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Neue Therapiemodalitäten bei Mukoviszidose

  • Silke van Koningsbruggen-RietschelEmail author
Leitthema
  • 36 Downloads

Zusammenfassung

Die zystische Fibrose (CF, Mukoviszidose) ist die häufigste lebensverkürzende genetische Erkrankung mit einer Inzidenz von ca. 1:3300. Die Forschung an neuen Therapieoptionen für CF ist intensiv und vielversprechend. Neben neuen symptomatischen Therapien werden zunehmend kurative Therapieansätze entwickelt. Pharmakologische Therapien, die den Basisdefekt der CF behandeln, stehen dem Patienten mittlerweile zur Verfügung; einige Modulatoren des Cystic Fibrosis Transmembrane Conductance Regulators (CFTR) sind für spezifische Mutationen zugelassen. Der Potenziator Ivacaftor, der die Öffnungswahrscheinlichkeit von CFTR erhöht, zeigt bei Klasse-III-Mutationen eine gute Wirksamkeit, wenn auch keine vollständige CFTR-Korrektur. Die Kombinationstherapie aus einem Korrektor (Lumacaftor oder Tezacaftor), der die Expressionsrate von CFTR bei F508del-Mutationen erhöht, und einem Potenziator (Ivacaftor) führt zu einer moderaten korrektiven CFTR-Wirkung bei F508del-homozygoten Patienten. Dreifachkombinationen aus zwei Korrektoren und einem Potenziator führen bei Patienten mit mindestens einem F508del-Allel zur Wiederherstellung der CFTR-Funktion, die in ihrem Ausmaß einer Heilung näherkommt. Neben mutationsspezifischen Therapieentwicklungen werden sog. mutationsagnostische Therapien entwickelt. Diese sind mutationsunabhängig und stehen somit allen CF-Patienten zur Verfügung wie z. B. Gentherapie, CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) und Bypass-Therapien wie Aktivierung alternativer Chloridkanäle und epitheliale Natriumkanal-(ENaC-)Blocker. Dieser Artikel gibt einen Überblick über den Basisdefekt der CF, über neue präklinische Entwicklungen, über klinische Studien, die mutationsspezifisch die Wirksamkeit verschiedener CFTR-Modulatoren untersuchen, über neue symptomatische Therapieoptionen und über die Entwicklung eines Models zur personalisierten Medizin bei CF.

Schlüsselwörter

CF-Lungenerkrankung CFTR-Modulatoren Gentherapie Symptomatische Therapien Organoide 

Novel treatment modalities for cystic fibrosis

Abstract

Cystic fibrosis (CF) is the most frequent life-shortening genetic disorder with an incidence of approximately 1:3300. The development of new treatment options is moving rapidly forward and looks very promising. Besides new modalities for symptomatic treatments, curative treatment approaches are also being developed. Pharmacological approaches to treat the basic defect of CF have become reality and several cystic fibrosis transmembrane conductance regulator (CFTR) modulators have already been licensed for specific mutations. The potentiator ivacaftor, which improves channel activity of CFTR has proven to be effective, although not fully corrective, in class III mutations. The combination treatment of a corrector (lumacaftor and tezacaftor), which improves cell-surface expression rate of CFTR in F508del mutations, in combination with a potentiator (ivacaftor) leads to a modestly efficacious corrective treatment in patients homozygous for F508del. Triple combinations of two correctors and one potentiator lead to restoration of CFTR function close to levels resembling a cure for CF in patients carrying at least one F508del mutation. In addition to the development of mutation-specific treatment, so-called mutation-agnostic approaches are also being developed. These are corrective treatments independent of the mutation class and therefore applicable to all CF patients, e.g. gene therapy, CRISPR-CAS9 and bypass approaches such as activation of alternative chloride channels and epithelial sodium channel (ENaC) blockers. This report provides an overview of the basic defect in CF, major approaches of preclinical research, clinical trials exploring the efficacy of several CFTR modulators as mutation-specific treatment options, new developments in symptomatic treatment options as well as personalized medicine to predict treatment responses.

Keywords

CF lung disease CFTR-modulators Gene therapy Symptomatic treatments Organoids 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

S. van Koningsbruggen-Rietschel gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine vom Autor durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Alton EW, Armstrong DK, Ashby D et al (2015) Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 3(9):684–691CrossRefGoogle Scholar
  2. 2.
    Alton EW, Beekman JM, Boyd AC et al (2017) Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax 72(2):137–147CrossRefGoogle Scholar
  3. 3.
    Davies JC, Moskowitz SM, Brown C et al (2018) VX-659-Tezacaftor-Ivacafotr in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 379:1599–1611CrossRefGoogle Scholar
  4. 4.
    deBoeck K, Amaral MD (2016) Progress in therapies for cystic fibrosis. Lancet Respir Med 4(8):662–674CrossRefGoogle Scholar
  5. 5.
    Dekkers JF, van der Ent CK, Beekman JM (2013) Novel opportunities for CFTR-targeting drug development using organoids. Rare Dis 11(1):e27112CrossRefGoogle Scholar
  6. 6.
    Dickson RP, Erb-Downward JR, Huffnagle GB (2013) The role of the bacterial microbiome in lung disease. Expert Rev Respir Med 7:245–257CrossRefGoogle Scholar
  7. 7.
    Donaldson SH, Solomon GM, Zeitlin PL et al (2017) Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508del CFTR. J Cyst Fibros 16:371–379CrossRefGoogle Scholar
  8. 8.
    Hagemeijer MC, Siegwart DJ, Strug LJ et al (2018) Translational research to enable personalized treatment of cystic fibrosis. J Cyst Fibros 17:46–51CrossRefGoogle Scholar
  9. 9.
    Harbeson SL, Morgan AJ, Liu JF et al (2017) Altering metabolic profiles of drugs by precision deuteration 2: discovery of a deuterated analog of Ivacaftor with differentiated pharmacokinetics for clinical development. J Pharmacol Exp Ther 361:359–367CrossRefGoogle Scholar
  10. 10.
    http://www.hitcf.org. Zugegriffen: 22. Dezember 2018
  11. 11.
    Keating D, Marigowda G, Burr L et al (2018) VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 379:1612–1620CrossRefGoogle Scholar
  12. 12.
    Kerem E, Konstan MW, deBoeck K et al (2014) Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomized, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2:539–547CrossRefGoogle Scholar
  13. 13.
    Li H, Salomon JJ, Sheppard DN et al (2017) Bypassing CFTR dysfunction in cystic fibrosis with alternative pathways for anion transport. Curr Opin Pharmacol 34:91–97CrossRefGoogle Scholar
  14. 14.
    Mijnders M, Kleizen B, Braakman I (2017) Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis. Curr Opin Pharmacol 34:83–90CrossRefGoogle Scholar
  15. 15.
    Naehrig S, Chao CM, Naehrlich L (2017) Cystic fibrosis—diagnosis and treatment. Dtsch Arztebl Int 114:564–574PubMedPubMedCentralGoogle Scholar
  16. 16.
    Orenti A, Zolin A, Naehrlich L et al (2018) ECFS patient Registry Annual Data Report 2016. European Cystic Fibrosis Society, KarupGoogle Scholar
  17. 17.
    Ramsey BW, Davies J, McElvaney NG et al (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365:1663–1672CrossRefGoogle Scholar
  18. 18.
    Ratjen F, Hug C, Marigowda G et al (2017) Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomized, placebo-controlled phase 3 trial. Lancet Respir Med 5:557–567CrossRefGoogle Scholar
  19. 19.
    Rosenfeld M, Wainwright CE, Higgins M et al (2018) Ivacaftor treatment of cystic fibrosis in children aged 12–24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med 6:545–553CrossRefGoogle Scholar
  20. 20.
    Sawicki GS, McKone EF, Pasta DJ et al (2015) Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med 192:836–842CrossRefGoogle Scholar
  21. 21.
    Schechter MS (2011) Nongenetic influences on cystic fibrosis outcomes. Curr Opin Pulm Med 17:448–454PubMedGoogle Scholar
  22. 22.
    Schwank G, Koo BK, Sasselli V et al (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13:653–658CrossRefGoogle Scholar
  23. 23.
    Sermet-Gaudelus I, Boeck KD, Casimir GJ et al (2010) Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med 182:1262–1272CrossRefGoogle Scholar
  24. 24.
    Snodgrass SM, Cihil KM, Cornuet PK et al (2013) Tgf-ß1 inhibits CFTR biogenesis and prevents functional rescue of F508del-CFTR in primary differentiated human bronchial epithelial cells. PLoS ONE 8(5):e63167CrossRefGoogle Scholar
  25. 25.
    Sosnay PR, Siklosi KR, Van Goor F et al (2013) Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 45(10):1160–1167CrossRefGoogle Scholar
  26. 26.
    Southern K, Patel S, Sinha IP et al (2018) Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis. Cochrane Database Syst Rev.  https://doi.org/10.1002/14651858.CD010966.pub2 CrossRefPubMedGoogle Scholar
  27. 27.
    TRAFFIC Study Group, TRANSPORT Study Group, Wainwright CE, Elborn JS, Ramsey BW et al (2015) Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med 373(3):220–231CrossRefGoogle Scholar
  28. 28.
    Wright FA, Strug LJ, Doshi VK et al (2011) Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet 43:539–546CrossRefGoogle Scholar
  29. 29.
    Zecevic M (2018) Proteostasis: new study results/development pipeline. Belgrade. Lecture European Cystic Fibrosis Society Conference 2018Google Scholar
  30. 30.
    Zielenski J, Tsui LC (1995) Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 29:777–807CrossRefGoogle Scholar
  31. 31.
    http://www.cff.org/Trials/Pipeline. Zugegriffen: 22. Dezember 2018
  32. 32.
    http://www.genet.sickkids.on.ca/app. Zugegriffen: 22. Dezember 2018
  33. 33.
    Taylor-Cousar JL, Munck A, Mc Kone EF et al (2017) Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 377:2013–2023CrossRefGoogle Scholar
  34. 34.
    Rowe SM, Daines C, Ringshausen FC et al (2017) Tezacaftor-ivacaftor in residual-function heterozygous with cystic fibrosis. N Engl J Med 377:2024–2035CrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Mukoviszidose-Zentrum Köln, Pädiatrische Pneumologie und Allergologie, Klinik und Poliklinik für Kinder- und JugendmedizinUniversität zu KölnKölnDeutschland

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