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Nonsense-mediated decay (NMD) is a major pathogenic mechanism underlying a diversity of genetic disorders. Nonsense variants tend to lead to more severe disease phenotypes and are often difficult targets for small molecule therapeutic development as a result of insufficient protein production. The treatment of cystic fibrosis (CF), an autosomal recessive disease caused by mutations in the CFTR gene, exemplifies the challenge of therapeutically addressing nonsense mutations in human disease. Therapeutic development in CF has led to multiple, highly successful protein modulatory interventions, yet no targeted therapies have been approved for nonsense mutations. Here, we have designed a CRISPR-Cas9-based strategy for the targeted prevention of NMD of CFTR transcripts containing the second most common nonsense variant listed in CFTR2, W1282X. By introducing a deletion of the downstream genic region following the premature stop codon, we demonstrate significantly increased protein expression of this mutant variant. Notably, in combination with protein modulators, genome editing significantly increases the potentiated channel activity of W1282X-CFTR in human bronchial epithelial cells. Furthermore, we show how the outlined approach can be modified to permit allele-specific editing. The described approach can be extended to other late-occurring nonsense mutations in the CFTR gene or applied as a generalized approach for gene-specific prevention of NMD in disorders where a truncated protein product retains full or partial functionality., (© 2020 The Authors.)

Behaviorist B.F. Skinner is not typically associated with the fields of personality assessment or projective testing. However, early in his career Skinner developed an instrument he named the verbal summator, which, at one point, he referred to as a device for "snaring out complexes," much like an auditory analogue of the Rorschach inkblots. Skinner's interest in the projective potential of his technique was relatively short lived, but whereas he used the verbal summator to generate experimental data for his theory of verbal behavior, several other clinicians and researchers exploited this potential and adapted the verbal summator technique for both research and applied purposes. The idea of an auditory inkblot struck many as a useful innovation, and the verbal summator spawned the tautophone test, the auditory apperception test, and the Azzageddi test, among others. This article traces the origin, development, and eventual demise of the verbal summator as an auditory projective technique.