आणविक और आनुवंशिक चिकित्सा

Treatment of Nonsense Mutations Using Stop Codon Read-through Therapeutics and Creation of Animal Models Using CRISPR-Cas9

Abstract

Kelly A. Turner and Francis YM Choy

Premature termination codons result when a mutation within a protein coding sequence causes an amino acidencoding sense codon to be interpreted as a stop codon. Often, this results in truncation and destruction of the mRNA transcript or a non-functional protein. Nonsense mutations account for approximately 11% of all described mutations that contribute to disease. A number of therapeutics, including suppressor tRNAs, gentamicin, and PTC124, have been developed that purport to promote the “read-through” of these premature termination codons so that they are interpreted as sense codons. This, theoretically, would reconstitute the full-length transcript and restore protein/enzyme function and ameliorate disease symptoms. Currently, the implementation of such therapeutics in a clinical setting has been slow due to factors such as toxicity and inefficiency. We will discuss these hurdles as well as the difficulties associated with determination of the required protein/enzyme level to reduce symptoms as well as breakthroughs in genome editing to create nonsense mutation animal models using the clustered regularly interspersed short palindromic repeats-CRISPR-associated protein 9 system.