Therapeutic Induction Of Dytrophin-positive Revertant Fibres In The Mdx Mouse
Funder
National Health and Medical Research Council
Funding Amount
$454,825.00
Summary
Revertant fibres are low-abundance, dystrophin-positive fibres found in muscle of DMD patients and animal models. These fibres appear to have a selective advantage over dystrophin negative fibres, as they accumulate with age. Characterisation of dystrophin mRNA has identified in-frame transcripts missing multiple exons, which either exclude a nonsense mutation or restore the reading frame around a deletion. We have designed antisense oligonucleotides (AOs) to bind regions flanking the exon conta ....Revertant fibres are low-abundance, dystrophin-positive fibres found in muscle of DMD patients and animal models. These fibres appear to have a selective advantage over dystrophin negative fibres, as they accumulate with age. Characterisation of dystrophin mRNA has identified in-frame transcripts missing multiple exons, which either exclude a nonsense mutation or restore the reading frame around a deletion. We have designed antisense oligonucleotides (AOs) to bind regions flanking the exon containing the dystrophin mutation in the mdx mouse. The AOs interfere with processing of the pre-mRNA to exclude the mutation and allow a slightly shortened dystrophin to be synthesised. The use of AOs to modify RNA processing allows the gene to function under the control of natural regulatory elements. We have shown that AOs can induce dystrophin expression and improve strength in dystrophic (mdx) mouse hindlimb muscles. We aim to improve upon these results by using AOs to block splice sites flanking consecutive exons, in order to induce dystrophin which mimics that of revertant fibres. As most revertant transcripts are missing multiple exons, we believe that the functional capacity of AO-induced dystrophin can be improved upon by removing multiple exons. An mdx mouse skeletal muscle cell line is used for evaluation AOs. However, in order to determine the efficacy of the induced dystrophin in cardiac and skeletal muscle, experiments must be performed on mice. Previous work, in vitro and in muscles of mdx mice have validated this approach. Combinations of AOs which show promise will be delivered by a) intravascular injection b) intraperitoneal injection in mdx mice. The efficacy of the treatment will be assessed by both continual and end point analysis, which includes physiological, clinical, molecular and histological testing. Particular attention will be directed to the well-being of the mice and any adverse side effects which may occur.Read moreRead less
Antisense Oligonucleotide Induced Exon Skipping As A Treatment For Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$363,055.00
Summary
Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to ....Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to dystrophin gene replacement therapies, due to the nature of the target (muscle fibres) and the size and complexity of the gene. This project will investigate an alternative genetic approach in cells expressing dystrophin (this gene is transcribed and processed differently in a variety cell types), whereby antisense oligonucleotides are used to redirect the processing of dystrophin pre-mRNA in the region of the DMD mutation. Although the DMD mutation would still be present at the gene level, the disease-causing mutation would be removed during the processing of the dystrophin pre-mRNA. Once a nonsense mutation has been removed or the reading frame restored from a DMD transcript, the resultant engineered dystrophin mRNA could be translated into a functional Becker-like protein.Read moreRead less
The Role Of The Osteoblast In Mediating Glucocorticoid-Induced Metabolic Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$825,254.00
Summary
Glucocorticoids (GC) exceed most other drugs in terms of numbers of patients treated and indications. Preventing or attenuating the deleterious effects of GC on fuel metabolism is therefore of great clinical significance. Our studies will create new knowledge regarding the mechanisms of GC-induced diabetes and osteoporosis, and will contribute to the development of new approaches that are essential to tackle the pressing medical problem of GC-induced disease.
Clinical Modulation Of The Hyperglycaemic Effect Of A 10-second Sprint In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$567,207.00
Summary
Although regular exercise provides a number of health benefits for individuals with Type 1 diabetes, it increases the risk of hypoglycaemia, which if severe can result in convulsion, coma and irreversible brain damages. Recently, we have made the surprising discovery that it is possible to prevent hypoglycaemia if exercise is combined with one or several short sprints. Our goal is to identify some of the clinical factors likely to interfere with the glucoregulatory benefits of sprinting.
I am a clinical scientist conducting translational and implementation research to improve diagnosis, management and understanding of airway diseases including asthma, COPD (chronic obstructive pulmonary disease), bronchiectasis and persistent cough.
Generation Of Induced Pluripotent Stem (iPS) Cells And Their Potential Use In Periodontal Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$798,350.00
Summary
Dental diseases affecting the gums (periodontal diseases) are extremely prevalent. The effects of periodontal disease can be particularly severe as loss of support for the teeth leads to loose teeth and severely compromised chewing function. If left untreated, the associated loss of function may necessitate extraction of the teeth. We propose to generate induced pluripotent stem cells from gums and explore whether they can be used to restore periodontal tissues damaged by periodontal disease.
Nutrition And Rehabilitation In Advanced Cancer Patients
Funder
National Health and Medical Research Council
Funding Amount
$225,991.00
Summary
This preliminary project aims to evaluate associations between cancer cachexia, psychosocial factors and cytokine levels in blood. The final decline of most patients with advanced cancer is associated with the cancer cachexia syndrome, triggered in part by cytokine release. Measuring cytokines may enable identification of patients about to enter this final stage. Further, factors like mood and social support appear to alter cytokine levels. The associations established by this study may point to ....This preliminary project aims to evaluate associations between cancer cachexia, psychosocial factors and cytokine levels in blood. The final decline of most patients with advanced cancer is associated with the cancer cachexia syndrome, triggered in part by cytokine release. Measuring cytokines may enable identification of patients about to enter this final stage. Further, factors like mood and social support appear to alter cytokine levels. The associations established by this study may point to treatment options that can delay the terminal phase while improving quality of life.Read moreRead less
The Role Of Nalp1 In Autoimmune Disease And Innate Immune Defense As Determined By Murine Genetic Deletion.
Funder
National Health and Medical Research Council
Funding Amount
$320,237.00
Summary
The innate immune system is a critical barrier against invading microorganisms, however when improperly regulated it can lead to autoimmune disease. Nalp1 is a protein that is important for innate immune recognition of anthrax infection, and is also involved in susceptibility to vitiligo and associated autoimmune diseases. This project seeks to create mice that are deficient for the gene encoding Nalp1 so as to further study the role of this protein in innate immune defense and autoimmunity.