Kunjin Replicons For Gene Therapy And Protein Manufacture
Funder
National Health and Medical Research Council
Funding Amount
$310,000.00
Summary
This grant seeks to provide proof of concept (PoC) for the use of the Kunjin replicon technology for gene therapy and protein production. (A) Protein production. Two Kunjin replicon constructs expressing green fluorescent protein (GFP) and secreted alkaline phosphatase (SEAP) are to be constructed and protein production monitored using FACS and SEAP bioactivity reporter kit (Roche), respectively. Protein production and biological activity of the proteins will be monitored in transient transfecti ....This grant seeks to provide proof of concept (PoC) for the use of the Kunjin replicon technology for gene therapy and protein production. (A) Protein production. Two Kunjin replicon constructs expressing green fluorescent protein (GFP) and secreted alkaline phosphatase (SEAP) are to be constructed and protein production monitored using FACS and SEAP bioactivity reporter kit (Roche), respectively. Protein production and biological activity of the proteins will be monitored in transient transfections and over an extended time period. Several cell lines, culture conditions and Kunjin replicon vector modifications will be tested. Arrangements have also been made to send the constructs to Roche, GSK, Eli Lilly, and Exelixis for side by side comparisons of this system with existing proprietary protein production echnologies. (B) Gene therapy. Two PoC gene therapy systems are proposed to be used for evaluation of Kunjin replicon vectors. (i) Tumours expressing granulocyte macrophage colony stimulating factor (GMCSF) by transfection cause the generation of anti-tumour CD8 T cells and subsequent tumour rejection. Current approaches include adoptive transfer of adeno-GM-CSF transfected tumour cells, a costly and laborious process resulting in only transient expression (Can. Imm. Immunother 2001 50:373). We intend to inject Kunjin replicon virus like particles into growing s.c. B16 melanomas and expect to see a high infection rate, a sustained high-level expression of GMCSF, and rejection of the tumour. In contrast to Kunjin, nearly all humans have antibody responses to adenovirus, and very high titres of adenovirus are required to obtain high infection and GM-CSF expression. Both factors limit adenovirus use in vivo. (ii) Transplant rejection can be inhibited by expression in the graft of CTLA4-Fc a reagent that blocks T cell co-stimulation enhancing allo-graft acceptance (Transplantation 2000 69:1806). High-level expression for over 100 days is expected to correlate with optimal graft acceptance. Our ability to use Kunjin to express beta galactosidase for several months in vivo without inflammation illustrates the potential for this approach (CIB ref 15). Initially we intend to use P815 cells injected i.p. into C57BL-6, where they are usually rejected within a few days. In contrast, P815 cells with Kunjin replicon-mediated CTLA4-Fc expression should survive for an extended period. Graft survival is easily monitored using FACS and anti-H-2d antibodies.Read moreRead less
The Effect Of Stress/strain And Fatigue Fracture Sites On Durability Of Modular Aortic Endografts And Arterial Walls
Funder
National Health and Medical Research Council
Funding Amount
$300,919.00
Summary
Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in 100 years because of the reduction in deaths from preventable and treatable diseases, and prolongation of life with chronic and incurable diseases. The older community (>65 years) continues to be active and productive contrary to prior predictions. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. As with many other diseases, prophylaxi ....Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in 100 years because of the reduction in deaths from preventable and treatable diseases, and prolongation of life with chronic and incurable diseases. The older community (>65 years) continues to be active and productive contrary to prior predictions. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. As with many other diseases, prophylaxis against aneurysmal disease is the most effective approach since 80% of those that rupture will result in death. Endoluminal grafting provides a much less invasive procedure and provides an attractive and elegant alternative to open surgery. The danger is that structural strengths will be compromised with failures due to lack of strength and inadequate device durability. The most practical endografts are those that are built up from modules but vulnerable sites affected by fatiguing and disruptive forces are being identified, in particular where a tube divides into two outflow channels – the bifurcation - and joins. To improve and protect the current device, and enable sound engineering for future devices, we need to know the nature, magnitude and location of these forces. The existing collaboration with medical specialist, Cook Aust., the Advanced Fluid Dynamics Laboratory (CSIRO, Melb.) and University of WA combines a multidisciplinary team working towards the design and durability of the next generation of endoluminal devices and percutaneous insertions. While Australia is at the forefront of development, its current place in the market can only be maintained by further product development. Optimising and improving endoluminal grafts will reduce the suffering of major surgery while prolonging a higher quality of life with a much less invasive procedure whose long-term effectiveness, and thereby acceptance is dependent upon reliable durability.Read moreRead less
A Novel Vaccine Platform For Trimeric Envelope Proteins: HIV-1 Envelope
Funder
National Health and Medical Research Council
Funding Amount
$139,250.00
Summary
Vaccines are urgently needed for the prevention of HIV/AIDS. The design of this vaccine candidate is based on the display of HIV-1 envelope spikes using a related primate retrovirus envelope with a more stable assembly to anchor the the spikes in a particle.
Minimal Structural Strength Required In Endoluminal Devices For Aortic Aneurysms: Mechanisms Of Rupture When They Fail.
Funder
National Health and Medical Research Council
Funding Amount
$102,794.00
Summary
Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in the last 100 years mainly because of the reduction in deaths from occlusive cardiovascular disease. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. The impact of this work would be to improve minimally invasive, effective prophylaxis against aneurysm of the abdominal aorta since 80% of those that rupture will result in death. Endoluminal ....Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in the last 100 years mainly because of the reduction in deaths from occlusive cardiovascular disease. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. The impact of this work would be to improve minimally invasive, effective prophylaxis against aneurysm of the abdominal aorta since 80% of those that rupture will result in death. Endoluminal grafting provides a much less invasive procedure and provides an attractive and elegant alternative to open surgery. The general drive in this field is towards miniaturisation. The danger is that structural strengths will be compromised with early failures due to lack of strength; and late failures due to inadequate device durability. This application proposes the development of a collaborative venture with the Department of Vascular Surgery, Royal Perth Hospital, Cook R and D (WA), the Advanced Fluid Dynamics Laboratory (CSIRO, Melbourne) and Centre for Health Services Research (University of WA) to investigate the dynamic flow forces involved in aneurysms of the abdominal aorta. It combines together expertise and facilities to examine the forces acting upon endoluminal stent grafts in pulsatile high pressure environments, the impact on the design, patency, effectiveness and longer-term outcomes. The multidisciplinary team provides a comprehensive approach for this developing area of high technology surgery throughout Australia and internationally. The benefits of this study will directly influence the design and durability of the next generation of endoluminal devices and percutaneous insertions. While Australia is at the forefront of development, its current place in the market can only be maintained by further product development.Read moreRead less
The NanoNautilus : A Breakthrough In The Successful Treatment Of Strokes And Other Cerebrovascular Diseases
Funder
National Health and Medical Research Council
Funding Amount
$187,212.00
Summary
Strokes are one of the biggest killers of Australians and are becoming increasingly so every year. Bleeding from the brain involves extremely delicate and dangerous medical treatments. The development of NanoNautilus [TM]---a remote-controlled steerable microcatheterusing world-first miniaturization technology---will revolutionise current practises and greatly reduce the current risk with medical intervention.
Exploitation Of Unique Growth Factors To Develop New Products For Infertility Treatment
Funder
National Health and Medical Research Council
Funding Amount
$132,525.00
Summary
Infertility comes at an enormous social and financial cost to Australian society; infertility is a major psychological burden on young couples and the technologies used to treat infertility, such as in vitro fertilisation (IVF), require expensive drugs to stimulate the ovary. The cost of these drugs to Medicare is expected to exceed $100 million p.a. over the next decade. A reproductive technology, which has always shown great potential to elevate some of this burden, is oocyte (egg) in vitro ma ....Infertility comes at an enormous social and financial cost to Australian society; infertility is a major psychological burden on young couples and the technologies used to treat infertility, such as in vitro fertilisation (IVF), require expensive drugs to stimulate the ovary. The cost of these drugs to Medicare is expected to exceed $100 million p.a. over the next decade. A reproductive technology, which has always shown great potential to elevate some of this burden, is oocyte (egg) in vitro maturation (IVM), which drastically reduces the use-cost of drugs and the stress to patients. However, oocyte IVM has been slow to live up to its potential and the technology is still not in widespread clinical practice, mainly due to disappointing success rates in women. We have been studying oocyte IVM in animals for many years, and have recently made a significant technological breakthrough, improving success rates by ~50%. In this field, a 50% increase in efficiency is substantial and has significant clinical and commercial application. Currently, we are the only group worldwide with this technology. Over the course of this 2-year project we will conduct follow-up experiments to refine this discovery and investigate the feasibility of using this approach to treat human infertility. We are already in negotiations with two medical device manufacturers to licence this technology. We expect that this project will lead to a series of products and technologies that will enter a clinical trial for the treatment of infertility within 2-3 years.Read moreRead less