Emily’s Entourage supported the research that resulted in the following publications.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (PNAS) OF THE UNITED STATES OF AMERICA
January 2022
Exon-skipping antisense oligonucleotides for cystic fibrosis therapy
AUTHORS
Young Jin Kim, Nicole Sivetz, Jessica Layne, Dillon M. Voss, Lucia Yang, Qian Zhang, Adrian R. Krainer
SUMMARY
Nonsense-mediated messenger RNA (mRNA) decay (NMD) degrades the CFTR-W1282X mRNA, leading to low levels of functional CFTR protein. A cocktail of two antisense oligonucleotides (ASOs) was developed by the study authors that promotes the skipping of exon 23 of the CFTR-W1282X mRNA. The resulting mRNA is NMD resistant and preserves the reading frame. Its translation produces CFTR-Δex23 protein that improves CFTR activity in human bronchial epithelial cells. The results set the stage for developing an ASO therapy for CF caused by the W1282X mutation.
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JOURNAL OF CYSTIC FIBROSIS
December 2020
Amphotericin B induces epithelial voltage responses in people with cystic fibrosis
AUTHORS
Rajeev S. Chorghade, Bo Ram Kim, Janice L. Launspach, Philip H. Karp, Michael J. Welsh, Martin D. Burke
SUMMARY
Marty Burke and colleagues report progression of their pioneering work to re-purpose an existing drug – Amphotericin B (AmB) – as a mutation agnostic therapy for CF. Prior studies in cell and animal models demonstrated that AmB effectively mimics key functions of the CFTR ion channel. In this study, the ability of AmB to alter nasal potential difference (NPD) – a clinical biomarker used to assess efficacy of potential CF therapies – in people with CF. In eight CF subjects not using modulators, AmB mediated NPD changes consistent with AmB recapitulating CFTR activity and similar to the effect of ivacaftor in CF subjects with the G551D-CFTR mutation.
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PEDIATRIC PULMONOLOGY
April 2020
Ataluren/ivacaftor combination therapy: Two N-of-1 trials in cystic fibrosis patients with nonsense mutations
AUTHORS
Jacelyn E. Peabody Lever, Venkateshwar Mutyam, Heather Y. Hathorne, Ning Peng, Jyoti Sharma, Lloyd J. Edwards, Steven M. Rowe
SUMMARY
Clinical study testing the hypothesis that ivacaftor in combination with the readthrough drug ataluren could be beneficial for CF subjects with nonsense mutations. No meaningful benefit was observed in two subjects, with ivacaftor or ivacaftor and ataluren; however, some benefits were observed of unknown significance, including minor increases in lung function and body mass index.
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JOURNAL OF CYSTIC FIBROSIS
December 2019
Functional rescue of c.3846G>A (W1282X) in patient-derived nasal cultures achieved by inhibition of nonsense mediated decay and protein modulators with complementary mechanisms of action
AUTHORS
Onofrio Laselva, Paul D.W. Eckford, Claire Bartlett, Hong Ouyang, Tarini N.A. Gundawardena, Tanja Gonska, Theo J. Moraes, Christin E. Bear
SUMMARY
Proof-of-concept studies that demonstrate pharmacological repair of CFTR function in nasal epithelial cells derived from CF subjects with the W1282X-CFTR mutation. Robust restoration of CFTR activity was observed with CFTR modulators in combination with an inhibitor of non-sense mediate degradation (NMD), a process that recognizes and destroys transcripts containing nonsense mutations (‘X mutations’).
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SCIENTIFIC REPORTS
November 2019
Nanomolar-potency ‘co-potentiator’ therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants
AUTHORS
Puay-wah Phuan, Joseph-Anthony Tan, Amber A. Rivera, Lorna Zlock, Dennis W. Nielson, Walter E. Finkbeiner, Peter M. Haggie, Alan S. Verkman
SUMMARY
High throughput screening is used to identify four additional classes of co-potentiators, CFTR modulators that work together with existing potentiators such as Ivacaftor to activate several rare CFTR mutants including CFTR1281 (the protein product generated by the. W1282X mutation) and N1303K-CFTR. These studies represent continued progression of a novel modulator paradigm that could have therapeutic utility for several rare CFTR mutations with no currently available therapy.
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NATURE
March 2019
Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia
AUTHORS
Katrina A. Muraglia, Rajeev S. Chorghade, Bo Ram Kim, Xiao Xiao Tang, Viral S. Shah, Anthony S. Grillo, Page N. Daniels, Alexander G. Cioffi, Philip H. Karp, Lingyang Zhu, Michael J. Welsh, Martin D. Burke
SUMMARY
Pioneering work by Marty Burke, University of Illinois Urbana-Champaign, to develop a new CF therapy by re-purposing an existing drug – Amphotericin B. In collaboration with the University of Iowa, studies in the CF pig revealed the potential therapeutic benefit of Amphotericin B in restoring lung immune defense mechanisms.
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NATURE COMMUNICATIONS
February 2019
Engineered transfer RNAs for suppression of premature termination codons
AUTHORS
John D. Lueck, Jae Seok Yoon, Alfredo Perales-Puchalt, Adam L. Mackey, Daniel T. Infield, Mark A. Behlke, Marshall R. Pope, David B. Weiner, William R. Skach, Paul B. McCray Jr., Christopher A. Ahern
SUMMARY
Therapeutic development of transfer RNAs (tRNAs) to recognize disease-causing nonsense mutations – such as W1282X – in the CFTR gene and permit synthesis of full length CFTR protein. This project was lead by Chris Ahern and John Lueck at the University of Iowa and involved scientists at The Wistar Institute in Philadelphia, PA, and The CFF Therapeutics lab in Lexington, MA. Project progression remains a priority of Emily’s Entourage with funding for James Dhalman at Georgia Tech to work on delivering therapeutic tRNAs to the lung.
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JOURNAL OF CYSTIC FIBROSIS
May 2018
Combination potentiator (co-potentiator’) therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators
AUTHORS
Puay-Wah Phuan, Jung-Ho Son, Joseph-Anthony Tan, Clarabella Li, Ilaria Musante, Loma Zlock, Dennis W. Neilson, Walter E. Finkbeiner, Mark J. Kurth, Luis J. Galietta, Peter M. Haggie, Alan S. Verkman
SUMMARY
A second manuscript for the Verkman group, at the University of California, San Francisco, extends the concept of using Ivacaftor with a second potentiator (a co-potentiator) to significantly elevate the activity of a second rare CFTR mutation (N1303K). Importantly, this study also includes the first demonstration that W1282X-CFTR can be activated by Ivacaftor and a co-potentiator in human nasal epithelial cells.
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JOURNAL OF CYSTIC FIBROSIS
January 2017
Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation
AUTHORS
Venkateshwar Mutyam, Emily Falk Libby, Ning Peng, Denis Hadjiliadis, Michael Bonk, George M. Solomon, Steven M. Rowe
SUMMARY
Clinical study conducted by Steven M. Rowe MD at University of Alabama at Birmingham that demonstrated significant therapeutic benefit of using Ivacaftor (VX-770) in a W1282X homozygous CF subject. The clinical benefits – reduced pulmonary exacerbations, weight gain, reduced insulin usage – support off-label use of this CF drug in W1282X CF subjects.
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THE JOURNAL OF BIOLOGICAL CHEMISTRY
November 2016
Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product
AUTHORS
Peter M. Haggie, Puay-Wah Phuan, Joseph-Anthony Tan, Haijin Xu, Radu G. Avramescu, Doranda Perdomo, Lorna Zlock, Dennis W. Nielson, Walter E. Finkbeiner, Gergely L. Lukacs, Alas S. Verkman
SUMMARY
Drug discovery project conducted at University of California, San Francisco (UCSF) by Alan Verkman, MD, PhD. The study identified potent ‘correctors’ and ‘potentiators’ for the truncated form of CFTR produced by the W1282X mutation, and validated a therapeutic approach for the W1282X mutation similar to that used for delF508.
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