The eye has become an excellent target for gene therapy, and gene augmentation
therapy of inherited
retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of
retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous
isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the
retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as
PTC124,
aminoglycoside antibiotics, and designer
aminoglycosides for overreading in-frame
nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary
retinal dystrophies. In-frame
nonsense mutations are single-
nucleotide alterations within the gene coding sequence resulting in a
premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated
proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the
premature termination codon into a
sense codon, thus restoring syntheses of full-length
proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for
PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of
nonsense mutations causing
retinal degeneration, as manifested in the human
Usher syndrome. In addition, a strong
retinal biocompatibility for
PTC124 and designer
aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating
nonsense mutation-based
retinal disorders.