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Creation of de novo cryptic splicing for ALS and FTD precision medicine.

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  • معلومة اضافية
    • المصدر:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
    • بيانات النشر:
      Publication: : Washington, DC : American Association for the Advancement of Science
      Original Publication: New York, N.Y. : [s.n.] 1880-
    • الموضوع:
      Amyotrophic Lateral Sclerosis*/genetics ; Amyotrophic Lateral Sclerosis*/therapy ; DNA-Binding Proteins*/genetics ; DNA-Binding Proteins*/metabolism ; Frontotemporal Dementia*/genetics ; Frontotemporal Dementia*/therapy ; Precision Medicine* ; RNA Splicing*; Animals ; Humans ; Mice ; Deep Learning ; Gene Editing ; HEK293 Cells ; RNA Splice Sites ; RNA-Binding Proteins/metabolism ; RNA-Binding Proteins/genetics
    • نبذة مختصرة :
      Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.
    • Comments:
      Update of: bioRxiv. 2023 Nov 15:2023.11.15.565967. doi: 10.1101/2023.11.15.565967. (PMID: 38014203)
      Comment in: Science. 2024 Oct 4;386(6717):24-25. doi: 10.1126/science.ads5951. (PMID: 39361768)
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    • Grant Information:
      MR/M008606/1 United Kingdom MRC_ Medical Research Council; CC0102 United Kingdom ARC_ Arthritis Research UK; 215593 United Kingdom WT_ Wellcome Trust; CC0102 United Kingdom CRUK_ Cancer Research UK; CC0102 United Kingdom MRC_ Medical Research Council; ZIA HD008966 United States ImNIH Intramural NIH HHS; CC0102 United Kingdom WT_ Wellcome Trust; U54 NS123743 United States NS NINDS NIH HHS; United Kingdom WT_ Wellcome Trust
    • الرقم المعرف:
      0 (DNA-Binding Proteins)
      0 (RNA Splice Sites)
      0 (RNA-Binding Proteins)
      0 (TARDBP protein, human)
    • الموضوع:
      Date Created: 20241003 Date Completed: 20241003 Latest Revision: 20241102
    • الموضوع:
      20250114
    • الرقم المعرف:
      PMC7616720
    • الرقم المعرف:
      10.1126/science.adk2539
    • الرقم المعرف:
      39361759