The CRISPR-Cas9 system has been employed to generate mutant alleles in a range of different organisms. However, so far there have not been reports of use of this system for efficient correction of a genetic disease. Here we show that mice with a dominant mutation in Crygc gene that causes cataracts could be rescued by coinjection into zygotes of Cas9 mRNA and a single-guide RNA (sgRNA) targeting the mutant allele. Correction occurred via homology-directed repair (HDR) based on an exogenously supplied oligonucleotide or the endogenous WT allele, with only rare evidence of off-target modifications. The resulting mice were fertile and able to transmit the corrected allele to their progeny. Thus, our study provides proof of principle for use of the CRISPR-Cas9 system to correct genetic disease.

The original, online version of this article contained a graphical abstract that was mislabeled, with the female somatic cells being labeled with AMH and the male cells being labeled with BMP2. The corrected graphical abstract, with the female somatic cells labeled with BMP2 and the male somatic cells labeled with AMH, is now included with both the online and print versions of our article. Both the erroneous and corrected graphical abstracts are also included below for the sake of comparison. We apologize for our initial mistake.

Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid–ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid–ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid–ligand interactions, namely SPA-LN. SPA-LN is optimized by maximizing both the affinity and specificity of native complex structures. The development strategy is different from those of previous nucleic acid–ligand scoring functions which focus on the affinity only in the optimization. The native conformation is stabilized while non-native conformations are destabilized by our optimization, making the funnel-like binding energy landscape more biased toward the native state. The performance of SPA-LN validates the development strategy and provides a relatively more accurate way to score the nucleic acid–ligand interactions.