I am an immunochemist-cell biologist investigating the involvement endosomes and lysosomes in different disease states. A primary focus has been on the group of diseases called lysosomal storage disorders where early diagnostic and effective treatment strategies have been and continue to be developed. Due to the multi-functionality of endosomes and lysosomes, these critical organelles are also involved in the pathology caused by other major diseases like bacterial infection and cancer, and this ....I am an immunochemist-cell biologist investigating the involvement endosomes and lysosomes in different disease states. A primary focus has been on the group of diseases called lysosomal storage disorders where early diagnostic and effective treatment strategies have been and continue to be developed. Due to the multi-functionality of endosomes and lysosomes, these critical organelles are also involved in the pathology caused by other major diseases like bacterial infection and cancer, and this is being actively investigated.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.
Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in ....Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.Read moreRead less
Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms c ....Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms common to more than one MPS type include mental deterioration, blindness, abdominal organ enlargement and bone growth problems leading to short stature and bone loss. My laboratory has had a long-term interest in developing treatment for MPS and our research led to the clinical implementation of enzyme replacement therapy (ERT) for MPS VI in 2005. While providing the first effective, multi-tissue treatment for MPS, our research showed that several tissues were not responsive to ERT. These are the brain, cartilage and cornea, thus children on ERT regimens will still suffer from mental retardation, arthritis and blindness. With the goal of treating these particular tissues we have developed a new approach to MPS therapy called substrate deprivation therapy (SDT). Instead of adding back the missing enzyme, SDT acts by decreasing gag production which in turn reduces the level of accumulated gag in cells. SDT results in the correction of MPS cells in culture and reduces several key clinical symptoms in the mouse model of MPS IIIA. In this proposal we will extend our research to evaluate the effect of SDT on brain and bone-joint pathology. Evaluation of efficacy will take place in the MPS VII mouse which exhibits both brain and bone disease and in a new model of MPS IVA developed specifically for this study which exhibits a joint pathology unique amongst the MPS disorders.Read moreRead less