One RNA trans-splicing therapeutic could address 97% of all Rett syndrome mutations.
Levels of MECP2 protein matter. Too little or too much protein can cause neurological problems. Complicating the situation is the fact that different types of brain cells produce varying levels of the MECP2 protein. Furthermore, due to X chromosome inactivation, about half of all cells in females with Rett already make normal amounts of MECP2.
Strategies that fix the underlying errors restore the normal levels of MECP2 without the possibility of introducing too much protein. Gene editing, RNA editing, and RNA trans-splicing fall into this category. Gene replacement does not fall into this category, as it is not possible to control how many copies of a gene enter into any given cell.
One Therapeutic For
Once RNA is copied from DNA various portions of the RNA are unnecessary and need to be removed. A specialized cellular machine called a splicesome removes the unnecessary regions and splices the remaining sections together to create the final processed RNA that is ready for translating into protein.
Dr. Stuart Cobb is pursuing Spliceosome-Mediated RNA Trans-splicing (SMaRT) technology which leverages the normal regulatory mechanisms within cells and should therefore produce the appropriate amount of MECP2 protein in each brain cell.
SMaRT works by providing an engineered healthy RNA molecule (RNA Trans-splicing Molecule or RTM) and hijacking the spliceosome to ensure that it gets spliced into the RNA in lieu of the diseased sections. The RTM encompasses a large enough section of the RNA to address 97% of all mutations.
Mutations not addressed are those found in exon 1 of the protein. If SMaRT is proven successful a separate RTM could be engineered for the remaining 3%.