LAUSR

The promise of personalized medicine for monogenic and complex polygenic diseases depends on the availability of strategies for targeted inhibition of disease‐associated polymorphic protein variants. Loss of function variants, including non‐synonymous single nucleotide variants (nsSNVs) and insertion/deletion producing a frameshift, account for the vast majority of disease‐related genetic changes. Because it is challenging to interpret the functional consequences of nsSNVs, they are considered a big barrier for personalized medicine. A method for inhibiting the specific expression of nsSNVs without editing the human genome will facilitate the elucidation of the biology of nsSNVs, but such a method is currently lacking. Here, I describe the phenomenon of membrane anchorage‐induced (MAGIC) knockdown of allele‐specific inhibition of protein and mRNA expression upon inner membrane tethering of point mutation‐specific monoclonal antibodies (mAb). This phenomenon is likely mediated by a mechanism distinct from the protein degradation pathways, as the epitope‐specific knockdown is replicated upon intracellular expression of a membrane‐anchored single domain intrabody that lacks the Fc domain of the mAb. By harnessing the MAGIC knockdown of epitope‐containing protein targets, I report a novel approach for inhibiting the expression of amino‐acid‐altering germline and somatic nsSNVs. As a proof‐of‐concept, I show the inhibition of human disease‐associated variants namely, FGFR4 p.G388R, KRAS p.G12D and BRAF p.V600E protein variants. This method opens up a new avenue for not just therapeutic suppression of undruggable protein variants, but also for functional interrogation of the nsSNVs of unknown significance.