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Research Publications

Emily’s Entourage supported the research that resulted in the following publications.


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. 

READ THE FULL PUBLICATION HERE


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.

READ THE FULL PUBLICATION HERE


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’).

READ THE FULL PUBLICATION HERE


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.

READ THE FULL PUBLICATION HERE


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.

READ THE FULL PUBLICATION HERE


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.

READ THE FULL PUBLICATION HERE


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. 

READ THE FULL PUBLICATION HERE


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.

READ THE FULL PUBLICATION HERE


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.

READ THE FULL PUBLICATION HERE


 

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