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New base editor extends machinery to correct single base pair mutations

Genetic diseases can be caused by the change as small as the mutation of a single A, G, C or T to one of the other four bases. Base editing is the potential to correct such single base pair mutations. Currently, it is possible to correct C to T. This is done by targeting a cytidine deaminase enzyme to the mutation. The enzyme converts a C to uracil, the functional equivalent of a T. The  Cas9 protein that targets the enzyme to the site of the mutation then also “nicks” the opposite strand of the DNA. The nick will then be repaired with an A to match the newly exchanged base and achieve correction of both strands of the double helix. 

Until now, it was not possible to edit any other bases than C -> T. This week, however, researchers from Harvard University published a new class of base editors that convert A to G. The new base editor was derived from an E. coli deaminase that works on RNA. Through creating millions of different mutations in this enzyme, David Liu and his team first created and then improved a version of the deaminase that acts on DNA rather than RNA. 

As a proof of principle, the new A -> G deaminase was used to correct the mutation that causes a disease that causes iron overload in the body known as hereditary haemochromatosis (HHC). This correction was done in cells and the researchers add that there is much work to be done before this base editor can be used to treat humans. Others not involved in the research, including Feng Zhang, Andrew Bassett and Robin Lovell-Badge commented in various news outlets that the approach used was impressive and the research was both clever and important for human health. 

The collection of base editors is still missing enzymes that can convert C to G and A to T.

 

Original article:

Nature

 

Digests for a general audience:

The Scientist

The Independent