This well-known proverb from the Gospel of Luke takes an exciting transformation in this month's Journal Club to

 Ribosome heal yourself

The possibility of this modified proverb coming to fruition as a potential treatment for certain patients with DBA came one step closer with the publication of a recent manuscript entitled: "Ataluren treatment of patients with nonsense mutation dystrophinopathy."  While the disease addressed in this Phase 2b clinical trial was muscular dystrophy, it seems reasonable to envision that the results from this trial may extend to certain patients with DBA.

 The patient sub-population in inherited genetic diseases that may benefit from the drug Ataluren is patients with nonsense mutations in protein coding genes.  In the trial with Ataluren the gene involved encodes the protein dystrophin, but the hope is that the effects may be generalizable to virtually any protein-coding gene causing a human disease, including the genes affected in DBA.

 I've discussed the types of mutations that occur in protein coding genes in this venue before.  These mutations affect the readout of the genetic information from mRNA to protein.  The protein-coding information contained within an mRNA begins with a start codon that initiates the synthesis of a protein.  The ribosome then moves down the mRNA reading the genetic code in groups of three bases, adding one amino acid at a time to the growing protein until the ribosome reaches a termination codon.  Once the ribosome encounters a termination codon, protein synthesis is halted and the protein is released from the ribosome where it can then perform whatever function it is destined to do within the cell.

 Nonsense mutations arise when there is a mutation in the gene that changes a base in the coding region of an mRNA from a codon that encodes an amino acid to a codon that now specifies termination.  These mutations fall somewhere between the initiation codon and the normal termination codon, thus resulting in premature termination of protein synthesis.  Premature termination often results in a protein that lacks all of its parts and so can result in the loss of a protein's function and cause a myriad of human diseases, depending on the protein affected.

 It has been known for many years that certain classes of antibiotics cause the misreading of termination codons allowing the ribosome to pass through a termination codon without stopping.  It was therefore thought that these drugs could potentially be used to treat diseases caused by nonsense mutations.  These drugs however have side effects that have diminished enthusiasm for their use in treating genetic diseases.  This did not, however, stop research into finding safer drugs with similar modes of action.

 One such drug was developed by the small pharmaceutical company called PTC Therapeutics, which was begun by University researchers studying the consequences of premature termination in yeast (here I will shamelessly give a shout out to the importance of basic science research and not knowing where such research will lead).  The drug, Ataluren, works by an unknown mechanism that allows ribosomes to read through premature termination codons while still allowing normal termination codons to function.  This drug showed promising results in model systems of different human genetic diseases and a proof-of-concept Phase 2a clinical trail.   The current study goes one step further to a Phase 2b randomized double-blind clinical trial comparing 2 doses of Ataluren with placebo.