Base editing rescue of spinal muscular atrophy in cells and in mice.

Tytuł:: Base editing rescue of spinal muscular atrophy in cells and in mice.
Autorzy:: Arbab M; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Matuszek Z; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Kray KM; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Du A; Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.
Newby GA; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Blatnik AJ; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Raguram A; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Richter MF; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Zhao KT; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Levy JM; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Shen MW; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.; Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Arnold WD; Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.; NextGen Precision Health, University of Missouri, Columbia, MO 65212, USA.
Wang D; Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.; RNA Therapeutics Institute, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.
Xie J; Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.
Gao G; Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.; Microbiology and Physiological Systems, UMass Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.
Burghes AHM; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Liu DR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Źródło:: Science (New York, N.Y.) [Science] 2023 Apr 21; Vol. 380 (6642), pp. eadg6518. Date of Electronic Publication: 2023 Apr 14.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-
MeSH Terms:: Gene Editing*
Muscular Atrophy, Spinal*/genetics
Muscular Atrophy, Spinal*/therapy
Survival of Motor Neuron 1 Protein*/genetics
Survival of Motor Neuron 2 Protein*/genetics
Animals ; Mice ; Fibroblasts/metabolism ; Motor Neurons/metabolism
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Grant Information:: R00 NS119743 United States NS NINDS NIH HHS; K99 HL163805 United States HL NHLBI NIH HHS; R00 HL163805 United States HL NHLBI NIH HHS; R35 GM118062 United States GM NIGMS NIH HHS; K99 NS119743 United States NS NINDS NIH HHS; R01 HD060586 United States HD NICHD NIH HHS; R01 EB022376 United States EB NIBIB NIH HHS; United States HHMI Howard Hughes Medical Institute; P01 HL053749 United States HL NHLBI NIH HHS; RM1 HG009490 United States HG NHGRI NIH HHS; T32 GM095450 United States GM NIGMS NIH HHS; U01 AI142756 United States AI NIAID NIH HHS
Substance Nomenclature:: 0 (Survival of Motor Neuron 1 Protein)
0 (SMN2 protein, mouse)
0 (Survival of Motor Neuron 2 Protein)
0 (Smn1 protein, mouse)
Entry Date(s):: Date Created: 20230330 Date Completed: 20230512 Latest Revision: 20240406
Update Code:: 20240406
PubMed Central ID:: PMC10270003
DOI:: 10.1126/science.adg6518
PMID:: 36996170
: Czasopismo naukowe

Pełny tekst

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from survival motor neuron (SMN) protein insufficiency resulting from SMN1 loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of SMN2 , an insufficient copy of SMN1 harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five SMN2 regulatory regions. Base editing converted SMN2 T6>C, restoring SMN protein levels to wild type. Adeno-associated virus serotype 9-mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average life span, which was enhanced by one-time base editor and nusinersen coadministration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.

Comment in: Nat Rev Drug Discov. 2023 May;22(5):353. (PMID: 37024675)

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