Small molecules targeting utrophin mRNA untranslated regions overcome post-transcriptional repression

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder that affects approximately 1 in 3500 males worldwide. DMD is caused by mutations in the DMD gene that lead to severe reduction or loss of dystrophin protein. Without appropriate dystrophin expression, patients experience progressive muscle degeneration and weakness that leads to early death around the third decade of life. While corticosteroids can be used to slow disease progression, there is no definitive cure for DMD.

In the absence of dystrophin, the autosomal homolog utrophin has been shown to partially replace dystrophin function. Utrophin is highly expressed during fetal development, but is actively down-regulated in adult muscle through numerous post-transcriptional repression mechanisms. Rather than supplement utrophin expression using gene therapy, this technology prevents repression of endogenous utrophin transcripts in adult muscle to enhance expression.

Scientists in the Khurana lab used high-throughput screening to identify small molecule compounds that increase utrophin expression by acting at the 5’ and/or 3’ untranslated regions (UTRs) of the utrophin transcript. Lead compounds were prioritized using an algorithm developed by the Inventors that incorporates specificity and dose-response characteristics. The top 5 hits from a SelleckChem Bioactive Compound library (detailed in Table 2 Loro, Emanuele et al.) are all approved by the FDA for clinical testing. In vivo validation of the top hit, trichostatin A (TSA) showed increased utrophin expression and muscle function after three months in a mouse model of DMD (see figure). A second screen comprising 96,000 small molecules revealed five additional novel compounds that may be developed as DMD therapeutics.

• Eight of the top 10 SelleckChem compounds increase utrophin expression over 1.5-fold
• Seven of the top 10 SelleckChem hits have been used in clinical trials which provide safety and tolerability information in humans
• Approach enables expression of full-length protein, in contrast to gene replacement strategies that are limited by vector size
• Use of small molecules avoids potential toxic immune response against viral vectors or transgenes