RNA Therapeutics for Diseases Caused by Nonsense Mutations

A method to suppress premature translation termination and NMD to generate full-length protein using target-specific guide RNAs.


Problem Solved by the Technology

A disease-modifying therapy for conditions caused by nonsense mutations, such as Duchenne or Becker muscular dystrophies and cystic fibrosis has long been sought, but to date, none has been found. A few therapies at various clinical phases of development either address the already-mutated RNA, or simply ameliorate the symptoms of the diseases. This invention is aimed to generate functional full length mRNAs and subsequently proteins to provide a cure for the diseases.



Researchers at the University of Rochester have developed a method for the site-specific conversion of a target uridine within an RNA chain into a pseudouridine through the introduction of a target-specific guide RNA into the cells. Guide RNAs can be conveniently designed and remain stable in vivo throughout the lifetime of the cells. Remarkably, uridine-to-pseudouridine conversion at a pre-mature stop codon of an mRNA results in NMD (nonsense-mediated mRNA decay) suppression and stop codon read-through (aka nonsense suppression), and consequently, synthesis of the full-length protein is restored. This approach can therefore be applied to diseases that are caused by nonsense mutations (e.g., some Duchenne muscular dystrophy patients bearing a nonsense mutation in the dystrophin gene, and some cystic fibrosis patients who have a nonsense mutation in the CFTR gene).


Chen, C., Zhao, X., Kierzek, R. and Yu, Y.-T. (2010) "A flexible RNA backbone within the polypyrimidine tract is required for U2AF65 binding and pre-mRNA splicing in vivo." Mol Cell Biol. 30, 4108-19.  PMID: 20606010.


Karijolich, J. and Yu, Y.-T. (2011) "Converting nonsense codons into sense codons by targeted pseudouridylation." Nature, 474, 395-398.

[This paper was highlighted in Nature by a News & Views commentary (Adrian R. Ferre-D’Amare, 2011, "Stop the nonsense." Nature, 474, 289-290), in Nature Chemical Biology as an editors’ choice from recent literature (TLS, 2011, Translation: "A pseudogenetic code." Nature Chemical Biology, 7, 496-497), and in many other journals, news papers, and magazines as well.]


Fernandez, I. S., Ng, C. L., Kelley, A. C., Wu, G., Yu, Y.-T. and Ramakrishnan, V.  (2013) "Unusual base pairing during the recoding of a stop codon containing pseudouridine."  Nature, 500, 107-110.

URV Reference Number: 6-1446
Patent Information:
Title Country Patent No. Issued Date
Nonsense Suppression and Genetic Codon Alteration by Targeted Modification United States 8,603,457 12/10/2013
Targeted Pre-mRNA/mRNA Modification and Gene Regulation United States 9,238,813 1/19/2016
For Information, Contact:
Weimin Kaufman
Licensing Manager
University of Rochester
Yi-Tao Yu
Xinliang Zhao
Gene Therapy