14.05.2020Wrona et al.: CRISPR-Directed Therapeutic Correction at the NCF1 Locus Is Challenged by Frequent Incidence of Chromosomal Deletions

Efficacy of gene editing may be improved by simultaneous targeting and editing of a gene and its pseudogenes, which is advantageous for their clinical application. Because this may lead to resurrection of non-processed pseudogenes, such approach has the potential to increase the overall correction efficacy of a gene-editing-based gene therapy. In this article Wrona et al. investigate such an approach for treatment of a pseudogene-associated disorder, the immuno­deficiency p47^phox-deficient chronic granulomatous disease (p47^phox CGD). Using CRISPR-Cas9 technology, they targeted and corrected the predominant disease-causing ΔGT mutation within the p47^phox-expressing NCF1 gene. The authors demonstrate that simultaneous targeting of the mutated NCF1 and its pseudogenes results in therapeutic CGD phenotype correction in vitro, however, it is accompanied by potentially harmful chromosomal deletions, mandating technological improvements to limit induction of multiple double-strand breaks on a single chromosome.

Full Article here: https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(20)30075-9

Cornelia Schauz