I am researching a treatment for cystic fibrosis (CF) called Eluforsen and I am trying to understand the mechanism by which an RNA molecule can restore proper protein function. In many research articles I come across the same sentence:

"Eluforsen, is an antisense RNA oligonucleotide designed to bind specifically to the mRNA region around the F508-encoding deletion and to restore CFTR protein function."

But I cant find any literature explaining how an antisense RNA molecule can restore function of a protein on its own. When I think of antisense RNA I think of RNA interference not restoring protein function.

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    – tyersome
    Jan 31 '20 at 20:44
  • $\begingroup$ nature.com/articles/nbt0102-47 $\endgroup$
    – canadianer
    Feb 1 '20 at 7:29

The root of the problem for a majority of cystic fibrosis patients is that they have two defective genes for a particular protein and at least one of these genes is defective because it is missing a 3-base codon for the amino acid at position 508 of the protein.

Eluforsen, also known as QR-010, is a somewhat modified 33-base RNA molecule. The bases in it are complementary to an area centered on the codon for amino acid 508 of the normal mRNA (messenger RNA) for the protein. Since the defective mRNA is missing 3 bases in the middle of this sequence, eluforsen binds to only 30 bases of the mRNA and has an unbound loop of three bases in the middle, as suggested by the wiggle in this diagram:

QR-010 mRNA matching [image from SEC]

Such a double-stranded stretch of mRNA is abnormal, of course, but the effect of its presence at least some of the time is to cause the mRNA to undergo repair in the duplex area in a manner which makes a break in the main strand opposite the loop and inserts RNA bases that are complementary to the three "excess" bases present in the eluforsen loop. Since these three bases are complementary to the normal mRNA bases at that point, the effect is to transform the defective mRNA into a normal mRNA. When the repaired mRNA is translated by a ribosome, a normal protein is produced, and some of the symptoms of the CF condition are reduced because of the presence of normal protein.

The mechanism which causes the mRNA to be repaired in this manner is not yet well understood(1). The condition improvement from a complementary mRNA fragment was noted back in 2004.(2) One hypothesis is that RNAse H is involved in the repair.(1) Some further information about QR‐010 effects can be found towards the end of reference (3).

(1) Matos & Matos, 2018

(2) Zamecnik et al., 2004

(3) Alton et al., 2016


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