Prevention Of Beta Cell Destruction In Type 1 Diabetes By Immunotherapy Using Parasite-derived Molecules.
Funder
National Health and Medical Research Council
Funding Amount
$518,443.00
Summary
To prevent type 1 diabetes, compounds that avert the autoimmune destruction of beta cells are needed. We are exploiting the potential of ñworm therapyî by mimicking the beneficial immune effects of parasite worm infection. We have identified the molecules that the parasite uses to influence host immune responses. We have demonstrated that these novel immune-modulatory worm molecules prevent diabetes in a mouse model. This offers great potential for the development of therapeutic interventions.
How does timing affect mammalian brain development and evolution? This project aims to generate fundamental knowledge on the origin of diversity in mammalian brain circuits by studying development of marsupials and rodents. The expected outcome is to elucidate how differences in the timing, rate and sequence of development of gene expression, cell differentiation and circuit formation can relate to the origin of key evolutionary innovations in the mammalian brain. The significance of understandi ....How does timing affect mammalian brain development and evolution? This project aims to generate fundamental knowledge on the origin of diversity in mammalian brain circuits by studying development of marsupials and rodents. The expected outcome is to elucidate how differences in the timing, rate and sequence of development of gene expression, cell differentiation and circuit formation can relate to the origin of key evolutionary innovations in the mammalian brain. The significance of understanding the dynamics of developmental systems that shape complex brain traits includes establishing new developmental paradigms in evolutionary theory, generating new tools to investigate and manipulate brain gene expression in vivo, and the potential discovery of the causes of neurodevelopmental dysfunction.Read moreRead less
Thalassaemia, is a common inherited disorder affecting haemoglobin synthesis. Synthesis of ?/?-globin chain is balanced during normal red blood cell production. Any disruption in the ratio of ?/?-globin chain results in anaemia. In this study, we will explore gene therapy strategies to restore balanced ?:? globin expression and ultimately improve the severely anaemic phenotype in ?-thalassaemia patients.
In Vivo Gene Transfer And Phenotype Correction Of Normal And Urea-cycle Deficient Primary Human Hepatocytes In Chimeric Mouse-human Livers: Towards Gene Therapy For Metabolic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$493,747.00
Summary
Genetic liver disease imposes a major health and economic burden. Existing medical treatments are frequently inadequate, often necessitating liver transplantation which carries its own limitations and risks. Using a gene therapy approach we have achieved life-long cure of mice with OTC-deficiency, a condition with a high risk of disability and death in affected infants. This application focuses on translating this success in mice through to human therapy.
The project aims to improve cochlear implant performance via integrated gene therapy. A neurotrophin gene cassette will be delivered to cells adjacent to the electrode array using electrical pulses. This drives regeneration of the auditory nerve fibres and considerably improves cochlear implant performance. This study will optimize the therapeutic gene construct and cochlear implant –based gene delivery controller, and undertake an initial clinical trial to evaluate safety and efficacy.
Repair Of Urea Cycle Defects In Mice By RAAV-mediated Gene Transfer: Towards Gene Therapy For Genetic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$445,578.00
Summary
Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the ....Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the development of improved AAV vectors with dramatically higher gene transfer efficiencies (up to two orders of magnitude in the liver). This places successful liver-directed gene therapy within reach. Initial human studies will only be possible in the context of severe diseases where existing therapies are high risk or inadequate. Accordingly, we have chosen the most common urea cycle defect, OTC deficiency, as a disease model. In its severe form neonatal hyperammonaemia is associated with a high risk of death and significant disability in those who survive the newborn period. Using the spf(ash) mouse model of OTC deficiency we propose to develop gene therapy strategies capable of achieving life-long disease cure. Preliminary data has confirmed feasibility, and suggests that the greater number of cells in the human liver requiring genetic repair will not prove insurmountable. The proposal focuses on issues critical to success in humans. These include strategies to minimise the number of repaired liver cells required for clinical benefit, overcoming the effects of liver growth, investigating the potential impact of OTC mutations on gene therapy, and establishing the likely efficiency of gene transfer in human liver cells and large animal livers equivalent in size to the human neonate. These studies are part of a long-term commitment to progress through to human clinical trials of gene therapy for urea cycle defects. The potential health and economic benefits are immense.Read moreRead less
Novel technology platform for gene delivery into intact cells. Delivery of DNA to cells is a crucial but highly inefficient process. This project will develop a way to manipulate the genetic code of cells efficiently and to easily generate stem cells from normal adult cells, thus avoiding controversial embryonic harvesting. This new technology will have potential benefits for research, agriculture and humans alike.
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
Identification And Evaluation Of Novel Epigenetic Targets For The Treatment Of ? Haemoglobin Disorders
Funder
National Health and Medical Research Council
Funding Amount
$740,809.00
Summary
Symptoms of ?-haemoglobin disorders appear after birth, when fetal haemoglobin (HbF) is replaced by aberrant adult haemoglobin (HbA). Interestingly, the persistent expression of HbF in patients reduces disease severity. This observation has created much interest in understanding the fetal to adult transition, since reversing it can benefit patients. Epigenetics plays a central role to this mechanism. Identifying components of this switch will form the basis of next generation therapies.