Paul D W Eckford1, Jacqueline McCormack1, Lise Munsie2, Gengming He3, Sanja Stanojevic4, Sergio L Pereira5, Karen Ho5, Julie Avolio6, Claire Bartlett4, Jin Ye Yang7, Amy P Wong7, Leigh Wellhauser1, Ling Jun Huan1, Jia Xin Jiang1, Hong Ouyang4, Kai Du1, Michelle Klingel4, Lianna Kyriakopoulou8, Tanja Gonska9, Theo J Moraes6, Lisa J Strug10, Janet Rossant11, Felix Ratjen12, Christine E Bear13. 1. Molecular Structure and Function, Hospital for Sick Children, Toronto, Canada. 2. CCRM, Toronto, Canada. 3. Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada. 4. Translational Medicine, Hospital for Sick Children, Toronto, Canada. 5. The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada. 6. Translational Medicine, Hospital for Sick Children, Toronto, Canada; Respiratory Medicine, Hospital for Sick Children, Toronto, Canada. 7. Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Canada. 8. Division of Genome Diagnostics, Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada. 9. Translational Medicine, Hospital for Sick Children, Toronto, Canada; Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Canada. 10. Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. 11. Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada. 12. Translational Medicine, Hospital for Sick Children, Toronto, Canada; Respiratory Medicine, Hospital for Sick Children, Toronto, Canada; University of Toronto, Toronto, Canada. 13. Molecular Structure and Function, Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada. Electronic address: bear@sickkids.ca.
Abstract
BACKGROUND: Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses. METHODS: The CFIT program is generating: 1) nasal cells from drug naïve patients suitable for culture and the study of drug responses in vitro, 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators. RESULTS: To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors. CONCLUSIONS: This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations.
BACKGROUND: Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses. METHODS: The CFIT program is generating: 1) nasal cells from drug naïve patients suitable for culture and the study of drug responses in vitro, 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators. RESULTS: To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors. CONCLUSIONS: This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations.
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