RNA-based control switch could be used to turn on gene therapies in cells

A new technique to turn therapeutic genes on in specific cells has been developed, potentially changing the future of gene therapies.

Researchers from the Massachusetts Institute of Technology (MIT) and Harvard University in Cambridge and Boston, Massachusetts, respectively, have engineered this biological switch.

'This brings new control circuitry to the emerging field of RNA therapeutics, opening up the next generation of RNA therapeutics that could be designed to only turn on in a cell-specific or tissue-specific way', said senior author, Professor James Collins from MIT's Department of Biological Engineering.

Some types of gene therapy rely on the introduction of genetic material, known as transgenes, into human cells to substitute for defective or missing genes. It has advanced rapidly in recent years, now being trialled in conditions such as a genetic form of neurodegeneration (see BioNews 1104).

However, transgenes can produce adverse effects when expressed in the wrong place. Hence, the researchers investigated ways to limit the changes to specific cell types, increasing the specificity of gene therapy and reducing off-target effects.

The teams at Harvard and MIT based their approach on a viral technique to control protein production in host cells. They engineered transgene sequences, known as eToehold switches, that are inactive when built into RNA. The transgene only becomes activated when the eToehold is in the presence of the correct type of cell which has a specific messenger RNA sequence. This activation, leads to the translation of the transgene into a specific protein with the potential to target certain diseases in specific cells or tissues.

'We engineered eToeholds that [are] specifically triggered by cell-specific RNAs… for example, an RNA that is only expressed in skin melanocytes,' said co-lead author, Dr Angelo Mao.

The team has successfully tested the system in yeast, plant, and human cells so far.

'eToeholds could enable more specific and safer RNA therapeutic and diagnostic approaches not only in humans but also plants and other higher organisms and be used as tools in basic research and synthetic biology,' added Professor Collins.

The study was published in Nature Biotechnology.