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
Treatment Of Virally-induced Cancers By RNA Interference.
Funder
National Health and Medical Research Council
Funding Amount
$389,250.00
Summary
Cancers require certain mutations and the over expression of genes to cause disease. Each cancer has a unique set of gene changes thus making it difficult to treat. However, it has become clear that the normal control mechanisms of many cancers are still intact but are repressed by the over expression of these oncogenes (or cancer genes). By turning off these oncogenes we can restore normal control to the cell and the cancer will die normally. We will use a new method of gene targeting called RN ....Cancers require certain mutations and the over expression of genes to cause disease. Each cancer has a unique set of gene changes thus making it difficult to treat. However, it has become clear that the normal control mechanisms of many cancers are still intact but are repressed by the over expression of these oncogenes (or cancer genes). By turning off these oncogenes we can restore normal control to the cell and the cancer will die normally. We will use a new method of gene targeting called RNA interference to turn off oncogenes. RNA interference involves treatment of cells with a small peice of genetic material that provides the cell with an identity pattern of the gene to be eliminated. The cell takes the pattern and turms off the genes expression. As long as the pattern only turns off the cancer gene all other genes will remain normal. We will test this using cervical cancer as a model as all these cancers are caused by infection with a virus that carries 2 oncogenes. It is these virus oncogenes that cause the cancer and therefore we know the exact target genes that need to be turned off. Most importantly these genes are not present in normal cells making it safe to target them by RNA interference. We have gathered an expert group of investigators with experience in cervical cancer and cancer genetics to address this problem. If successful we will have proven this new technique can work against cervical cancer and this method could then be applied to any cancer. We would then be able to start human trials. Cervical cancer kills over 300 women in Australia each year, is the leading cause of cancer death in Aboriginal women, is 2nd most common cancer of women in the world and is the leading cancer killer worldwide in women under 50.Read moreRead less
Designer RNA-binding Proteins For Research And Therapeutic Purposes
Funder
National Health and Medical Research Council
Funding Amount
$557,480.00
Summary
It has become clear recently that ribonucleic acids play many roles in the switching on and off of genes in humans and other organisms. These molecules play roles in a number of diseases, including HIV-AIDS, hepatitis, and a large number of inherited disorders. We propose to build a library of protein molecules that can bind specifically to a wide range of RNA targets and modulate their function. These molecules have the capacity to act as therapeutics for a wide range of diseases.
ALS4 Mice Show TDP-43 Protein Mislocalization In Motor Neurons Characteristic Of Sporadic ALS Patients; Suggesting This Model Is Likely To Reveal Important Patho-mechanistic Disease Insights
Funder
National Health and Medical Research Council
Funding Amount
$108,466.00
Summary
SETX gene mutations cause an inherited motor neurone disease (MND) known as ALS4. Our current understanding of MND was revolutionized by the discovery that a protein known as TDP-43 is the main component of protein accumulations found in dying human motor neurones. We have generated a unique mouse model of ALS disease that will be useful for research purposes, but may also prove effective for drug testing.
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.
Current combination antiviral therapy can't cure an HIV infection because long-lived T-cells carrying latent HIV DNA can rekindle the infection when drugs are removed. We will study elements in HIV genetic code that control expression of HIV proteins from latent HIV. A detailed molecular understanding of the structure and function of these HIV RNA elements and the viral and host cell factors that interact with them will expose new targets for therapy of latent HIV.
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.
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.
Investigation Into The Alternative Splicing Of Steroid Hormone Regulated Genes In Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Steroid hormones have imortant roles in breast tissue growth and differentiation. We have identified several proteins called PRMT6 and CAPER's , that are involved in steroid hormone signaling and control the alternative splicing of RNA, the process in which several different proteins can be produced from a single gene. Our aim is to study these proteins in an effort to understand how they influence alternative splicing and to identify genes they control in relation to breast cancer.