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Site-Blocking Oligos (SBO) Upregulate Utrophin for Treatment of Duchenne Muscular Dystrophy (DMD)
University of Pennsylvania
Nucleotide
Musculoskeletal disease
Target Identification or Validation
• PMO-based SBOs complementary to the let-7c binding site in UTRN 3′UTR, with the goal of inhibiting let-7c interaction with UTRN mRNA and thus upregulating utrophin.
• The solution is a set of synthetic site-blocking oligonucleotides (SBO) which inhibits natural degradation of utrophin mRNA. These SBOs block downregulation of utrophin, increasing its expression in muscle cells which alleviates DMD symptoms. The invention works by binding to a site in utrophin mRNA which is usually targeted for degradation. Utrophin-upregulating SBOs may be used in combination with other upregulation strategies to further increase cellular expression of therapeutic utrophin.
• To increase production of therapeutic utrophin in muscle cells, a set of five SBOs ranging from 24-29 base pairs were synthesized. All SBOs target the same utrophin mRNA 3’-UTR region. The SBOs increase utrophin expression by hybridizing to the Let-7c microRNA binding site. This prevents Let-7c microRNA from binding to utrophin mRNA and facilitating degradation through the RNA-induced silencing complex. Utrophin-upregulating SBOs are created using a nucleic acid mimic known as a phosphorodiamidate morpholino oligonucleotide (PMO) to decrease undesirable toxicity and increase tissue accumulation.
WO2022109432A2
PMO-based let-7c site blocking oligonucleotide (SBO) mediated utrophin upregulation in mdx mice, a therapeutic approach for
Duchenne muscular dystrophy (DMD). Sci Rep, (2020)
