According to a study, researchers examine mRNA drugs offer a promising new approach to deliver therapeutic replacement proteins, and novel strategies designed to engineer more stable and active proteins are further enhancing the potential of mRNA therapies. Specific examples of sequence engineering that led to improved expression, duration, and enzymatic activity of target proteins. The study was published in Nucleic Acid Therapeutics.
The researchers described the methods they used to engineer specific protein sequences and demonstrated the positive effects this had on protein expression in mice. Sequence engineering was also able to improve the thermostability and activity of the therapeutic enzymes.
Developing protein variants with improved stability and activity should reduce necessary dosing frequency, and hence improve patient compliance. Messenger RNA (mRNA) is a promising new class of therapeutics that has potential for treatment of diseases in fields such as immunology, oncology, vaccines, and inborn errors of metabolism.
mRNA therapy has several advantages over DNA-based gene therapy, including the lack of the need for nuclear import and transcription, as well as limited possibility of genomic integration. One drawback of mRNA therapy, especially in cases such as metabolic disorders where repeated dosing will be necessary, is the relatively short in vivo half-life of mRNA (∼6–12 h).
They hypothesize that protein engineering designed to improve translation, yielding longer-lasting protein, or modifications that would increase enzymatic activity would be helpful in alleviating this issue. In this study, we present two examples where sequence engineering improved the expression and duration, as well as enzymatic activity of target proteins in vitro. We then confirmed these findings in wild-type mice. This work shows that rational engineering of proteins can lead to improved therapies in vivo.