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Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.
Sadras, Ido; Kerem, Eitan; Livnat, Galit; Sarouk, Ifat; Breuer, Oded; Reiter, Joel; Gileles-Hillel, Alex; Inbar, Ori; Cohen, Michael; Gamliel, Ayelet; Stanleigh, Noemie; Gunawardena, Tarini; Bartlett, Claire; Gonska, Tanja; Moraes, Theo; Eckford, Paul D W; Bear, Christine E; Ratjen, Felix; Kerem, Batsheva; Wilschanski, Michael; Shteinberg, Michal; Cohen-Cymberknoh, Malena.
Afiliação
  • Sadras I; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Kerem E; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel. Electronic address: eitank@hadassah.org.il.
  • Livnat G; Cystic Fibrosis Center, Carmel Medical center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Israel.
  • Sarouk I; Pediatric Pulmonology Unit, The National Center for Cystic Fibrosis, Sheba Medical Center, Tel Hashomer and the Sackler Faculty of Medicine, Safra Children's Hospital, Tel Aviv University, Israel.
  • Breuer O; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Reiter J; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Gileles-Hillel A; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Inbar O; The Cystic Fibrosis Foundation of Israel, Israel.
  • Cohen M; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Gamliel A; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Stanleigh N; Department of Genetics, The Life Sciences Institute, Hebrew University, Jerusalem Israel.
  • Gunawardena T; Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada.
  • Bartlett C; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada.
  • Gonska T; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Division of Gastroenterology, Hepatology & Nutrition, Division of Respiratory Medicine, SickKids Hospital, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.
  • Moraes T; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Division of Gastroenterology, Hepatology & Nutrition, Division of Respiratory Medicine, SickKids Hospital, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.
  • Eckford PDW; Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada.
  • Bear CE; Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.
  • Ratjen F; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Division of Gastroenterology, Hepatology & Nutrition, Division of Respiratory Medicine, SickKids Hospital, Toronto, ON, Canada; Department of Physiology and Pediatrics, University of Toronto, Toronto, ON, Canada.
  • Kerem B; Department of Genetics, The Life Sciences Institute, Hebrew University, Jerusalem Israel.
  • Wilschanski M; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
  • Shteinberg M; Cystic Fibrosis Center, Carmel Medical center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Israel.
  • Cohen-Cymberknoh M; Cystic Fibrosis Center, Hadassah Hebrew Medical Center and Faculty of Medicine, Hadassah-Hebrew University Medical Center, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
J Cyst Fibros ; 22(6): 1062-1069, 2023 Nov.
Article em En | MEDLINE | ID: mdl-37331863
ABSTRACT

BACKGROUND:

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA.

METHODS:

Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment.

RESULTS:

Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity.

CONCLUSIONS:

This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibrose Cística Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibrose Cística Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article