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Poison exon

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Poison exons (PEs) are a class of cassette exons that contain premature termination codons. Inclusion of a PE in a transcript thus targets the transcript for degradation via nonsense-mediated decay.[1] [2]

Discovery

PEs were initially characterized in RNA-binding proteins from the SR protein family.[1] [2]

Regulation

Differential splicing of PEs is implicated in biological processes such as differentiation, tumorigenesis, and T cell expansion.[3][4]

Therapeutic relevance

As PE inclusion results in transcript degradation, targeted PE inclusion or exclusion is being evaluated as a therapeutic strategy. This strategy may prove especially applicable towards targets whose gene products are not easily ligandable such as "undruggable" proteins. Targeting PE inclusion/exlusion has been demonstrated with both small molecules and antisense oligonucleotides.[5]

Stoke Therapeutics is evaluating a strategy termed Targeted Augmentation of Nuclear Gene Output (TANGO).[6] Targeting exon 20N in SCN1A mRNA with the antisense oligonucleotide STK-001 blocks inclusion of this PE, leading to elevated levels of the productive SCN1A transcript and the gene product sodium channel protein 1 subunit alpha (NaV1.1). In mouse models of Dravet syndrome, which is driven by mutations in SCN1A,[7] STK-001 was able to reduce incidence of electrographic seizures and sudden unexpected death in epilepsy and prolong survival.[8][9] As of October 2024, STK-001 is being evaluated in phase 2 clinical trials (NCT04740476).[10]

Remix Therapeutics developed REM-422, which is an oral small molecule that promotes PE inclusion in the oncogene MYB. REM-422 was discovered through a screening campaign for molecules that promote PE inclusion in MYB. Subsequent in vitro experiments showed that REM-422 selectively facilitates binding of the U1 snRNP complex to oligonucleotides containing the MYB 5' splice site sequence. In various acute myeloid leukemia (AML) cell lines, REM-422 leads to degradation of MYB mRNA and lower MYB protein levels. REM-422 demonstrated antitumor activity in mouse xenograft models of acute myeloid leukemia.[11] As of October 2024, REM-422 is being evaluated in phase 1 clinical trials (NCT06118086, NCT06297941).[12][13]

PTC Therapeutics is evaluating the oral small molecule PTC518 as a treatment for Huntington's disease.[14] As of October 2024, PTC518 is being evaluated in phase 2 clinical trials (NCT05358717).[15]

References

  1. ^ a b Ni, Julie Z.; Grate, Leslie; Donohue, John Paul; Preston, Christine; Nobida, Naomi; O’Brien, Georgeann; Shiue, Lily; Clark, Tyson A.; Blume, John E.; Ares, Manuel (2007-03-15). "Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay". Genes & Development. 21 (6): 708–718. doi:10.1101/gad.1525507. ISSN 0890-9369. PMC 1820944. PMID 17369403.
  2. ^ a b Lareau, Liana F.; Inada, Maki; Green, Richard E.; Wengrod, Jordan C.; Brenner, Steven E. (April 2007). "Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements". Nature. 446 (7138): 926–929. Bibcode:2007Natur.446..926L. doi:10.1038/nature05676. ISSN 1476-4687. PMID 17361132.
  3. ^ Leclair, Nathan K.; Brugiolo, Mattia; Urbanski, Laura; Lawson, Shane C.; Thakar, Ketan; Yurieva, Marina; George, Joshy; Hinson, John Travis; Cheng, Albert; Graveley, Brenton R.; Anczuków, Olga (November 2020). "Poison Exon Splicing Regulates a Coordinated Network of SR Protein Expression during Differentiation and Tumorigenesis". Molecular Cell. 80 (4): 648–665.e9. doi:10.1016/j.molcel.2020.10.019. PMC 7680420. PMID 33176162.
  4. ^ Karginov, Timofey A.; Ménoret, Antoine; Leclair, Nathan K.; Harrison, Andrew G.; Chandiran, Karthik; Suarez-Ramirez, Jenny E.; Yurieva, Marina; Karlinsey, Keaton; Wang, Penghua; O’Neill, Rachel J.; Murphy, Patrick A.; Adler, Adam J.; Cauley, Linda S.; Anczuków, Olga; Zhou, Beiyan (2024-09-13). "Autoregulated splicing of TRA2 β programs T cell fate in response to antigen-receptor stimulation". Science. 385 (6714): eadj1979. Bibcode:2024Sci...385j1979K. doi:10.1126/science.adj1979. ISSN 0036-8075. PMID 39265028.
  5. ^ Sheridan, Cormac (2024-08-01). "A new class of mRNA drugs targets poison exons". Nature Biotechnology. 42 (8): 1159–1161. doi:10.1038/s41587-024-02355-4. ISSN 1546-1696. PMID 39143167.
  6. ^ Lim, Kian Huat; Han, Zhou; Jeon, Hyun Yong; Kach, Jacob; Jing, Enxuan; Weyn-Vanhentenryck, Sebastien; Downs, Mikaela; Corrionero, Anna; Oh, Raymond; Scharner, Juergen; Venkatesh, Aditya; Ji, Sophina; Liau, Gene; Ticho, Barry; Nash, Huw (2020-07-09). "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression". Nature Communications. 11 (1): 3501. Bibcode:2020NatCo..11.3501L. doi:10.1038/s41467-020-17093-9. ISSN 2041-1723. PMC 7347940. PMID 32647108.
  7. ^ Isom, Lori L.; Knupp, Kelly G. (July 2021). "Dravet Syndrome: Novel Approaches for the Most Common Genetic Epilepsy". Neurotherapeutics. 18 (3): 1524–1534. doi:10.1007/s13311-021-01095-6. PMID 34378168.
  8. ^ Han, Zhou; Chen, Chunling; Christiansen, Anne; Ji, Sophina; Lin, Qian; Anumonwo, Charles; Liu, Chante; Leiser, Steven C.; Meena; Aznarez, Isabel; Liau, Gene; Isom, Lori L. (2020-08-26). "Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome". Science Translational Medicine. 12 (558). doi:10.1126/scitranslmed.aaz6100. ISSN 1946-6234. PMID 32848094.
  9. ^ Wengert, Eric R.; Wagley, Pravin K.; Strohm, Samantha M.; Reza, Nuha; Wenker, Ian C.; Gaykema, Ronald P.; Christiansen, Anne; Liau, Gene; Patel, Manoj K. (January 2022). "Targeted Augmentation of Nuclear Gene Output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet Syndrome". Brain Research. 1775: 147743. doi:10.1016/j.brainres.2021.147743. PMID 34843701.
  10. ^ https://www.clinicaltrials.gov/study/NCT04740476. {{cite web}}: Missing or empty |title= (help)
  11. ^ Prajapati, Sudeep; Cameron, Michael; Dunyak, Bryan M.; Shan, Mengge; Siu, Y. Amy; Levin-Furtney, Samantha; Powe, Joshua; Burchfiel, Eileen T.M.; Cabral, Sarah E.; Harney, Alycen M.; Keenan, Regina K.; Larpenteur, Kevin M.; Maag, Jesper L.V.; Snyder, Andrew R.; Nguyen, Dan T. (2023-11-02). "REM-422, a Potent, Selective, Oral Small Molecule mRNA Degrader of the MYB Oncogene, Demonstrates Anti-Tumor Activity in Mouse Xenograft Models of AML". Blood. 142 (Supplement 1): 1425. doi:10.1182/blood-2023-182676. ISSN 0006-4971.
  12. ^ https://clinicaltrials.gov/study/NCT06118086?term=NCT06118086&rank=1. {{cite web}}: Missing or empty |title= (help)
  13. ^ https://clinicaltrials.gov/study/NCT06297941. {{cite web}}: Missing or empty |title= (help)
  14. ^ Bhattacharyya, Anuradha; Trotta, Christopher R.; Narasimhan, Jana; Wiedinger, Kari J.; Li, Wencheng; Effenberger, Kerstin A.; Woll, Matthew G.; Jani, Minakshi B.; Risher, Nicole; Yeh, Shirley; Cheng, Yaofeng; Sydorenko, Nadiya; Moon, Young-Choon; Karp, Gary M.; Weetall, Marla (2021-12-15). "Small molecule splicing modifiers with systemic HTT-lowering activity". Nature Communications. 12 (1): 7299. doi:10.1038/s41467-021-27157-z. ISSN 2041-1723.
  15. ^ https://clinicaltrials.gov/study/NCT05358717. {{cite web}}: Missing or empty |title= (help)
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