Publications
Detailed Information
Discovery of novel disease-causing mutation in SSBP1 and its correction using adenine base editor to improve mitochondrial function : Discovery of novel disease-causing mutation in <i>SSBP1 </i>and its correction using adenine base editor to improve mitochondrial function
Cited 0 time in
Web of Science
Cited 0 time in Scopus
- Authors
- Issue Date
- 2024-09
- Publisher
- Nature Publishing Group
- Citation
- Molecular Therapy - Nucleic Acids, Vol.35 No.3, p. 102257
- Abstract
- Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified fi ed a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fi broblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (<= 30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (<= 10% editing). Despite this, NG-ABE8eWQedited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with SSBP1 mutations.
- ISSN
- 2162-2531
- Files in This Item:
- There are no files associated with this item.
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.