Monash researchers develop new gene therapy tool

Gene therapy – the insertion of genes into cells to treat disease – holds great potential for conditions such as cardiovascular disease and cancers. Yet efficient and safe delivery of the genes to the right cells remains a significant, longstanding challenge.

Gene therapy – the insertion of genes into cells to treat disease – holds great potential for conditions such as cardiovascular disease and cancers. Yet efficient and safe delivery of the genes to the right cells remains a significant, longstanding challenge.

Associate Professor Christoph Hagemeyer from the Australian Centre for Blood Diseases (ACBD) has led a team that has developed a way of improving targeted gene transfer.

Currently, a virus called rAAV (recombinant adeno-associated virus) is used clinically as a vector to change DNA sequences in the body.

“The main issue with these viruses is that they have a certain tropism, which means they naturally go to a certain area of the body,” Associate Professor Hagemeyer said. “Most go to the liver and few go to the heart and other organs.

“People avoid that by using specific ‘promoters’ that are only active in certain organs, for example, heart specific promoters so that wherever the virus goes it will only be active in the heart,” he said.

The Central Clinical School-led scientists used an antibody as an alternative, in this case choosing an antibody that naturally attaches to a damaged blood vessel wall; the antibody then directed the virus specifically to this area.

“The application in this case is to treat vessel disease like atherosclerosis or vasculitis so anywhere where the lining of the vessel wall is inflamed we can use our antibody to bring virus to this area, then put in a therapy to stop the inflammation.”

The experiments had an unexpected, beneficial outcome. “The antibody on the surface of the virus masked the natural target of the virus so it’s not going to the original source but where we tell is to go. So we can direct the virus away from the liver to vessel walls – this is the first time this was done.”

Although other scientists had achieved a similar outcome with targeted viruses by building in a targeting motif into the vector, they had to use a new virus design for each new target, Associate Professor Hagemeyer said. The researchers’ technique meant scientists could use any existing therapeutic virus.

Their findings were published in Molecular Therapy — Methods & Clinical Development.

“That’s a technological advance we presented in our paper. It was very unexpected that we could redirect the natural tropism but it seems to be that we are masking or blocking some of the natural features on the surface of the virus that mediates this natural tropism,” he said.

“I think this has a lot of potential for clinical use as there’s strongly growing interest at the moment either to repair gene defects or put in new genes that can combat disease. The field is finally making some progress to personalise gene therapy to potentially correct life-threatening genetic effects in children and adults.”

Associate Professor Hagemeyer said the technique, a flexible platform technology for targeted gene transfer, would add to the toolbox that scientists, pharmaceutical companies and researchers will have to assemble targeted gene therapy vectors in a better, more streamlined way.

First author on the paper was PhD student Dr Hannah Pearce, who was supervised by Associate Professor Hagemeyer and who graduated from the Central Clinical School in 2017. The fruitful collaboration with Associate Professor Paul Gregorevic from the Baker IDI Heart and Diabetes Institute was instrumental in the study.

Reference
Pearce HA, Qian H, Connell TU, Huang D, Gottstein C, Donnelly PS, Peter K, Gregorevic P, Hagemeyer CE. Site-Specific Glycation and Chemo-enzymatic Antibody Sortagging for the Retargeting of rAAV6 to Inflamed Endothelium. Mol Ther Methods Clin Dev. 2019 Jul 23;14:261-269. doi: 10.1016/j.omtm.2019.07.003. eCollection 2019 Sep 13.