Treatment Of Lysosomal Storage Disorder Patients By Drug-enhanced Premature Stop Codon Read-through
Funder
National Health and Medical Research Council
Funding Amount
$431,764.00
Summary
Lysosomal storage disorders are a devastating set of genetic diseases with very severe clinical symptoms. In this project, we will investigate a new treatment strategy that is non-invasive and that will be applicable for a wide range of lysosomal storage disorder patients. The therapy will over-ride the molecular genetic lesion and will be preferentially targeted for patients who are at the severe end of the clinical spectrum, where treatment options are currently limited.
PROTEIN PROFILING FOR THE IDENTIFICATION AND MONITORING OF LYSOSOMAL STORAGE DISORDERS AND OTHER NEUROLOGICAL DISEASES
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Lysosomal storage disorders (LSD) are a group of more than 45 progressive genetic diseases, that result from the absence or impaired function of a specific enzyme in each of the body's cells. Lysosomes rid the cell of excess waste. Impaired enzyme function halts this process and waste begins to accumulate (or 'store') in the cell. Disease severity and patient longevity is variable, but severely affected patients often die by their mid-teens. LSD can affect the skeleton and joints, respiratory an ....Lysosomal storage disorders (LSD) are a group of more than 45 progressive genetic diseases, that result from the absence or impaired function of a specific enzyme in each of the body's cells. Lysosomes rid the cell of excess waste. Impaired enzyme function halts this process and waste begins to accumulate (or 'store') in the cell. Disease severity and patient longevity is variable, but severely affected patients often die by their mid-teens. LSD can affect the skeleton and joints, respiratory and cardiovascular systems, the brain, the eyes, the ears and the airways. As affected children become older, symptoms worsen. Patients often require frequent hospitalisation, and medical and surgical intervention. Approximately 10 to 15% of the general population are affected or carriers of an LSD. In Australia, one LSD child is born in every 5,000 live births. Diagnosis often takes several years, and families often have other children before their affected child is diagnosed. LSD are, therefore, a considerable burden to not only the families but also to the health care system. The goal of the Lysosomal Diseases Research Unit is Diagnosis at birth and effective therapy for lysosomal storage disorders. To this end we have been working toward the development of a newborn screening program for LSD and improved methods for the diagnosis and monitoring of therapy in this group of diseases. In this project we propose to develop and evaluate the use of protein profiling (looking at many diagnostic markers at the same time) to achieve these goals. The technology developed in this project will have potential application beyond LSD. Lysosomal dysfunction has been implicated in Alzheimer's disease and Parkinson's disease; in addition lysosomal proteins are reported to be involved in the spread of some cancers and may be useful markers for early detection. We will collaborate with other research groups to further develop protein profiling in these areas.Read moreRead less
Understanding Skeletal Development: A Non-proteolytic Mechanism Of Aggrecan Resorption In The Growth Plate
Funder
National Health and Medical Research Council
Funding Amount
$563,044.00
Summary
Bone formation requires resorption of a cartilage template. We challenge the dogma that cartilage resorption is only by PROTEASES, and propose instead that GLYCOSIDASES might also be involved. Aims: Demonstrate that chondrocytes release glycosidases that are important for bone formation. Significance: New information for the design of reconstructive therapies for people with congenital and acquired limb deficiencies or inherited disorders such as arthritis and chondrodysplasias may be gained.
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
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
Is The Eye A Window To The Brain In Sanfilippo Syndrome?
Funder
National Health and Medical Research Council
Funding Amount
$852,967.00
Summary
Study of the retina and optic nerve permits evaluation of central nervous system – these structures contain both neurons and glia and are outgrowths of the developing brain. Therefore, eye examination may allow us to study the brain and monitor brain disease and the effect of therapy. This project will determine whether brain disease in a childhood-onset disorder (Sanfilippo syndrome) and treatment of it, can be monitored in this way.
A SYSTEMS BIOLOGY APPROACH TO SCREENING, DIAGNOSIS AND PROGNOSIS FOR LYSOSOMAL STORAGE DISORDERS
Funder
National Health and Medical Research Council
Funding Amount
$900,781.00
Summary
Lysosomal storage disorders (LSD) are inherited and, at present, can only be detected in children after symptoms are obvious. We are developing newborn screening for LSD to detect affected babies before the onset of irreversible symptoms. As most LSD babies appear normal at birth it is important to be able to predict disease severity or rate of disease progression; this will help doctors know when to give therapy, which therapy is best and provide families with appropriate genetic counseling.
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