Editing Nonsense mutation (section)

== Therapeutics targeting nonsense mutation diseases ==
Therapeutics for diseases caused by nonsense mutations attempt to recapitulate wild-type function by decreasing the efficacy of NMD, facilitating readthrough of the premature stop codon during translation, or editing the genomic nonsense mutation.<ref name=":10">{{Cite journal |last1=Morais |first1=Pedro |last2=Adachi |first2=Hironori |last3=Yu |first3=Yi-Tao |date=2020-06-20 |title=Suppression of Nonsense Mutations by New Emerging Technologies |journal=International Journal of Molecular Sciences |volume=21 |issue=12 |pages=4394 |doi=10.3390/ijms21124394 |pmc=7352488 |pmid=32575694|doi-access=free }}</ref>

[[Antisense oligonucleotide]]s to suppress the expression of NMD and translation termination proteins are being explored in animal models of nonsense mutation-induced disease.<ref name=":10" /><ref>{{Cite journal |last1=Huang |first1=Lulu |last2=Aghajan |first2=Mariam |last3=Quesenberry |first3=Tianna |last4=Low |first4=Audrey |last5=Murray |first5=Susan F. |last6=Monia |first6=Brett P. |last7=Guo |first7=Shuling |date=August 2019 |title=Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations |journal=Nucleic Acid Therapeutics |volume=29 |issue=4 |pages=175–186 |doi=10.1089/nat.2019.0779 |pmc=6686700 |pmid=31070517}}</ref> Other RNA therapeutics under investigation include synthetic suppressor tRNAs that enable [[ribosome]]s to insert an amino acid, instead of initiating chain termination, upon encountering premature stop codons.<ref name=":10" />

[[CRISPR gene editing|CRISPR-Cas9]] based single nucleotide substitutions have been used to generate amino acid codons from stop codons, achieving an editing success rate of 10% in cell cultures.<ref>{{Cite journal |last1=Lee |first1=Choongil |last2=Hyun Jo |first2=Dong |last3=Hwang |first3=Gue-Ho |last4=Yu |first4=Jihyeon |last5=Kim |first5=Jin Hyoung |last6=Park |first6=Se-eun |last7=Kim |first7=Jin-Soo |last8=Kim |first8=Jeong Hun |last9=Bae |first9=Sangsu |date=2019-08-07 |title=CRISPR-Pass: Gene Rescue of Nonsense Mutations Using Adenine Base Editors |journal=Molecular Therapy |volume=27 |issue=8 |pages=1364–71 |doi=10.1016/j.ymthe.2019.05.013 |pmc=6698196 |pmid=31164261}}</ref>

Read-through has been achieved using small molecule drugs such as [[aminoglycoside]]s and negamycin.<ref name=":10" /> An [[oxadiazole]], [[ataluren]] (previously PTC124), facilitates the selective read-through of aberrant stop codons, rendering it a potential therapeutic against nonsense mutation-induced disease.<ref>{{Cite journal |last1=Welch |first1=Ellen M. |last2=Barton |first2=Elisabeth R. |last3=Zhuo |first3=Jin |last4=Tomizawa |first4=Yuki |last5=Friesen |first5=Westley J. |last6=Trifillis |first6=Panayiota |last7=Paushkin |first7=Sergey |last8=Patel |first8=Meenal |last9=Trotta |first9=Christopher R. |last10=Hwang |first10=Seongwoo |last11=Wilde |first11=Richard G. |last12=Karp |first12=Gary |last13=Takasugi |first13=James |last14=Chen |first14=Guangming |last15=Jones |first15=Stephen |date=2007-05-03 |title=PTC124 targets genetic disorders caused by nonsense mutations |url=https://pubmed.ncbi.nlm.nih.gov/17450125 |journal=Nature |volume=447 |issue=7140 |pages=87–91 |doi=10.1038/nature05756 |issn=1476-4687 |pmid=17450125|bibcode=2007Natur.447...87W |s2cid=4423529 }}</ref> Ataluren, sold under the tradename Translarna, is currently an approved treatment for Duchenne muscular dystrophy in the [[European Economic Area|European Economic area]] and [[Brazil]].<ref>{{Cite web |title=PTC Therapeutics |url=https://www.ptcbio.com/our-pipeline/approved-medicines/ |access-date=2022-12-01 |website=PTC Therapeutics {{!}} Measured by Moments |language=en-US}}</ref><ref name=":7">{{Cite web |date=2021-10-26 |title=ANVISA approves PTC Translarna indication expansion to ambulatory children |url=https://www.pharmaceutical-technology.com/news/anvisa-ptc-translarna-indication-children/ |access-date=2022-12-01 |website=Pharmaceutical Technology |language=en-US}}</ref> However, phase III trials of Ataluren as a cystic fibrosis therapeutic have failed to meet their primary endpoints.<ref name=":8">{{Cite journal |last1=Kerem |first1=Eitan |last2=Konstan |first2=Michael W |last3=De Boeck |first3=Kris |last4=Accurso |first4=Frank J |last5=Sermet-Gaudelus |first5=Isabelle |last6=Wilschanski |first6=Michael |last7=Elborn |first7=J Stuart |last8=Melotti |first8=Paola |last9=Bronsveld |first9=Inez |date=2014-07-01 |title=Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial |journal=The Lancet Respiratory Medicine |volume=2 |issue=7 |pages=539–547 |doi=10.1016/S2213-2600(14)70100-6 |pmc=4154311 |pmid=24836205}}</ref><ref>{{Cite journal |last1=Konstan |first1=M. W. |last2=VanDevanter |first2=D. R. |last3=Rowe |first3=S. M. |last4=Wilschanski |first4=M. |last5=Kerem |first5=E. |last6=Sermet-Gaudelus |first6=I. |last7=DiMango |first7=E. |last8=Melotti |first8=P. |last9=McIntosh |first9=J. |last10=De Boeck |first10=K. |last11=ACT CF Study Group |date=July 2020 |title=Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF) |journal=Journal of Cystic Fibrosis|volume=19 |issue=4 |pages=595–601 |doi=10.1016/j.jcf.2020.01.007 |pmc=9167581 |pmid=31983658}}</ref>