Rebuilding a protective allele with ADAR site-directed RNA editing

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  Figure 1. Copying a cardioprotective human allele into hepatic mRNA (A) The p.Asn352Ser variant of B4GALT1, enriched in the Old Order Amish, roughly halves the galactosyltransferase activity without abolishing the enzyme and is associated with lower LDL-C and fibrinogen and reduced cardiovascular risk. (B) An editing oligonucleotide delivered to the liver base-pairs with B4galt1 mRNA and recruits endogenous ADAR, which deaminates the target adenosine to inosine; the ribosome reads inosine as guanosine, substituting Asn352 for Ser. Transcript and protein abundances are unchanged, but galactosyltransferase activity falls by ∼30%; plasma glycoproteins lose terminal galactose, sialic acid, and core fucose; and ApoB-containing lipoproteins, fibrinogen, and cholesteryl ester transfer protein (CETP) are cleared faster. (C) Human genetics brackets the therapeutic window from both sides: about half of normal activity is protective, while complete deficiency causes a congenital disorder of glycosylation in humans and growth delay with early death in mice. The ∼30% activity reduction achieved here sits inside the protective window and derives from editing only 9%–18% of transcripts—an amplification…