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In Silico Analysis of Potential Off-Target Sites to Gene Editing for Mucopolysaccharidosis Type I Using the CRISPR/Cas9 System: Implications for Population-Specific Treatments

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source: PloS one

year: 2022

authors: Carneiro P,de Freitas MV,Matte U


Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase deficiency encoded by the IDUA gene. Therapy with CRISPR/Cas9 is being developed for treatment, however a detailed investigation of off-target effects must be performed. This study aims to evaluate possible off-targets for a sgRNA aiming to correct the most common variant found in MPS I patients (p.Trp402*). A total of 272 potential off-target sequences was obtained and 84 polymorphic sites were identified in these sequences with a frequency equal to or greater than 1% in at least one of the populations. In the majority of cases, polymorphic sites decrease the chance of off-target cleavage and a new PAM was created, which indicates the importance of such analysis. This study highlights the importance of screening off-targets in a population-specific context using Mucopolysaccharidosis type I as an example of a problem that concerns all therapeutic treatments. Our results can have broader applications for other targets already clinically in use, as they could affect CRISPR/Cas9 safety and efficiency.

organization: Post-Graduation Program on Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

DOI: 10.1371/journal.pone.0262299