A NOVEL APPROACH FOR TARGETING DNA TO DENDRITIC CELLS IN VIVO FOR VACCINE DEVELOPMENT AND CANCER IMMUNOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$430,250.00
Summary
The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor populati ....The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor population of cells known as dendritic cells, which are present in blood and other tissues, play an important role in eliciting the effects of DNA vaccines. However, current methods for delivering DNA to these cells often lack selectivity in delivery, and-or use viruses to deliver the DNA. This can pose the risk of allergic type reactions and-or possibly cause tumours. The use of small membranous vesicles known as liposomes, made of phospholipids, has recently attracted considerable interest as DNA delivery vehicles, since these are considered safe, and have the potential to deliver large quantities of DNA. Although DNA can easily be packaged inside liposomes, it is has not been easy to target the liposomes and their contents (eg. encapsulated DNA) to specific cells (such as dendritic cells) within the body. We have recently produced a novel chelator lipid molecule which can be used to conveniently attach onto the liposome surface specific targeting molecules, such as engineered forms of antibody fragments, that can target or steer the liposomes together with their payload (eg. the DNA), directly to dendritic cells. This project will test the potential for using such targeted liposomes as DNA vaccines by examining whether liposomes containing DNA for a model antigen can be used in vaccinations to inhibit the growth and metastasis of a highly metastatic tumour (melanoma) in mice.Read moreRead less
Phosphonated Calixarenes For The Targeted Intracellular Delivery Of Anticancer Agents
Funder
National Health and Medical Research Council
Funding Amount
$322,267.00
Summary
Many anticancer drugs have severe side effects due to their potency and non-specificity of action. To improve the treatment outcome for thousands of cancer patients, we aim to engineer calixarene-based nanocarriers that bypass normal tissues to selectively deposit drugs and imaging agents into tumour cells. Such delivery systems will optimize the performance of a host of anticancer agents that act within cells, and enable drug treatment and monitoring to be simultaneously realised.
Structure And Function Of Antimicrobial Therapies And Their Interaction With Upper Respiratory Biofilms
Funder
National Health and Medical Research Council
Funding Amount
$320,891.00
Summary
Bacterial infections of the upper respiratory tract are a major public health problem affecting millions of Australians. Commonly prescribed antibiotics are often not able to eradicate all bacteria as the bacteria often reside in a protective, self-produced gel-like matrix known as biofilm. This Fellowship aims to unravel the interaction of modern anti-infective therapeutics with the biofilm for the development of the next generation of safe and efficacious anti-biofilm strategies.
Engineered Histones As DNA Carriers With Application In Therapeutic Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy ....We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy approaches is the low efficiency of nuclear uptake of introduced DNA, where it has been estimated that < 1% of the DNA taken up is actually expressed. Our proposal seeks to develop approaches to enhance non-viral-mediated gene delivery, in particular by optimising this critical, limiting step of the delivery of exogenous DNA to the nucleus. We intend to apply knowledge from studies of nuclear targeting and chromatin assembly to improve gene transfer technologies. We will build on our work showing that specific signals for nuclear import - nuclear targeting signals (NTSs) - can be used to enhance nuclear gene delivery and expression. Since DNA in the normal cellular context is in the form of chromatin - a specific complex with proteins such as histones - we intend to use reconstituted chromatin as the transfecting DNA, whereby histones engineered to include NTSs and other modular sequence elements will be used. Chromatin should not only enable NTSs and other sequence modules to be linked to the DNA but also protect against nuclease-mediated degradation prior to nuclear entry, condense the DNA to enable more efficient cellular-nuclear entry, and ensure expression of the transfected reporter gene by presenting it to the cell in a physiological context. Our approaches should contribute to bringing gene therapy closer to reality in the clinic.Read moreRead less
Nanomedicines Immunotargeting: Hitting The Target Or Lost In Translation ?
Funder
National Health and Medical Research Council
Funding Amount
$413,042.00
Summary
Nanomedicines are some of the most exciting novel approaches to improving the way we detect, manage and treat cancers. This cross-disciplinary project aims to provide a rigorous understanding of how nanomedicines penetrate solid tumour tissues. To validate in vitro tumour model developed in the project, in vivo studies will be carried out in a mice model. The penetration and distribution of nanomedicines inside tumour tissues after intravenous administration will be determined.
Platform Nanotechnologies For Oral Delivery Of Drugs, Therapeutic Protein And Peptide Delivery
Funder
National Health and Medical Research Council
Funding Amount
$437,034.00
Summary
The development of reliable oral delivery systems for problem drugs and biologics is one of the biggest challenges faced by the pharmaceutical industry in recent times. In order to tackle these challenges, I have developed programmable nanoparticles capable of efficiently deliver wide range of drugs including large peptides and proteins orally.
Treatment Of Genetic Liver Disease By Homologous Recombination In Vivo, Coupled With A Pharmoco-genetic Strategy For Selective Expansion Of Genetically Repaired Hepatocytes
Funder
National Health and Medical Research Council
Funding Amount
$920,836.00
Summary
This project seeks to exploit recent advancements in our ability to precisely “edit” and correct mutations underlying human genetic diseases. To improve therapeutic efficiencies of the system, we will deliver the technology using highly efficient virus-based systems and apply a novel post-repair selection process to preferentially repopulate the liver with gene-repaired cells. Demonstration of the strategy in a humanised mouse model will provide important preclinical data for human applications.
A Novel Tumour-targeting Nanoliposome Drug Delivery System For The Treatment Of Malignant Gliomas
Funder
National Health and Medical Research Council
Funding Amount
$445,097.00
Summary
Most patients with malignant brain tumours die within a year after diagnosis due to the difficulty in effectively delivering drugs to the tumour cells. We aim to develop a safe and novel drug delivery system to effectively deliver anticancer drugs and novel anticancer agents to brain tumour cells that remain in normal brain after surgery. The success of this project will bring us a step forward in our efforts to significantly improve the survival rate and quality of life of such patients.
The Use Of Gene-Silencing Nanodrugs To Inhibit Lung Cancer Growth
Funder
National Health and Medical Research Council
Funding Amount
$452,950.00
Summary
Lung cancer accounts for the most cancer deaths worldwide. This research proposal will use state-of-the-art nanomedicines designed to penetrate lung tumours and suppress a gene which drives cancer growth and resistance to chemotherapy drugs. Our results could underpin new approaches that revolutionise more effective and less toxic treatments for a highly lethal malignancy.
Site-specific Integration Of Functional Genomic Loci: Applications In Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$442,664.00
Summary
Gene therapy strategies have traditionally focused on the delivery of therapeutic genes by viral vectors. Mindful of the limitations and potential problems of viral gene delivery, non-specific viral integration and limited transgene expression, this investigation will explore the delivery and site-specific integration of large genomic fragments into human stem cells. It is anticipated this approach will avoid some of the problems associated with poor gene expression and insertional oncogenesis.