Cristian Ciobanu, Murali Yanda, Adi Zeidan, Jessica Izzi, William B. Guggino, Liudmila Cebotaru
{"title":"Amelioration of airway and GI disease in G551D-CF ferrets by AAV1 and AAV6","authors":"Cristian Ciobanu, Murali Yanda, Adi Zeidan, Jessica Izzi, William B. Guggino, Liudmila Cebotaru","doi":"10.1038/s41434-024-00469-7","DOIUrl":null,"url":null,"abstract":"Gene therapy for CF has concentrated on targeting the lung. Here we took a different approach by injecting into the cephalic vein and spraying into the trachea of G551D, CF ferrets either AAV1 or 6 containing Δ27-264-CFTR, a truncated version of CFTR. Treatment with the potentiator VX-770 was halted for 7 days before instillation to induce a disease phenotype. Indeed, all ferrets were pancreas-insufficient when they entered the study. Four ferrets (three receiving AAV1 and one AAV6) were necropsied 48 days after vector delivery, and four (three receiving AAV6, one AAV1) were euthanized or died prior to the planned necropsy. AAV1 or AAV6 vector genomes, mRNA expression, and CFTR protein were detected in all tracheal and lung samples and in the liver, pancreas, and ileum of the treated ferrets. Surface and basal airway cells, pancreatic and bile ducts, and ileal crypts and villi were successfully transduced. Obstruction of the airways accompanied by pulmonary hemorrhaging, plugged pancreatic and bile ducts as well as mucous plugs in the ileum were noticed in untreated but absent from transduced ferrets necropsied at 48 days. Transduction of G551D ferrets suggests that a combination of systemic and airway application may be the preferred route of delivery for CF.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00469-7.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene Therapy","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41434-024-00469-7","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Gene therapy for CF has concentrated on targeting the lung. Here we took a different approach by injecting into the cephalic vein and spraying into the trachea of G551D, CF ferrets either AAV1 or 6 containing Δ27-264-CFTR, a truncated version of CFTR. Treatment with the potentiator VX-770 was halted for 7 days before instillation to induce a disease phenotype. Indeed, all ferrets were pancreas-insufficient when they entered the study. Four ferrets (three receiving AAV1 and one AAV6) were necropsied 48 days after vector delivery, and four (three receiving AAV6, one AAV1) were euthanized or died prior to the planned necropsy. AAV1 or AAV6 vector genomes, mRNA expression, and CFTR protein were detected in all tracheal and lung samples and in the liver, pancreas, and ileum of the treated ferrets. Surface and basal airway cells, pancreatic and bile ducts, and ileal crypts and villi were successfully transduced. Obstruction of the airways accompanied by pulmonary hemorrhaging, plugged pancreatic and bile ducts as well as mucous plugs in the ileum were noticed in untreated but absent from transduced ferrets necropsied at 48 days. Transduction of G551D ferrets suggests that a combination of systemic and airway application may be the preferred route of delivery for CF.
期刊介绍:
Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.