Writing RNA modifications / RNA therapeutics

The success of the COVID vaccines marked a historic event, in which mRNA molecules were employed as therapeutics for the first time. Critical to the success of the vaccine was the use of modified building blocks: specifically all uridines in the vaccine were replaced with methylpseudouridines. Given the ease to design and synthesize mRNA, the potential for mRNA based therapeutics is vast - yet, it also imposes numerous challenges. Our lab seeks to harness our understanding of how RNA modifications act naturally towards improved RNA therapeutics. In doing so, we are utilizing our evolving ability to ‘read’ RNA modifications in order to develop abilities to ‘write’ modifications.

There are two key directions we are currently focusing on. One direction is using endogenous RNA modifying enzymes in order to correct genetic mutations. Some RNA modifications - if introduced at the mutated site - have the potential of correcting these mutations and restoring the proper code. In already published work we have dissected the mechanisms and requirements for recruitment of a pseudouridylation and deamination machineries towards target sites, with the goals of inducing stop-codon readthrough and recoding, respectively. We are currently systematically studying dozens of additional RNA modifying enzymes.

In parallel, a major challenge of mRNA therapeutics is the relatively short half life of RNA. We are exploring whether introduction of RNA modifications can increase the stability and translatability of nucleic-acid based therapeutics.

Publications