SingleCut CRISPR efficiently restored dystrophin expression in human engineered heart muscle and demonstrated broad applicability across a range of Duchenne mutations
Study published online in the journal Science Advances
CAMBRIDGE, Mass. – January 31, 2018 – Exonics Therapeutics, Inc., a biotechnology company focused on developing SingleCut CRISPR technology to repair mutations causing Duchenne muscular dystrophy and other neuromuscular diseases, recently demonstrated the application of SingleCut CRISPR technology for efficient in vivo correction of dystrophin expression in a mouse model of Duchenne. Today, Exonics announced the publication of a proof-of-concept study suggesting the Company’s SingleCut CRISPR approach has the potential to efficiently correct a larger spectrum of mutations and prevent cardiac abnormalities associated with Duchenne in human engineered heart muscle (EHM).
Dilated cardiomyopathy, characterized by contractile dysfunction and ventricular chamber enlargement, is a leading cause of death in patients with Duchenne, a devastating muscle disease for which there is currently no cure. Researchers identified optimal guide RNAs to direct Cas9 to the top 12 exons that, when skipped, can restore the expression of dystrophin, the key protein missing in children with Duchenne. Using optimized guide RNA sequences, the study evaluated the efficiency of guide RNAs across a diverse, representative sample of Duchenne patient mutations.
Using only a single-guide RNA in CRISPR-Cas9 genome editing efficiently restored contractile dysfunction in EHM to a level comparable to healthy EHM in a wide spectrum of mutation types, indicating the approach’s potential to eliminate mutations and restore the production of normal dystrophin protein. Further, the research shows that EHM may serve as a suitable preclinical tool to evaluate therapeutic efficacy of gene editing.
“This study demonstrates the simplicity, efficacy and specificity of Exonics’ SingleCut CRISPR approach to correcting Duchenne mutations,” said Eric Olson, Ph.D., co-author of the research, founder and chief science advisor of Exonics, and professor and chair of the Department of Molecular Biology at UT Southwestern Medical Center. “Even relatively large and complex deletions may be corrected and dystrophin expression restored by making only a single cut in the DNA sequence, without the need for multiple guide RNAs.”
“This research underscores the potential of our SingleCut CRISPR technology to help efficiently correct many of the gene mutations that cause Duchenne and other serious neuromuscular diseases,” said John Ripple, chief executive officer of Exonics. “Combined with the encouraging results from a prior published preclinical study in a Duchenne mouse model, we have a solid foundation from which to continue building our development program.”
The research article, titled, “Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genomic editing,” was published online in the journal Science Advances.
About Exonics Therapeutics
Exonics Therapeutics has developed SingleCut CRISPR, a gene repair technology that has the potential to effectively halt the progression of certain genetic neuromuscular diseases. In multiple Duchenne muscular dystrophy preclinical models, Exonics has used SingleCut CRISPR to genetically repair and restore dystrophin, the key protein missing in children with Duchenne. Exonics is initially focused on correcting mutations that cause Duchenne in order to develop a therapy to treat many children with the devastating disease, for which there is no cure. Exonics’ technology is licensed from UT Southwestern Medical Center and is based on the research of Eric Olson, Ph.D., Exonics’ founder and chief science advisor. Exonics is located in Cambridge, Mass. For more information, please visit www.exonicstx.com.