RNA trans-splicing therapy in Rett Syndrome

Stuart Cobb, PhD and Chris Sibley, PhD | University of Edinburgh

$1,158,475 AWARDED

While traditional gene therapy (gene replacement) shows great promise for Rett Syndrome it also has inherent challenges: gene therapy can produce too much MeCP2 protein and cause toxicity; different brain cell types produce widely varying levels of MeCP2 protein; females are mosaic with roughly 50% of cells making normal amounts of MeCP2

An alternative technology called Spliceosome-Mediated RNA Trans-splicing (SMaRT) represents an attractive option to overcome these hurdles. This approach works by correcting the RNA transcribed from the gene before it is translated into MECP2 protein. Specifically, by hijacking a cell’s natural RNA splicing machinery to join a therapeutic RNA trans-splicing molecule (RTM) to ‘healthy’ parts of the endogenous gene, entire regions harboring disease-causing mutations can be ‘bypassed’. Because large chunks of the RNA sequence can be replaced, a single RTM could effectively correct 97% of the Rett mutations.

This approach would restore MECP2 protein levels towards normal without the possibility of elevating MECP2 towards toxic thresholds. Moreover, the approach would selectively raise levels of functional MECP2 protein only in the cells where the mutant copy of MECP2 is expressed, leaving cells expressing the healthy copy of MECP2 unchanged.

To increase the level of RNA splicing expertise on this project Dr. Cobb has recruited a new highly qualified collaborator, Chris Sibley, at the University of Edinburgh, who should significantly benefit the project and further improve the chances of its success.


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