Synthesis and evaluation of novel antisense oligonucleotides for Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant progressive neuromuscular disorder caused by CTG repeat expansion in the 3’- UTR of the DMPK gene. This mutation causes formation of toxic RNA transcripts that accumulate in nuclear foci and sequester RNA-binding proteins such as MBNL, resulting in widespread defects in alternative splicing and cellular dysfunction. No curative treatment is available for DM1 patients. Given the central role of toxic CUG repeat RNA in DM1 pathogenesis, therapeutic strategies aimed at eliminating or silencing these mutant transcripts represent a promising approach. Among these, antisense oligonucleotides (ASOs) have emerged as particularly attractive candidates due to their ability to selectively target and degrade disease-causing RNA through RNase-H-mediated mechanisms. Despite the several FDA approved ASOs -based therapies, the clinical translation of ASOs remains challenging, largely due to limitations in cellular uptake, nuclear delivery, and tissue specificity, which highlights the need for the design of next-generation ASOs with improved pharmacological properties. From an organic chemistry perspective, the design and synthesis of such conjugates require precise chemical strategies for incorporating lipophilic moieties into oligonucleotide scaffolds. The controlled introduction of these groups, whether at the 3' or 5' terminus, or at internal positions within the sequence, demands the development of purpose-built functionalized monomers compatible with solid-phase oligonucleotide synthesis. This chemistry-driven approach forms the backbone of the present work.