Ayal Hendel, PhD
Stanford School of Medicine, Stanford, California, US
CTG/CAG repeat tracts represent the genetic basis for more than a dozen inherited dominant neurological disorders including Myotonic Dystrophy type 1 (DM1) and Huntington’s disease that currently have no cure. Despite the multitude pathologies underlying these devastating disorders, they all share common etiology: the expansion of CTG/CAG repeats. Interestingly, expanded CTG/CAG repeats have been shown to be prone to double-strand breaks (DSBs). Moreover, it was shown that the repair of the DSBs leads mainly to repeat contractions. These findings suggest that controlled DSBs might provide a way to induce repeat contractions that will correct disease-causing mutation and reduce disease risk. Dr. Hendel’s research will harness a unique genome editing technology in combination with induced pluripotent stem cells to examine the contribution of DSB repair to the stimulation of repeat contractions in DM1 cells, ultimately exploring new cellular and molecular DM1 pathological mechanisms involved in myotonic dystrophy.
Suzanne Rzuczek, PhD
Scripps Research Institute Florida, US
Dr. Rzuzcek, in conjunction with the Disney Lab of The Scripps Institute, plans on using small molecules to disrupt the interaction between repeating CUG RNA and MBNL1 (muscleblind-like 1 protein), freeing it to function normally. The Disney Lab, of which Dr. Rzuczek is a member, has designed and synthesized several compounds that specifically bind the expanded CUG RNA and disrupt the interaction with MBNL1 in vitro. These compounds contain CUG-binding small molecules tethered together by a spacer. This approach is called modular assembly. Recently the spacer has been optimized to increase bioactivity and cell uptake. Dr. Rzuczek and her colleagues will improve the activity of the modularly assembled compounds using two approaches. The first will use the repeating DM1 RNA as a template to assemble small compounds with their optimized spacer into large modularly assembled structures within cells. This process is known as in situ click chemistry. The second approach will screen many small molecules that are similar to the known binders of DM1 RNA. Hit compounds will be screened in cells using a method that detects low levels of bioactivity. Compounds that are active in cells will be modularly assembled on the Disney-optimized spacer to enhance the interaction with DM1 RNA and improve bioactivity. If successful, these compounds could become a treatment for myotonic dystrophy.