Future therapies for cystic fibrosis

doi:10.1038/s41467-023-36244-2

Review

. 2023 Feb 8;14(1):693.

doi: 10.1038/s41467-023-36244-2.

Future therapies for cystic fibrosis

Lucy Allen¹, Lorna Allen¹, Siobhan B Carr^{2

3}, Gwyneth Davies^{4

5}, Damian Downey⁶, Marie Egan⁷, Julian T Forton^{8

9}, Robert Gray^{10

11}, Charles Haworth^{12

13}, Alexander Horsley^{14

15}, Alan R Smyth^{16

17}, Kevin W Southern^{18

19}, Jane C Davies^{20

21}

Affiliations

¹ Cystic Fibrosis Trust, London, UK.
² Royal Brompton & Harefield Hospital, Guy's & St Thomas' Trust, London, UK.
³ National Heart & Lung Institute, Imperial College London, London, UK.
⁴ UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
⁵ Great Ormond Street Hospital for Children, London, UK.
⁶ Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
⁷ Yale University, New Haven, CT, USA.
⁸ Noah's Ark Children's Hospital for Wales, Cardiff, UK.
⁹ School of Medicine, Cardiff University, Cardiff, UK.
¹⁰ Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
¹¹ Western General Hospital, Edinburgh, UK.
¹² Royal Papworth Hospital and Department of Medicine, Cambridge, UK.
¹³ University of Cambridge, Cambridge, UK.
¹⁴ Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK.
¹⁵ Manchester Adult CF Centre, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁶ School of Medicine, University of Nottingham, Nottingham, UK.
¹⁷ NIHR Nottingham Biomedical Research Centre, Nottingham, UK.
¹⁸ Department of Women's and Children's Health, University of Liverpool, Liverpool, UK.
¹⁹ Institute in the Park, Alder Hey Children's Hospital, Liverpool, UK.
²⁰ Royal Brompton & Harefield Hospital, Guy's & St Thomas' Trust, London, UK. J.C.Davies@imperial.ac.uk.
²¹ National Heart & Lung Institute, Imperial College London, London, UK. J.C.Davies@imperial.ac.uk.

PMID: 36755044
PMCID: PMC9907205
DOI: 10.1038/s41467-023-36244-2

Review

Future therapies for cystic fibrosis

Lucy Allen et al. Nat Commun. 2023.

. 2023 Feb 8;14(1):693.

doi: 10.1038/s41467-023-36244-2.

Authors

Affiliations

¹ Cystic Fibrosis Trust, London, UK.
² Royal Brompton & Harefield Hospital, Guy's & St Thomas' Trust, London, UK.
³ National Heart & Lung Institute, Imperial College London, London, UK.
⁴ UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
⁵ Great Ormond Street Hospital for Children, London, UK.
⁶ Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
⁷ Yale University, New Haven, CT, USA.
⁸ Noah's Ark Children's Hospital for Wales, Cardiff, UK.
⁹ School of Medicine, Cardiff University, Cardiff, UK.
¹⁰ Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
¹¹ Western General Hospital, Edinburgh, UK.
¹² Royal Papworth Hospital and Department of Medicine, Cambridge, UK.
¹³ University of Cambridge, Cambridge, UK.
¹⁴ Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK.
¹⁵ Manchester Adult CF Centre, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁶ School of Medicine, University of Nottingham, Nottingham, UK.
¹⁷ NIHR Nottingham Biomedical Research Centre, Nottingham, UK.
¹⁸ Department of Women's and Children's Health, University of Liverpool, Liverpool, UK.
¹⁹ Institute in the Park, Alder Hey Children's Hospital, Liverpool, UK.
²⁰ Royal Brompton & Harefield Hospital, Guy's & St Thomas' Trust, London, UK. J.C.Davies@imperial.ac.uk.
²¹ National Heart & Lung Institute, Imperial College London, London, UK. J.C.Davies@imperial.ac.uk.

PMID: 36755044
PMCID: PMC9907205
DOI: 10.1038/s41467-023-36244-2

Abstract

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

PubMed Disclaimer

Conflict of interest statement

Lu. Allen, Lo. Allen, J.T.F., and K.W.S. declare no competing interests. S.B.C. has received grants from the NIHR and undertaking consultancy work for Vertex Pharmaceuticals and Chiesi. She has performed advisory roles for Profile Pharma, Pharmaxis and Vertex Pharmaceuticals. Siobhan is the chair of the UK CF registry steering committee and the European CF society patient registry scientific committee. G.D. has performed clinical trial leadership roles and received speaker honoraria from Vertex Pharmaceuticals, and speaker honoraria from Chiesi Ltd for educational events. She holds current grants from UKRI, NIHR and CF Trust. D.D. has received honoraria and/or grants from, Vertex, Proteostasis, Chiesi, Gilead and Insmed. M.E. is a consultant for Xanadu Bio Sciences. R.G. has received speaker fees from Vertex and Chiesi and and provided consultancy work for Chiesi. C.H. has performed clinical trial leadership roles, and educational and/or advisory activities for 30 Technology, Aradigm, Chiesi, CSL Behring, Gilead, Grifols, GSK, Insmed, Janssen, Meiji, Mylan, Novartis, Pneumagen, Shionogi, Teva, Vertex and Zambon. A.H. has performed clinical trial leadership roles, and educational or advisory activities for the following: Boehringer Ingelheim Pharma GmbH, Celtaxys Pharmaceuticals, Flatley Labs, Galapagos NV, Roche-Genentech, Krystal Biotech, Novabiotics, Pulmocide, Vertex Pharmaceuticals. He holds current grants from EPSRC, UKRI, CF Trust, JP Moulton charity, North West Lung Centre Charity. A.R.S. has received research grants; honoraria for lectures; and support for attending meetings from Vertex Pharmaceuticals (all outside the submitted work). A.R.S. has patents issued (Camara M, Williams P, Barrett D, Halliday N, Knox A, Smyth A, Fogarty A, Barr H, Forrester D. Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof (US-2016131648-A1), outside the submitted work. J.C.D. has performed clinical trial leadership roles, and educational and/or advisory activities for the following: Abbvie, Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Eloxx, Enterprise, Galapagos NV, Genentech, ImevaX GmbH, Ionis, LifeArc, Nivalis Therapeutics, Inc., Krystal Biotech, Novartis, PARI Medical Holding GmbH, ProQR Therapeutics III B.V., Proteostasis Therapeutics INC., Pulmocide, Raptor Pharmaceuticals Inc, Recode, Vertex Pharmaceuticals.

Figures

**Fig. 1. Improvements in median predicted survival in UK pwCF over recent years.**
From the CF Trust Patient Registry Report (https://www.cysticfibrosis.org.uk/sites/default/files/2022-03/2020%20Annual%20data%20report%20-%20Version%203.pdf).

**Fig. 2. A large number of new approaches to CF therapy are progressing through from preclinical to clinical trial stages.**
Further detail can be found in the following review articles: CFTR modulator therapies, genetic therapies, mRNA-directed approaches and read-through agents, mucoactive and airway hydrating drugs^,, anti-infectives and anti-inflammatories.

See this image and copyright information in PMC

Cited by

Fatty acid abnormalities in cystic fibrosis-the missing link for a cure?
Drzymała-Czyż S, Walkowiak J, Colombo C, Alicandro G, Storrösten OT, Kolsgaard M, Bakkeheim E, Strandvik B. Drzymała-Czyż S, et al. iScience. 2024 Oct 11;27(11):111153. doi: 10.1016/j.isci.2024.111153. eCollection 2024 Nov 15. iScience. 2024. PMID: 39620135 Free PMC article. Review.
Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective.
Mayer-Hamblett N, Clancy JP, Jain R, Donaldson SH, Fajac I, Goss CH, Polineni D, Ratjen F, Quon BS, Zemanick ET, Bell SC, Davies JC, Jain M, Konstan MW, Kerper NR, LaRosa T, Mall MA, McKone E, Pearson K, Pilewski JM, Quittell L, Rayment JH, Rowe SM, Taylor-Cousar JL, Retsch-Bogart G, Downey DG. Mayer-Hamblett N, et al. Lancet Respir Med. 2023 Oct;11(10):932-944. doi: 10.1016/S2213-2600(23)00297-7. Epub 2023 Sep 9. Lancet Respir Med. 2023. PMID: 37699421 Free PMC article. Review.
Active microgel particle swarms for intrabronchial targeted delivery.
Chen H, Law J, Wang Y, Chen Z, Du X, Fang K, Wang Z, Duan F, Sun Y, Yu J. Chen H, et al. Sci Adv. 2025 Mar 14;11(11):eadr3356. doi: 10.1126/sciadv.adr3356. Epub 2025 Mar 12. Sci Adv. 2025. PMID: 40073130 Free PMC article.
The relationship between cancer risk and cystic fibrosis: the role of CFTR in cell growth and cancer development.
Indra R, Černá V. Indra R, et al. RSC Med Chem. 2025 May 27. doi: 10.1039/d5md00203f. Online ahead of print. RSC Med Chem. 2025. PMID: 40438286 Free PMC article. Review.
Cystic Fibrosis Treatment Landscape: Progress, Challenges, and Future Directions.
Yıldız CA, Gökdemir Y, Erdem Eralp E, Ergenekon P, Karakoç F, Karadağ B. Yıldız CA, et al. Turk Arch Pediatr. 2025 Mar 3;60(2):117-125. doi: 10.5152/TurkArchPediatr.2025.24257. Turk Arch Pediatr. 2025. PMID: 40091461 Free PMC article.

See all "Cited by" articles

References

1. Castellani C, Massie J, Sontag M, Southern KW. Newborn screening for cystic fibrosis. Lancet Respir. Med. 2016;4:653–661. - PubMed
1. Barben J, et al. The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe. J. Cyst. Fibros. 2017;16:207–213. - PubMed
1. Dijk FN, McKay K, Barzi F, Gaskin KJ, Fitzgerald DA. Improved survival in cystic fibrosis patients diagnosed by newborn screening compared to a historical cohort from the same centre. Arch. Dis. Child. 2011;96:1118–1123. - PubMed
1. Kerem E, Conway S, Elborn S, Heijerman H, Consensus C. Standards of care for patients with cystic fibrosis: a European consensus. J. Cyst. Fibros. 2005;4:7–26. - PubMed
1. Castellani C, et al. ECFS best practice guidelines: the 2018 revision. J. Cyst. Fibros. 2018;17:153–178. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- Genetic Alliance
- MedlinePlus Health Information

[1] Castellani C, Massie J, Sontag M, Southern KW. Newborn screening for cystic fibrosis. Lancet Respir. Med. 2016;4:653–661. - PubMed

[2] Castellani C, Massie J, Sontag M, Southern KW. Newborn screening for cystic fibrosis. Lancet Respir. Med. 2016;4:653–661. - PubMed

[3] Barben J, et al. The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe. J. Cyst. Fibros. 2017;16:207–213. - PubMed

[4] Barben J, et al. The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe. J. Cyst. Fibros. 2017;16:207–213. - PubMed

[5] Dijk FN, McKay K, Barzi F, Gaskin KJ, Fitzgerald DA. Improved survival in cystic fibrosis patients diagnosed by newborn screening compared to a historical cohort from the same centre. Arch. Dis. Child. 2011;96:1118–1123. - PubMed

[6] Dijk FN, McKay K, Barzi F, Gaskin KJ, Fitzgerald DA. Improved survival in cystic fibrosis patients diagnosed by newborn screening compared to a historical cohort from the same centre. Arch. Dis. Child. 2011;96:1118–1123. - PubMed

[7] Kerem E, Conway S, Elborn S, Heijerman H, Consensus C. Standards of care for patients with cystic fibrosis: a European consensus. J. Cyst. Fibros. 2005;4:7–26. - PubMed

[8] Kerem E, Conway S, Elborn S, Heijerman H, Consensus C. Standards of care for patients with cystic fibrosis: a European consensus. J. Cyst. Fibros. 2005;4:7–26. - PubMed

[9] Castellani C, et al. ECFS best practice guidelines: the 2018 revision. J. Cyst. Fibros. 2018;17:153–178. - PubMed

[10] Castellani C, et al. ECFS best practice guidelines: the 2018 revision. J. Cyst. Fibros. 2018;17:153–178. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Future therapies for cystic fibrosis

Affiliations

Future therapies for cystic fibrosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical