The aim of this proposal is to evaluate a novel therapy option for children with a genetic disorder called mucopolysaccharidosis (MPS). MPS arise from the build up of complex carbohydrates in cells within the body due to the deficiency of an enzyme required for their degradation. By decreasing the synthesis of carbohydrate we can manipulate the level of stored carbohydrate and alleviate the pathology associated with MPS. The novel therapy is based on a chemical modification of glucose that inhib ....The aim of this proposal is to evaluate a novel therapy option for children with a genetic disorder called mucopolysaccharidosis (MPS). MPS arise from the build up of complex carbohydrates in cells within the body due to the deficiency of an enzyme required for their degradation. By decreasing the synthesis of carbohydrate we can manipulate the level of stored carbohydrate and alleviate the pathology associated with MPS. The novel therapy is based on a chemical modification of glucose that inhibits carbohydrate synthesis and is termed substrate deprivation therapy.Read moreRead less
Regulation Of ADAMTS-5 Activity By Keratan Sulphate-binding Exosites
Funder
National Health and Medical Research Council
Funding Amount
$213,342.00
Summary
Arthritis and musculoskeletal conditions are the predominant cause of disability in Australia. The burden of arthritis is felt not only by patients, their families and carers, but also the labour market and the national economy. There is a pressing need to identify new targets for design of inexpensive arthritis therapies. The TNF antagonists have proved effective in managing rheumatoid arthritis (RA), but they are expensive, administered by injection, and in general, only prescribed in Australi ....Arthritis and musculoskeletal conditions are the predominant cause of disability in Australia. The burden of arthritis is felt not only by patients, their families and carers, but also the labour market and the national economy. There is a pressing need to identify new targets for design of inexpensive arthritis therapies. The TNF antagonists have proved effective in managing rheumatoid arthritis (RA), but they are expensive, administered by injection, and in general, only prescribed in Australia for patients who respond poorly to DMARDs. Their long-term efficacy and safety is not yet determined. There are no treatments for osteoarthritis (OA), the disease that occurs more frequently with age and is characterised by destruction of cartilage and aggrecan. New drugs that protect against aggrecan breakdown are urgently needed for OA and they would also be valuable adjunct therapies to the DMARDs for treatment of RA. We have discovered that the major aggrecan-degrading enzyme is ADAMTS-5. ADAMTS-5 is, therefore, a potential target for arthritis therapies. Unfortunately, drugs targeting the active site of ADAMTS-5 are predicted to fail, given the wide tissue distribution of ADAMTS-5, the high level of homology between the active site of ADAMTS enzymes and matrix metalloproteinases (MMPs), and the notorious failure of MMP active site inhibitors in clinical trials. The aim of this project is to determine whether ancillary domains of ADAMTS-5 are a viable alternative target to the active site. We have evidence to suggest that keratan sulphate, which is covalently attached to the aggrecan core protein, can modulate aggrecan cleavage by ADAMTS enzymes. We aim to identify opportunities for developing antagonists that block keratan sulphate binding, or keratan sulphate analogues that block enzyme binding to its substrate. The data will inform the pharmaceutical industry on new directions for modulating aggrecanolysis by ADAMTS-5.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.
Therapy For CNS Degeneration In MPS Disorders That Targets Both Glycosaminoglycan And Ganglioside Storage.
Funder
National Health and Medical Research Council
Funding Amount
$368,043.00
Summary
Children with seven of the eleven types of mucopolysaccharidosis (MPS) disorders exhibit a profound, irreversible neurological deterioration that manifests in infancy. This results from the continual buildup of undegraded sugar and fat in brain cells. The goal of this proposal is to prevent the accumulation of lipid alone or both lipid and sugar in the brain in order to alter the progression of neurological disease. Treatment will be assessed in mouse models of MPS.
Cartilage Destruction In Arthritis: Mechanism Of Aggrecanase And Matrix Metalloproteinase Action In Vivo And In Vitro
Funder
National Health and Medical Research Council
Funding Amount
$703,180.00
Summary
Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal development. However unregulated enzyme activity resulting in ....Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal development. However unregulated enzyme activity resulting in accelerated cartilage breakdown leads to the pathology recognised as arthritis. While some activities of the MMP and ADAMTS families have been studied in the laboratory, there have been no in vivo studies to determine which family is responsible for cartilage destruction, and which is therefore most appropriate for targeting by drugs. This project will create genetically-modified mice, resistant to either the MMP or the ADAMTS enzymes. The mice will be used in experimental arthritis models to determine which enzymes play the major role in initiating disease, which enzymes are involved in disease progression and which enzymes may be important for repair. In parallel studies, the highly specialised matrix molecule, keratan sulphate, will be studied for its role in cartilage destruction. There is preliminary evidence to suggest that keratan sulphate may be involved in the regulation of ADAMTS activity. The possible direct and indirect modalities of keratan sulphate action will be investigated. The results of this arthritis project will (a) yield new information on the mechanism of disease action; (b) identify targets for the rational design of disease-modifying drugs; (c) elucidate biochemical processes involved in normal skeletal growth and cartilage repair; and (d) provide new in vivo models for testing the efficacy of arthritis therapies.Read moreRead less