Novel “smart” gene delivery system heals broken hearts

Cardiovascular disease kills one Australian every 12 minutes. Improved treatments are essential for tackling this major health problem. Researchers at The University of Queensland have developed a new gene therapy-based treatment to guide hearts to heal themselves.

Targeted transfection of nanoparticles carrying a Cy3-labelled microRNA (Cy3-miR) into human fetal cardiac fibroblast cells. Image shows Rab5 positive (green) early endosomes; LAMP1 positive (grey) lysosomes and transfected Cy3-miR (red), confirming that these Cy3-miR-carrying nanoparticles are absent in either the early endosome or lysosome, but present in late endosome.

Viral vectors are the current gold standard for gene therapy-based treatments; however, they have numerous drawbacks, including limited payload capacity, lack of cell-type specificity, and risk of possible mutations. To overcome these limitations, a collaboration between the Tissue Engineering and Microfluidics Group and Stem Cell Engineering Group at the Australian Institute for Bioengineering and Nanotechnology has developed synthetic self-assembling nanoparticles to deliver targeted therapeutic treatment for heart disease.

The researchers designed and developed the new biomaterial system for targeted delivery of therapeutic factors into particular cells within injured hearts, with the aim of transitioning the damaged heart tissue to functional heart tissue through a process known as direct reprogramming.

The team’s initial findings, published in Biomacromolecules, confirm that these nanoparticles permitted delivery of large DNA plasmids (and small microRNA), and furthermore, their successful translation to protein, but only in cells that expressed a particular set of ligands at their membrane – that is, cell-specific (targeted) delivery.

“This novel delivery system, which we are now applying to reprogram cardiac fibroblasts, will hopefully offer a new pathway to repair lost cardiac tissue post a heart attack, and moreover, may in the future be utilised for the development of a range of gene therapy-based tissue repair strategies,” explained Professor Justin Cooper-White, research team leader.

“Being able to access key equipment essential for the project and the help and assistance provided by the ANFF personnel has contributed significantly to the success of this project,” said Justin.

The work conducted in ANFF-Q utilised confocal imaging for immunofluorescent imaging and AFM microscopy for assessment of particle size and morphology. Contributions from ANFF-Q personnel were critical to moving this project forward.

Dr Elena Taran provided training for confocal microscopy and also gave suggestions and advice on taking high-resolution images. She was always available to provide help and assistance in terms of troubleshooting. Dr Kinnari Shelat advised on sample preparation and helped with AFM microscopy imaging. She was very helpful in sharing any information regarding the AFM microscope,” explained Dr Bingzhao Xia, co-author of the paper.

“The project is ongoing, with two other manuscripts in the process of being finalised in 2018. Continuous interactions with ANFF-Q personnel and use of the state-of-the-art equipment is a critical requirement for the current and future work,” said Dr Joan Li, research team member.

This novel “smart” gene delivery system for both plasmids and miRNA has many attractive characteristics, offering a safer and more efficient alternative to standard viral vector and liposomal systems. This research project can potentially lead to more specific and effective treatment options for people suffering from certain cardiovascular diseases.