Downregulation Of N-myc Oncogene Expression As A Therapeutic Strategy For Childhood Neuroblastoma.
Funder
National Health and Medical Research Council
Funding Amount
$145,990.00
Summary
Neuroblastoma is a common cancer of young children which, despite the use of powerful anticancer drugs that cure other childhood cancers, has only a 40% survival rate. Many laboratories have shown that the most aggressive neuroblastoma tumours, which are most resistant to the action of anticancer drugs, have an abnormal number of copies of a cancer-associated gene, called N-myc. Patients whose tumours have multiple N-myc copies have dismal survival prospects, and new treatments for such patients ....Neuroblastoma is a common cancer of young children which, despite the use of powerful anticancer drugs that cure other childhood cancers, has only a 40% survival rate. Many laboratories have shown that the most aggressive neuroblastoma tumours, which are most resistant to the action of anticancer drugs, have an abnormal number of copies of a cancer-associated gene, called N-myc. Patients whose tumours have multiple N-myc copies have dismal survival prospects, and new treatments for such patients are urgently needed. Several studies, using models of neuroblastoma cells growing in the laboratory, have shown that it is possible to create small fragments of genetic material which can specifically switch off the N-myc gene. When this happens, the neuroblastoma cells behave in a less aggressive and malignant way. We have recently shown that these genetic fragments are capable of reducing the growth of tumours in mice which have been genetically manipulated to develop neuroblastoma. We now want to develop new types of genetic fragments (DNAzymes) that will be even more effective at switching off N-myc and inhibiting neuroblastoma development, because these fragments may be extremely valuable for treating neuroblastoma in patients.Read moreRead less
Plasmids are additional mini-chromosomes carried by many bacteria. They carry information that enables their hosts to prosper in otherwise hostile environments. Plasmids spread rapidly between bacteria, efficiently disseminating plasmid-borne information throughout bacterial populations. Many plasmids carry information that increases the virulence of their host. The emergence of multi-drug resistant bacteria and the rapid spread of the information enabling bacteria to withstand most antibiotics ....Plasmids are additional mini-chromosomes carried by many bacteria. They carry information that enables their hosts to prosper in otherwise hostile environments. Plasmids spread rapidly between bacteria, efficiently disseminating plasmid-borne information throughout bacterial populations. Many plasmids carry information that increases the virulence of their host. The emergence of multi-drug resistant bacteria and the rapid spread of the information enabling bacteria to withstand most antibiotics available today, were mediated by plasmids. Plasmids also carry information that ensures their own survival. Consequently, their hosts retain the plasmids even when it is no longer beneficial for them to do so. For example, plasmids mediating resistance to antibiotics are not lost when bacterial hosts are grown in the absence of those antibiotics. That is because plasmids have control systems, which ensure both that replication of the plasmid keeps pace with that of its host, and that the plasmid does not produce so many copies of itself that it overwhelms its host or places it at a competitive disadvantage amongst other bacteria. This project examines the intricate regulatory system that enables two groups of antibiotic-resistance plasmids to ensure that, on average, each plasmid molecule is replicated once per bacterial cell cycle. This system uses a tertiary RNA structure as a molecular switch, an antisense RNA as the regulator of this switch, and a protein that interacts with DNA sequences on the plasmid and with a bacterial protein, to initiate replication. Information gained from studies of plasmid systems is essential to the development of treatments for the elimination of antibiotic-resistance and virulence-contributing plasmids from populations of pathogenic bacteria. Antisense RNAs are not only a powerful research tool, but are also being developed for therapeutic use. Understanding how these RNAs interact with their targets will increase their effectiveness.Read moreRead less
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
Targeting The Oncoprotein MDMX As A Novel Treatment For Triple Negative Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$561,672.00
Summary
Breast cancer (BrCa) is a leading cause of cancer death in women worldwide. BrCas unable to respond to current therapies have the worst outcomes. We propose a novel strategy to treat these cancers, based on our new findings. Our two protein targets are: (1) MDMX, that we found drives BrCa with its partner, (2) mutant p53, which causes cancer spread. We plan to directly target these drivers of aggressive BrCas, using new drugs that individually show great promise in trials in a number of cance
Targeting Complement C5a Receptor 2 As A Disease-modifying Treatment For Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$636,329.00
Summary
Motor neuron disease (MND) is a devasting terminal condition that has no effective treatment. We have identified a novel drug which inhibits an immune protein that can potentially treat MND. In this project we will test this drug in rodent models of MND, and validate its effectiveness in relevant MND immune cells. Ultimately, this project will identify a new potential drug for MND.