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RNA editing tools could create new disease therapies

30 October 2017
Appeared in BioNews 924

A new molecular tool to change individual letters in an RNA sequence may open up new possibilities for gene therapy.

Scientists at the Broad Institute in Cambridge, Massachusetts, developed a method similar to the CRISPR/Cas9 genome editing system for DNA.

'This new ability to edit RNA opens up more potential opportunities to... treat many diseases, in almost any kind of cell,' Professor Feng Zhang, who led the research, told the BBC.

DNA sequences encode instructions to make proteins, and are used as templates to make RNA molecules. RNA is transported through the cell to structures called ribosomes, where the proteins are made.

Most mutations in DNA which cause disease change these protein-making instructions. For example, they may produce a protein that does not function properly.

While most gene therapy strategies target DNA sequences, the team in this latest research replaced the DNA-binding Cas9 enzyme in the CRISPR-Cas9 system with Cas13 enzyme, which binds to RNA. They then fused the Cas13 to another enzyme called ADAR2, which converts the base or 'letter' A (adenine) to I (inosine, a molecule which is read as guanine) in RNA. Finally, they added a guide RNA molecule to target the system to the precise RNA sequence to be edited.

Professor Darren Griffin at the University of Kent said the new system provided 'a much needed research tool and a possible future route for targeted therapy'.

He noted that RNA editing may have benefits over DNA editing. 'By targeting the message (RNA) rather than the DNA itself, this means that effects on genes can be modified for a short amount of time, and at particular crucial stages,' he said. 'Importantly, the effects of the manipulation are transient and can thus be removed when no longer needed.'

The system, called RNA Editing for Programmable A to I Replacement, or REPAIR, was used in human cells to correct mutations which cause Fanconi anaemia and X-linked nephrogenic diabetes insipidus.

The research, published in Science, showed that REPAIR could correct the mutations up to 50 percent of the time, with a low number of off-target effects.

However, REPAIR is still a long way from the clinic. Dr Ben Davies of the University of Oxford, who was not involved in the research, said: 'The REPAIR system is … associated with off-target activity.  These effects are reduced …, but off-target RNA edits are still ultimately detectable.'

The researchers now plan to improve REPAIR's efficiency and produce a system which can deliver REPAIR to cells in an animal model.


The latest developments in genome editing will be discussed at the session 'What Next for Genome Editing? Politics and the Public', at the Progress Educational Trust's upcoming public conference 'Crossing Frontiers: Moving the Boundaries of Human Reproduction'.

The conference is taking place in London on Friday 8 December 2017. Full details - including sessions, speakers and how to book your place - can be found here.

SOURCES & REFERENCES
CRISPR hacks enable pinpoint repairs to genome
Nature News |  25 October 2017
'Incredible' editing of life's building blocks
BBC News | 
Researchers engineer CRISPR to edit single RNA letters in human cells
MIT News |  25 October 2017
RNA Editing Possible with CRISPR-Cas13
The Scientist |  25 October 2017
RNA editing with CRISPR-Cas13
Science |  25 October 2017
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