Project Details

Antisense strategy for correction of splice mutations in progressive genetic diseases in children

Dina Yagel, PhD

Summary

BACKGROUND: Premessenger RNA splicing is a necessary step in the production of a functional protein product, yet many mutations are known to lead to aberrant splicing and cause genetic diseases. One prominent technique for correcting splicing-related mutations is through the use of antisense oligonucleotides (ASOs). Recently, there have been significant advances in the clinical application of ASOs for correcting splice mutations, including an FDA approval for several antisense drugs. GAP: Despite its enormous potential, ASO therapy is currently only applied to a very small number of childhood genetic diseases. HYPOTHESIS: 1. Antisense oligonucleotides can be used to correct splice mutations in a large number of genetic diseases; 2. Novel ASO designs can make antisense therapy more effective and easier to generalize to other diseases. METHODS: Synthesize ASOs based on novel in silico tools developed in our lab, transfect them to fibroblasts, and measure the result by expression studies. Fibroblasts will be derived from patients with a variety of representative splicing-related mutations causing genetic diseases such as A-T, NEPAN, Collagen VI-like dystrophy, Costeff, and DNAJC12 deficiency. RESULTS: We identified two splice mutations in the ATM gene that are amenable to ASO therapy. One is a relatively common mutation, for which ASOs increased levels of wild type ATM mRNA, as well as the production of functional protein. For the other mutation we developed a novel modality that has the potential to be widely applicable well beyond splice mutations. IMPACT: In addition to a potential treatment for the diseases we target here, we expect knowledge gained in this project to be directly applicable to a very wide range of splice mutations. Through early intervention, one can hope to stop the disease progression and improve the clinical manifestation.