Design of efficacious somatic cell genome editing strategies for recessive and polygenic diseases

Jared Carlson-Stevermer, Amritava Das, Amr A. Abdeen, David Fiflis, Benjamin I Grindel, Shivani Saxena, Tugce Akcan, Tausif Alam, Heidi Kletzien, Lucille Kohlenberg, Madelyn Goedland, Micah J. Dombroe and Krishanu Saha ()
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Jared Carlson-Stevermer: University of Wisconsin-Madison
Amritava Das: University of Wisconsin-Madison
Amr A. Abdeen: University of Wisconsin-Madison
David Fiflis: University of Wisconsin-Madison
Benjamin I Grindel: University of Wisconsin-Madison
Shivani Saxena: University of Wisconsin-Madison
Tugce Akcan: University of Wisconsin-Madison
Tausif Alam: University of Wisconsin-Madison
Heidi Kletzien: University of Wisconsin-Madison
Lucille Kohlenberg: University of Wisconsin-Madison
Madelyn Goedland: University of Wisconsin-Madison
Micah J. Dombroe: University of Wisconsin-Madison
Krishanu Saha: University of Wisconsin-Madison

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Compound heterozygous recessive or polygenic diseases could be addressed through gene correction of multiple alleles. However, targeting of multiple alleles using genome editors could lead to mixed genotypes and adverse events that amplify during tissue morphogenesis. Here we demonstrate that Cas9-ribonucleoprotein-based genome editors can correct two distinct mutant alleles within a single human cell precisely. Gene-corrected cells in an induced pluripotent stem cell model of Pompe disease expressed the corrected transcript from both corrected alleles, leading to enzymatic cross-correction of diseased cells. Using a quantitative in silico model for the in vivo delivery of genome editors into the developing human infant liver, we identify progenitor targeting, delivery efficiencies, and suppression of imprecise editing outcomes at the on-target site as key design parameters that control the efficacy of various therapeutic strategies. This work establishes that precise gene editing to correct multiple distinct gene variants could be highly efficacious if designed appropriately.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20065-8

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DOI: 10.1038/s41467-020-20065-8

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