{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:44:50Z","timestamp":1788425090483,"version":"build-2803163510"},"reference-count":78,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NINDS","award":["R21NS099450"],"award-info":[{"award-number":["R21NS099450"]}]},{"name":"NIH\/NIAID","award":["U42OD011140"],"award-info":[{"award-number":["U42OD011140"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,15]]},"abstract":"<jats:p>\n                    Phenylalanine hydroxylase\u2013deficient (PAH-deficient) phenylketonuria (PKU) results in systemic hyperphenylalaninemia, leading to neurotoxicity with severe developmental disabilities. Dietary phenylalanine (Phe) restriction prevents the most deleterious effects of hyperphenylalaninemia, but adherence to diet is poor in adult and adolescent patients, resulting in characteristic neurobehavioral phenotypes. Thus, an urgent need exists for new treatments. Additionally, rodent models of PKU do not adequately reflect neurocognitive phenotypes, and thus there is a need for improved animal models. To this end, we have developed\n                    <jats:italic>PAH<\/jats:italic>\n                    -null pigs. After selection of optimal CRISPR\/Cas9 genome-editing reagents by using an in vitro cell model, zygote injection of 2 sgRNAs and Cas9 mRNA demonstrated deletions in preimplantation embryos, with embryo transfer to a surrogate leading to 2 founder animals. One pig was heterozygous for a\n                    <jats:italic>PAH<\/jats:italic>\n                    exon 6 deletion allele, while the other was compound heterozygous for deletions of exon 6 and of exons 6\u20137. The affected pig exhibited hyperphenylalaninemia (2000\u20135000 \u03bcM) that was treatable by dietary Phe restriction, consistent with classical PKU, along with juvenile growth retardation, hypopigmentation, ventriculomegaly, and decreased brain gray matter volume. In conclusion, we have established a large-animal preclinical model of PKU to investigate pathophysiology and to assess new therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.141523","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T11:02:14Z","timestamp":1602673334000},"source":"Crossref","is-referenced-by-count":41,"title":["A porcine model of phenylketonuria generated by CRISPR\/Cas9 genome editing"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4175-7777","authenticated-orcid":true,"given":"Erik A.","family":"Koppes","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh School of Medicine, and Universityof Pittsburgh Medical Center (UPMC) Children\u2019s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany 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