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Publication Detail
Mutation-Independent Allele-Specific Editing by CRISPR-Cas9, a Novel Approach to Treat Autosomal Dominant Disease.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Christie KA, Robertson LJ, Conway C, Blighe K, DeDionisio LA, Chao-Shern C, Kowalczyk AM, Marshall J, Turnbull D, Nesbit MA, Moore CBT
  • Publication date:
  • Journal:
    Mol Ther
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    CRISPR-Cas9, allele specificity, autosomal dominant disease, gene therapy, patient-specific, personalised medicine
CRISPR-Cas9 provides a tool to treat autosomal dominant disease by non-homologous end joining (NHEJ) gene disruption of the mutant allele. In order to discriminate between wild-type and mutant alleles, Streptococcus pyogenes Cas9 (SpCas9) must be able to detect a single nucleotide change. Allele-specific editing can be achieved by using either a guide-specific approach, in which the missense mutation is found within the guide sequence, or a protospacer-adjacent motif (PAM)-specific approach, in which the missense mutation generates a novel PAM. While both approaches have been shown to offer allele specificity in certain contexts, in cases where numerous missense mutations are associated with a particular disease, such as TGFBI (transforming growth factor β-induced) corneal dystrophies, it is neither possible nor realistic to target each mutation individually. In this study, we demonstrate allele-specific CRISPR gene editing independent of the disease-causing mutation that is capable of achieving complete allele discrimination, and we propose it as a targeting approach for autosomal dominant disease. Our approach utilizes natural variants in the target region that contain a PAM on one allele that lies in cis with the causative mutation, removing the constraints of a mutation-dependent approach. Our innovative patient-specific guide design approach takes into account the patient's individual genetic make-up, allowing on- and off-target activity to be assessed in a personalized manner.
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