Ask the Experts with Matthew Mulvey: What is “Big DNA”?

While significant progress has been made in the field of genomic medicine, substantive challenges remain in achieving its tremendous potential.

83% of genes are too big to be accommodated by the adeno-associated virus (AAV) vector, which is the current standard platform for gene delivery. As a result, our ability to treat the majority of diseases of global significance, which are complex, polygenic diseases caused by multiple genes, is limited.

Replay aims to address this issue using its synHSV™ high payload capacity technology platform, which can deliver up to 30x the payload of AAV and that enables genes to be delivered in their natural form.

Matt Mulvey, Chief Technology Officer at Replay, explains more:

“DNA is the digital instruction code for life. It is what allows life on Earth to exist and propagate. Since it is a codescript, it can be modified, either gradually over time through evolution by natural selection, or as a result of intentional engineering, to adapt life to new environments or to generate new functions.

The field of synthetic biology attempts to transform the DNA code into a read/write medium capable of achieving specific purposes in biology. When the mechanism by which the DNA code specifies protein sequences was deciphered and scientists could assemble small DNA pieces, it enabled proteins to be manufactured on an industrial scale. The most common form of this process is the industrial production of therapeutic enzymes and antibodies that have been approved for the treatment of a broad range of diseases.

HSV: 150kb vs. AVV: 4.8kb

New emerging technologies will soon be available that will allow scientists to rapidly and efficiently synthesize and assemble large pieces of DNA, known as ‘Big DNA’.

This will allow the science of synthetic biology to go beyond the limitations of current approaches and to create and administer genomically rewritten or ‘reprogramed’ cells to treat human diseases. Ultimately, as the ability to write Big DNA improves, it will become possible to redesign and build entire genomes to generate synthetic organisms of industrial and medical significance.

A key challenge in the development of Big DNA therapeutics is how to efficiently deliver them to cells and ensure that they are functional and behave in a physiological manner. At Replay we have, amongst other things, developed synHSV™, a high payload capacity HSV vector capable of delivering large genes, genomic genes, multiple genes and multiple transcriptional regulators. This capability has the potential to extend the reach of genomic medicines and has the possibility to transform the therapeutic landscape for patients.”