| abstract |
As described herein, an alternatively spliced intronic sequence is induced in the presence of a small molecule, e.g., Compound (I). Thus, in the presence of Compound (I), an intronic sequence is converted into an "intron-derived exon" that can be spliced into the mature mRNA transcript, leading to a frameshift in the mRNA open reading frame and in frame premature stop codons. The premature termination of translation triggers nonsense mediated mRNA decay and a concomitant reduction in the amount of protein encoded by the mRNA. Conversely, in the absence of Compound (I), the intronic sequence is spliced out of the pre-mRNA without causing a change to the mRNA's reading frame. In one aspect, Compound (I) can be 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol having the structure of: HTT-C3 Compound (I) can be orally administered with broad biodistribution for the treatment of Huntington's Disease by production of a small molecule-induced alternatively spliced transcript. |