ABSTRACT
A large number of diseases are caused by premature stop mutations that often lead to a complete loss o f protein function and a severe reduction in mRNA levels due to nonsense-mediated mRNA decay (NMD). Two main approaches to develop treatments for diseases caused by premature stop mutations have been investigated. The first is to reduce the efficiency of translation termination through the use of pharmacological agents or by the expression of suppressor tRNAs. The second approach is to replace the premature stop muta tion with wild-type sequence using gene repair techniques. Although each of these approaches have been demonstrated using in vitro studies or mouse models, currendy only strategies using pharmacological agents to suppress stop mutations have reached preliminary clinical trials. The future of suppression therapy will require finding ways to increase the efficacy of current compounds to suppress premature stop mutations without side effects, or to design or discover safe new compounds that suppress premature stop mutations with increased efficiency. In ad dition, combined therapies that simultaneously suppress a premature stop mutation and in hibit NM D of the nonsense-containing mRNA may be the most effective way to increase the efficiency of suppression therapy.
