage disorders (LSD) are inherited diseases that affect about 1 in 7700 Australian children; all share common physical symptoms include heart and breathing difficulties, stiff joints, skeletal deformities, enlarged head, and a characteristic facial appearance. Two-thirds of patients will also develop brain disease. The lysosome is a component of each cell in the human body; its role it is to break down and remove waste from the cell. This involves a series of proteins (enzymes) that ....Lysosomal storage disorders (LSD) are inherited diseases that affect about 1 in 7700 Australian children; all share common physical symptoms include heart and breathing difficulties, stiff joints, skeletal deformities, enlarged head, and a characteristic facial appearance. Two-thirds of patients will also develop brain disease. The lysosome is a component of each cell in the human body; its role it is to break down and remove waste from the cell. This involves a series of proteins (enzymes) that act in sequence. A LSD arises when the lysosome lacks the activity of one protein in this chain. The loss of protein activity impairs the waste removal process. Waste begins to 'store', clogging the cell and interfering with its usual functions. This gives rise to devastating symptoms that worsen over time as storage increases. Brain disease in LSD has profound effects on the child: mental capacity declines, they become hyperactive and aggressive and progressively lose learned skills (e.g. walking, talking) and ability to control bodily functions. Artifically made protein is being successfully used to treat some LSD via intravenous injection. However, it is not able to access the brain because of a protective barrier that surrounds it. This project tests a method to deliver protein to the brain to reduce and stop waste build-up. It involves the injection of artificially made protein into the fluid surrounding the brain and spinal cord using techniques being used to treat other diseases. This method is likely to be the quickest way in which we can treat both the body AND the brain of an affected child. We have diagnosed animal models who were born with a LSD with brain disease, called MPS IIIA. Their symptoms are similar to that seen in humans over the course of the disease, making them ideal for study in this project. Success in this project will allow us to advance this treatment to human trials.Read moreRead less
Development Of A Safe And Effective Treatment For Neuropathology In MPS IIIA.
Funder
National Health and Medical Research Council
Funding Amount
$665,320.00
Summary
MPS IIIA is an inherited disorder that results in progressive brain disease in affected children. The disorder cannot be treated at present because it has not been possible to find an effective way to deliver treatment to the brain. This project seeks to evaluate a method to overcome this problem. Findings in this project can be applied to other, similar disorders that affect the brain.
This project aims to investigate novel ways to treat children with the inherited brain disorder known as MPS IIIA. This condition is currently untreatable and children generally die in their teens. We will use a mouse model of this condition to examine the effectiveness of combining two different treatment approaches, in order to maximise outcomes.