Small particles with big potential: Antibody targeting to suppress cancer causing genes

7 June 2016

Researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) have been awarded $515,000 in funding for an Australian Research Council (ARC) Linkage grant with project partner Avidity NanoMedicines. The ARC Linkage Projects scheme promotes collaborations between higher education researchers and industry organisations to perform innovative research that can contribute to Australia’s economic, cultural and social benefits.

The project looks to develop agents that can efficiently deliver small interfering ribonucleic acid (siRNA) into tumour cells. The goal will be to use these delivery systems to reduce expression of genes in diseases that are characterised by aberrant expression or overexpression of specific genes, such as cancer.

siRNA therapy is still in the research and development phase due to the complexity involved in delivering RNA or DNA to the target cells. Avidity Nanomedicines are pioneering new technology by coupling siRNA to antibodies that seek out cancer cells.  The MIPS team is led by Professor Colin Pouton of the Drug Delivery, Disposition and Dynamics theme, who has long been interested in gene therapy. In particular, he interested in how viruses can achieve delivery of RNA or DNA into the cytoplasm of host cells.

Usually when a cell takes up foreign particles, such as complexes DNA or RNA, it destroys those objects using intracellular enzymes. “Viruses are very successful in escaping that fate, and are effective in transporting and incorporating their RNA or DNA into the cells,” said Professor Pouton.  “Some viruses have evolved mechanisms to escape the degradative pathway, a trait that is highly desirable for cancer treatment.”

Unfortunately the use of viruses for delivery of RNA comes with many problems and risks, including the possibility that the body can react to the virus and induce an inflammatory reaction.  Additionally, viruses are difficult to manufacture on a large scale. There is therefore a move in the field towards the use of synthetic delivery systems, which are safer to use and more suitable for mass production.

MIPS’ partner in the project, Avidity NanoMedicines, is a USA-based biopharmaceutical company that specialises in developing antibody targeting systems that can deliver siRNA to specific cells. Together with Professor Pouton and the rest of the MIPS team, the researchers are hoping to use the attributes that viruses have evolved to escape the degradative pathway to design antibody-based delivery systems that can target specific cells and mimic viral mechanisms to escape being destroyed.

“MIPS has the infrastructure and the expertise to conduct the multidisciplinary research that is required for this project,” said Dr Andrew Geall, Vice President of Formulations and Chemistry at Avidity NanoMedicines. “The combination of world-class researchers with powerful imaging and analytical instruments makes MIPS an attractive partner for us.”

MIPS researchers involved in the project include Dr Bim Graham (Medicinal Chemistry theme) and Dr Angus Johnston (Monash University node leader of the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology), who will be involved in investigating the efficiency of the delivery systems developed at Avidity NanoMedicines. Dr Erica Sloan (Drug Discovery Biology theme) will then take promising delivery systems and test them first in tumour cells, then on tumours in mice, to see how effective they are in turning off an overactive gene.

Amongst the research infrastructure that will be used in the project is the Helen Macpherson Smith Trust HMSTrust Laboratory, which is an open-access laboratory containing state-of-the-art analytical instruments. One of the three Monash Biomedical Imaging pre-clinical facilities, also based at MIPS, will provide world-class biomedical imaging equipment for visualising tumours in rodent animal models of cancer.

Professor Pouton believes that this project can unlock the utility of the siRNA delivery technology for a wide range of diseases.

“While cancer is the most obvious disease to target, this technology has the potential to be applicable for the treatment of any disease where there is an excessive activity of a certain gene,” said Professor Pouton.