WO2020115231A1 - Methods and compositions for treating cystic fibrosis airways - Google Patents

Abstract

The present invention relates to resolving D1 (RvD1) compound for use in the treatment of cystic fibrosis. Inventors have performed ex vivo studies on primary cultures of alveolar macrophages and bronchial epithelial cells from children with CF and in human bronchial epithelial cell lines. They have also performed in vivo studies in homozygous F508del-CFTR mice treated with vehicle control or RvD1 (1-100 nM). They have shown that RvD1 increased the CF ASL height in human bronchial epithelium and restored the nasal trans-epithelial potential difference in CF mice by decreasing the amiloride-sensitive Na+ absorption and stimulating CFTR-independent Cl- secretion. They have observed that RvD1 decreased TNFα induced IL-8 secretion and enhanced the phagocytic and bacterial killing capacity of human CF alveolar macrophages. Thus, RvD1 resolves CF airway pathogenesis and has therapeutic potential in CF lung disease.

Description

METHODS AND COMPOSITIONS FOR TREATING CYSTIC

FIBROSIS AIRWAYS

FIELD OF THE INVENTION:

The invention is in the field of pneumonology. More particularly, the invention relates to methods and compositions for treating cystic fibrosis airways disease.

BACKGROUND OF THE INVENTION:

Cystic fibrosis (CF) airways is characterized by a chronic infection and inflammation. It is the most common lethal monogenic disorder in Caucasians, with an incidence of one bird in 2500-4000 and 70,000 affected people worldwide and kills most of them in their 20s. More particularly, cystic fibrosis (CF) lung disease is characterised by dysregulated ion transport that promotes chronic bacterial infection and inflammation. Efficient mucociliary clearance relies on adequate hydration of the airway surface liquid (ASL). This is achieved through a balance between sodium absorption, mediated by the Epithelial Sodium Channel (ENaC), and chloride secretion via CFTR and calcium-activated chloride channels. In cystic fibrosis (CF), this ion transport equilibrium is impaired, leading to a reduced ASL height that favours chronic bacterial infection and persistent inflammation (1).

Despite the robust inflammatory response, CF lungs fail to clear bacteria and are more susceptible to infections. Pseudomonas aeruginosa is a key CF pathogen and its early acquisition is predictive of an accelerated decline in lung function (2). Impaired alveolar macrophage-mediated phagocytosis and bacterial killing have been reported in CF patients (3). Recent studies in young children with CF have identified neutrophil elastase, as a key risk factor for the onset and early progression of CF lung disease (5) that could contribute to Na+ hyper absorption in CF airways by stimulating ENaC activity (6) and that neutrophil expression correlates with lung damage and did not depend on inflammatory status (7).

Cystic fibrosis is an autosomal recessive disease linked to mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) whose nature determines the clinical expression and severity of the disease, affecting mainly the respiratory, digestive and genital systems. CFTR, a chloride-ion channel, is involved in the changes of surface liquid covering airway epithelial cells. Dehydration of the surface liquid leads to altered muco-ciliary clearance, inflammation and infections at the mucosal epithelia. CF is also characterized by a default of resolution of inflammation. Several reports provide evidence for a correlation between chronic inflammatory disease and abnormal production or activity of the specialised pro-resolution lipid mediators (SPMs) including resolvins and lipoxins (8). Previous reports have shown that SPMs are abnormally produced in CF (9, 10, 11) suggesting that the altered resolution of inflammation in CF is due to a reduced SPMs biosynthesis in the airway of patients. Furthermore, there is a significant correlation between the levels of RvDl in plasma and sputum of CF patients with the biomarkers of inflammation (IL8 and IL l b) and lung function (12).

SPMs have been shown to halt neutrophil infiltration, enhance macrophage phagocytosis of apoptotic neutrophils and attenuate NFKB activation in mouse models of lung inflammation (13). Moreover, RvDl promoted differentiation of alternatively activated (M2) macrophages, improved bacterial killing and the containment of a bacterial challenge in mouse models of lung infection by P. aeruginosa (14).

CFTR mutations that reduce CFTR protein function cause accumulation of thick, sticky mucus in the bronchi of the lungs, loss of exocrine pancreatic function, impaired intestinal secretion, and an increase in the concentration of chloride in the sweat (15). In patients with CF, lack of CFTR Cl(-) channel function leads to progressive pulmonary damage and ultimately to death. Chronic lung disease is the major cause of mortality and morbidity in CF patients. Patients with CF require numerous therapies to manage these symptoms (16), including mucolytic and antibiotic agents and chest physiotherapy to treat the airway disease and digestive enzymes to replace the loss of exocrine pancreatic function. These and other interventions have increased life expectancy dramatically, but improvement is needed to reduce the high treatment burden and increase survival (17).

One of the challenges of treating cystic fibrosis airway disease has been to design a therapy which will overcome the mucus pluging in the airways and the chronic bacterial infection and inflammation. Current therapies involve drugs which correct the function of CFTR but this strategy is expensive and do not correct all CFTR mutations. Other strategies have been plagued by the side effects of pro-inflammatory responses.

A CFTR potentiator (Ivacaftor, VX770) has been developed by Vertex Pharmaceuticals (Ramsey BW et al. N Engl J Med, 2011) and has been approved for the treatment of CF patients carrying the G551D mutation (2-5% of all patients). This drug has failed for CF patients with F508del. Several CFTR correctors have been reported to be active in vitro (18). A combination (Orkambi) of potentiator (Ivacaftor, VX770) and corrector (Lumacaftor, VX809) have been approved for the treatment of CF in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. The impact of this extremely expensive treatment ($250,000-per-year by patient) on inflammation is still controversial. Other CFTR correctors designed to target this mutation are in development at the in vitro level or under clinical trial. Two anti-inflammatory drugs are ongoing on phase 2 clinical development (Lenabasum developed by Corbus Pharmaceutical Inc. and Acebilustat developed by Cetlaxsys).

Accordingly, there is a need to develop new drugs that will be suitable for preventing or treating CF airways.

SUMMARY OF THE INVENTION:

The invention relates to resolvin D1 (RvDl) compound for use in the treatment of cystic fibrosis airways. In particular, the invention is defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION:

Inventors have performed ex vivo studies on primary cultures of alveolar macrophages and bronchial epithelial cells from children with CF and in human bronchial epithelial cell lines. They have also performed in vivo studies in homozygous F508del-CFTR mice treated with vehicle control or RvDl (0.1-100 nM).

They have shown that RvDl increased the CF ASL height in human bronchial epithelium and restored the nasal trans-epithelial potential difference in CF mice by decreasing the amiloride-sensitive Na+ absorption and stimulating CFTR-independent Cl- secretion. They found that RvDl (0.1 to lOOnM) was similar or even more potent than the combination of corrector and potentiator (Orkambi, VX809 10pm + VX770 10 pm) used to restore CFTR function on the same cell cultures. They have observed that RvDl decreased TNFa induced IL- 8 secretion by airway epithelial cells and enhanced the phagocytic and bacterial killing capacity of human CF alveolar macrophages.

Thus, RvDl resolves CF airway pathogenesis and has therapeutic potential in CF lung disease.

Accordingly, the invention relates to resolvin D1 (RvDl) compound for use in the treatment of cystic fibrosis airways.

In a particular embodiment, the invention relates to a method for treating cystic fibrosis airways in a subject in need thereof comprising a step of administering said subject with a therapeutically effective amount of resolving D1 (RvDl) compound.

As used herein, the terms“treating” or“treatment” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).

As used herein, the term“cystic fibrosis airways” refers to an autosomal recessive disease linked to mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) whose nature determines the clinical expression and severity of the disease, affecting mainly the respiratory, digestive and genital systems. This disease is primarily related to lung disease, in particular for 95% of patients, death results from progressive respiratory failure associated with impaired mucus clearance and excessive overgrowth of bacteria and fungi in the airways. The lung disease is characterized by 1) abnormal salt and water transport in the airway epithelium, such that too much sodium and too little chloride crosses the epithelial membrane; 2) a defect in glutathione transport out of airway epithelial cells; 3) inspissated secretions and oxidant damage, in part related to salt, water, and glutathione transport abnormalities; 4) impaired ciliary motility associated with thick secretions; 5) chronic colonization with denitrifmg organisms such as Pseudomonas aeruginiosa and Aspergillus fumigatus; and 6) chronic bronchoconstriction associated with recruitment of neutrophils and other inflammatory cells and associated release of bronchoconstricting mediators and, as a result of all of these factors, chronic, progressively worsening, dyspnea.

As used herein, the term“subject” refers to any mammals, such as a rodent, mice, pig, and a primate. Particularly, in the present invention, the subject is a human afflicted with or susceptible to be afflicted with cystic fibrosis airways. In particular, the subject harbors a mutation in CFTR protein. In a particular embodiment, the subject have at least one of the 6 classes of CF mutations including most common mutation F508del-CFTR as well as more rare mutations with no therapeutic tools currently available (premature stop codon).

As used herein, the term“CFTR protein” refers to the CFTR protein of 1480 amino acids also called Cystic Fibrosis Transmembrane Regulator. The CFTR protein is a chloride (C1-) channel and is found in the membranes of intestinal and respiratory mucosa. The CFTR protein is represented by the NCBI reference sequence: P13569.3 (SEQ ID NO: 1)

SEQ ID NO: 1 :

1 mqrsplekas vvsklffswt rpilrkgyrq rlelsdiyqi psvdsadnls eklerewdre 61 laskknpkli nalrrcffwr fmfygiflyl gevtkavqpl llgriiasyd pdnkeersia

121 iylgiglcll fivrtlllhp aifglhhigm qmriamfsli ykktlklssr vldkisigql

181 vsllsnnlnk fdeglalahf vwiaplqval lmgliwellq asafcglgfl ivlalfqagl

241 grmmmkyrdq ragkiserlv itsemieniq svkaycweea mekmienlrq telkltrkaa 301 yvryfnssaf ffsgffvvfl svlpyalikg iilrkiftti sfcivlrmav trqfpwavqt

361 wydslgaink iqdflqkqey ktleynlttt evvmenvtaf weegfgelfe kakqnnnnrk 421 tsngddslff snfsllgtpv lkdinfkier gqllavagst gagktsllmv imgelepseg

481 kikhsgrisf csqfswimpg tikeniifgv sydeyryrsv ikacqleedi skfaekdniv 541 lgeggitlsg gqrarislar avykdadlyl ldspfgyldv ltekeifesc vcklmanktr

601 ilvtskmehl kkadkililh egssyfygtf selqnlqpdf ssklmgcdsf dqfsaerrns 661 iltetlhrfs legdapvswt etkkqsfkqt gefgekrkns ilnpinsirk fsivqktplq

721 mngieedsde plerrlslvp dseqgeailp risvistgpt lqarrrqsvl nlmthsvnqg 781 qnihrkttas trkvslapqa nlteldiysr rlsqetglei seeineedlk ecffddmesi

841 pavttwntyl ryitvhksli fvliwclvif laevaaslvv lwllgntplq dkgnsthsrn

901 nsyaviitst ssyyvfyiyv gvadtllamg ffrglplvht litvskilhh kmlhsvlqap

961 mstlntlkag gilnrfskdi ailddllplt ifdfiqllli vigaiavvav lqpyifvatv

1021 pvivafimlr ayflqtsqql kqlesegrsp ifthlvtslk glwtlrafgr qpyfetlfhk

1081 alnlhtanwf lylstlrwfq mriemifvif fiavtfisil ttgegegrvg iiltlamnim

1141 stlqwavnss idvdslmrsv srvfkfidmp tegkptkstk pykngqlskv miienshvkk 1201 ddiwpsggqm tvkdltakyt eggnaileni sfsispgqrv gllgrtgsgk stllsaflrl 1261 lntegeiqid gvswdsitlq qwrkafgvip qkvfifsgtf rknldpyeqw sdqeiwkvad

1321 evglrsvieq fpgkldfvlv dggcvlshgh kqlmclarsv lskakillld epsahldpvt 1381 yqiirrtlkq afadctvilc ehrieamlec qqflvieenk vrqydsiqkl lnerslfrqa

1441 ispsdrvklf phmsskcks kpqiaalkee teeevqdtrl

As used herein, the term“CFTR gene” refers to the CFTR gene which is located on chromosome 7 and which may be found in NCBI GenBank locus ACOOOl 11 and AC000061, the contents of which are incorporated herein in their entirety by reference. The cDNA for the CFTR gene is found in Audrezet et ak, Hum. Mutat. (2004) 23 (4), 343-357. A nucleic acid sequence for human CFTR is represented by SEQ ID NO: 2.

SEQ ID NO: 2 (NCBI Reference Sequence: NM_000492.3)

1 aattggaagc aaatgacatc acagcaggtc agagaaaaag ggttgagcgg caggcaccca

61 gagtagtagg tctttggcat taggagcttg agcccagacg gccctagcag ggaccccagc

121 gcccgagaga ccatgcagag gtcgcctctg gaaaaggcca gcgttgtctc caaacttttt

181 ttcagctgga ccagaccaat tttgaggaaa ggatacagac agcgcctgga attgtcagac

241 atataccaaa tcccttctgt tgattctgct gacaatctat ctgaaaaatt ggaaagagaa

301 tgggatagag agctggcttc aaagaaaaat cctaaactca ttaatgccct tcggcgatgt

361 tttttctgga gatttatgtt ctatggaatc tttttatatt taggggaagt caccaaagca

421 gtacagcctc tcttactggg aagaatcata gcttcctatg acccggataa caaggaggaa

481 cgctctatcg cgatttatct aggcataggc ttatgccttc tctttattgt gaggacactg

541 ctcctacacc cagccatttt tggccttcat cacattggaa tgcagatgag aatagctatg

601 tttagtttga tttataagaa gactttaaag ctgtcaagcc gtgttctaga taaaataagt

661 attggacaac ttgttagtct cctttccaac aacctgaaca aatttgatga aggacttgca

721 ttggcacatt tcgtgtggat cgctcctttg caagtggcac tcctcatggg gctaatctgg

781 gagttgttac aggcgtctgc cttctgtgga cttggtttcc tgatagtcct tgcccttttt

841 caggctgggc tagggagaat gatgatgaag tacagagatc agagagctgg gaagatcagt

901 gaaagacttg tgattacctc agaaatgatt gaaaatatcc aatctgttaa ggcatactgc

961 tgggaagaag caatggaaaa aatgattgaa aacttaagac aaacagaact gaaactgact

1021 cggaaggcag cctatgtgag atacttcaat agctcagcct tcttcttctc agggttcttt

1081 gtggtgtttt tatctgtgct tccctatgca ctaatcaaag gaatcatcct ccggaaaata

1141 ttcaccacca tctcattctg cattgttctg cgcatggcgg tcactcggca atttccctgg

1201 gctgtacaaa catggtatga ctctcttgga gcaataaaca aaatacagga tttcttacaa

1261 aagcaagaat ataagacatt ggaatataac ttaacgacta cagaagtagt gatggagaat

1321 gtaacagcct tctgggagga gggatttggg gaattatttg agaaagcaaa acaaaacaat

1381 aacaatagaa aaacttctaa tggtgatgac agcctcttct tcagtaattt ctcacttctt 1441 ggtactcctg tcctgaaaga tattaatttc aagatagaaa gaggacagtt gttggcggtt 1501 gctggatcca ctggagcagg caagacttca cttctaatgg tgattatggg agaactggag 1561 ccttcagagg gtaaaattaa gcacagtgga agaatttcat tctgttctca gttttcctgg 1621 attatgcctg gcaccattaa agaaaatatc atctttggtg tttcctatga tgaatataga 1681 tacagaagcg tcatcaaagc atgccaacta gaagaggaca tctccaagtt tgcagagaaa 1741 gacaatatag ttcttggaga aggtggaatc acactgagtg gaggtcaacg agcaagaatt 1801 tctttagcaa gagcagtata caaagatgct gatttgtatt tattagactc tccttttgga 1861 tacctagatg ttttaacaga aaaagaaata tttgaaagct gtgtctgtaa actgatggct 1921 aacaaaacta ggattttggt cacttctaaa atggaacatt taaagaaagc tgacaaaata 1981 ttaattttgc atgaaggtag cagctatttt tatgggacat tttcagaact ccaaaatcta 2041 cagccagact ttagctcaaa actcatggga tgtgattctt tcgaccaatt tagtgcagaa 2101 agaagaaatt caatcctaac tgagacctta caccgtttct cattagaagg agatgctcct 2161 gtctcctgga cagaaacaaa aaaacaatct tttaaacaga ctggagagtt tggggaaaaa 2221 aggaagaatt ctattctcaa tccaatcaac tctatacgaa aattttccat tgtgcaaaag 2281 actcccttac aaatgaatgg catcgaagag gattctgatg agcctttaga gagaaggctg 2341 tccttagtac cagattctga gcagggagag gcgatactgc ctcgcatcag cgtgatcagc 2401 actggcccca cgcttcaggc acgaaggagg cagtctgtcc tgaacctgat gacacactca 2461 gttaaccaag gtcagaacat tcaccgaaag acaacagcat ccacacgaaa agtgtcactg 2521 gcccctcagg caaacttgac tgaactggat atatattcaa gaaggttatc tcaagaaact 2581 ggcttggaaa taagtgaaga aattaacgaa gaagacttaa aggagtgctt ttttgatgat 2641 atggagagca taccagcagt gactacatgg aacacatacc ttcgatatat tactgtccac 2701 aagagcttaa tttttgtgct aatttggtgc ttagtaattt ttctggcaga ggtggctgct 2761 tctttggttg tgctgtggct ccttggaaac actcctcttc aagacaaagg gaatagtact 2821 catagtagaa ataacagcta tgcagtgatt atcaccagca ccagttcgta ttatgtgttt 2881 tacatttacg tgggagtagc cgacactttg cttgctatgg gattcttcag aggtctacca 2941 ctggtgcata ctctaatcac agtgtcgaaa attttacacc acaaaatgtt acattctgtt 3001 cttcaagcac ctatgtcaac cctcaacacg ttgaaagcag gtgggattct taatagattc 3061 tccaaagata tagcaatttt ggatgacctt ctgcctctta ccatatttga cttcatccag 3121 ttgttattaa ttgtgattgg agctatagca gttgtcgcag ttttacaacc ctacatcttt 3181 gttgcaacag tgccagtgat agtggctttt attatgttga gagcatattt cctccaaacc 3241 tcacagcaac tcaaacaact ggaatctgaa ggcaggagtc caattttcac tcatcttgtt 3301 acaagcttaa aaggactatg gacacttcgt gccttcggac ggcagcctta ctttgaaact 3361 ctgttccaca aagctctgaa tttacatact gccaactggt tcttgtacct gtcaacactg 3421 cgctggttcc aaatgagaat agaaatgatt tttgtcatct tcttcattgc tgttaccttc 3481 atttccattt taacaacagg agaaggagaa ggaagagttg gtattatcct gactttagcc 3541 atgaatatca tgagtacatt gcagtgggct gtaaactcca gcatagatgt ggatagcttg 3601 atgcgatctg tgagccgagt ctttaagttc attgacatgc caacagaagg taaacctacc 3661 aagtcaacca aaccatacaa gaatggccaa ctctcgaaag ttatgattat tgagaattca 3721 cacgtgaaga aagatgacat ctggccctca gggggccaaa tgactgtcaa agatctcaca 3781 gcaaaataca cagaaggtgg aaatgccata ttagagaaca tttccttctc aataagtcct 3841 ggccagaggg tgggcctctt gggaagaact ggatcaggga agagtacttt gttatcagct 3901 tttttgagac tactgaacac tgaaggagaa atccagatcg atggtgtgtc ttgggattca 3961 ataactttgc aacagtggag gaaagccttt ggagtgatac cacagaaagt atttattttt 4021 tctggaacat ttagaaaaaa cttggatccc tatgaacagt ggagtgatca agaaatatgg 4081 aaagttgcag atgaggttgg gctcagatct gtgatagaac agtttcctgg gaagcttgac 4141 tttgtccttg tggatggggg ctgtgtccta agccatggcc acaagcagtt gatgtgcttg 4201 gctagatctg ttctcagtaa ggcgaagatc ttgctgcttg atgaacccag tgctcatttg 4261 gatccagtaa cataccaaat aattagaaga actctaaaac aagcatttgc tgattgcaca 4321 gtaattctct gtgaacacag gatagaagca atgctggaat gccaacaatt tttggtcata 4381 gaagagaaca aagtgcggca gtacgattcc atccagaaac tgctgaacga gaggagcctc 4441 ttccggcaag ccatcagccc ctccgacagg gtgaagctct ttccccaccg gaactcaagc 4501 aagtgcaagt ctaagcccca gattgctgct ctgaaagagg agacagaaga agaggtgcaa 4561 gatacaaggc tttagagagc agcataaatg ttgacatggg acatttgctc atggaattgg 4621 agctcgtggg acagtcacct catggaattg gagctcgtgg aacagttacc tctgcctcag 4681 aaaacaagga tgaattaagt ttttttttaa aaaagaaaca tttggtaagg ggaattgagg 4741 acactgatat gggtcttgat aaatggcttc ctggcaatag tcaaattgtg tgaaaggtac 4801 ttcaaatcct tgaagattta ccacttgtgt tttgcaagcc agattttcct gaaaaccctt 4861 gccatgtgct agtaattgga aaggcagctc taaatgtcaa tcagcctagt tgatcagctt 4921 attgtctagt gaaactcgtt aatttgtagt gttggagaag aactgaaatc atacttctta 4981 gggttatgat taagtaatga taactggaaa cttcagcggt ttatataagc ttgtattcct 5041 ttttctctcc tctccccatg atgtttagaa acacaactat attgtttgct aagcattcca 5101 actatctcat ttccaagcaa gtattagaat accacaggaa ccacaagact gcacatcaaa 5161 atatgcccca ttcaacatct agtgagcagt caggaaagag aacttccaga tcctggaaat 5221 cagggttagt attgtccagg tctaccaaaa atctcaatat ttcagataat cacaatacat 5281 cccttacctg ggaaagggct gttataatct ttcacagggg acaggatggt tcccttgatg 5341 aagaagttga tatgcctttt cccaactcca gaaagtgaca agctcacaga cctttgaact 5401 agagtttagc tggaaaagta tgttagtgca aattgtcaca ggacagccct tctttccaca 5461 gaagctccag gtagagggtg tgtaagtaga taggccatgg gcactgtggg tagacacaca 5521 tgaagtccaa gcatttagat gtataggttg atggtggtat gttttcaggc tagatgtatg

5581 tacttcatgc tgtctacact aagagagaat gagagacaca ctgaagaagc accaatcatg

5641 aattagtttt atatgcttct gttttataat tttgtgaagc aaaatttttt ctctaggaaa

5701 tatttatttt aataatgttt caaacatata taacaatgct gtattttaaa agaatgatta

5761 tgaattacat ttgtataaaa taatttttat atttgaaata ttgacttttt atggcactag

5821 tatttctatg aaatattatg ttaaaactgg gacaggggag aacctagggt gatattaacc

5881 aggggccatg aatcaccttt tggtctggag ggaagccttg gggctgatgc agttgttgcc

5941 cacagctgta tgattcccag ccagcacagc ctcttagatg cagttctgaa gaagatggta

6001 ccaccagtct gactgtttcc atcaagggta cactgccttc tcaactccaa actgactctt

6061 aagaagactg cattatattt attactgtaa gaaaatatca cttgtcaata aaatccatac

6121 atttgtgtga aa.

As used herein, the term "gene" has its general meaning in the art and refers to means a DNA sequence that codes for or corresponds to a particular sequence of amino acids which comprise all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed.

As used herein the“allele" has its general meaning in the art and refers to an alternative form of a gene (one member of a pair) that is located at a specific position on a specific chromosome which, when translated result in functional or dysfunctional (including non existent) gene products.

As used herein, the term“mutation” has its general meaning in the art and refers to any detectable change in genetic material, e.g. DNA, RNA, cDNA, or any process, mechanism, or result of such a change. This includes gene mutations, in which the structure (e.g. DNA sequence) of a gene is altered, any gene or DNA arising from any mutation process, and any expression product (e.g. protein or enzyme) expressed by a modified gene or DNA sequence. Mutations include deletion, insertion or substitution of one or more nucleotides. The mutation may occur in the coding region of a gene (i.e. in exons), in introns, or in the regulatory regions (e.g. enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, promoters) of the gene. Generally a mutation is identified in a subject by comparing the sequence of a nucleic acid or polypeptide expressed by said subject with the corresponding nucleic acid or polypeptide expressed in a control population. Where the mutation is within the gene coding sequence, the mutation may be a“missense” mutation, where it replaces one amino acid with another in the gene product, or a“non sense” mutation, where it replaces an amino acid codon with a stop codon. A mutation may also occur in a splicing site where it creates or destroys signals for exon-intron splicing and thereby lead to a gene product of altered structure. A mutation in the genetic material may also be“silent”, i.e. the mutation does not result in an alteration of the amino acid sequence of the expression product. In the context of the instant application, mutations identified in CFTR gene or protein are designated pursuant to the nomenclature of Dunnen and Antonarakis (2000). For instance, ">" indicates a substitution at DNA level; (underscore) indicates a range of affected residues, separating the first and last residue affected; "del" indicates a deletion, "dup" indicates a duplication; "ins" indicates a insertion, "inv" indicates an inversion and "con" indicates a conversion. More particularly,“X” denotes that an amino acid is changed to a stop codon (X).

As used herein, the term“homozygous” refers to an individual possessing two copies of the same allele. As used herein, the term“homozygous mutant” refers to an individual possessing two copies of the same allele, such allele being characterized as the mutant form of a gene.

As used herein, the term“heterozygous” refers to an individual possessing two different alleles of the same gene, i.e. an individual possessing two different copies of an allele, such alleles are characterized as mutant forms of a gene.

In some embodiments, the subject harbors at least one mutation in the CFTR gene. The CFTR gene mutations were classified into six classes according to their resulting damaging effect on the protein. Class I encompasses frameshift, splicing, or nonsense mutations that introduce premature termination codons (PTC), resulting in severely reduced or absent CFTR expression (e.g. W1282X, 1717-1G->A, G542X, R553X, 2183 AA>G). Class II mutations lead to misfolding, premature degradation by the endoplasmic reticulum (ER) quality-control system, and impaired protein biogenesis, severely reducing the number of CFTR molecules that reach the cell surface (e.g. F508del, 2184delA). The gene product having mutations of class III is properly synthesized, transported and incorporated into the cell membrane, but has decreased activity caused by abnormal regulation of the protein. These mutations are frequently situated within one of the nucleotide binding domain (eg. G551D, R560T). Class IV mutations alter the channel conductance by impeding the ion conduction pore, leading to a reduced unitary conductance (e.g. R117H, R334W). Class V CFTR mutations do not change the conformation of the protein but alter its abundance by introducing promoter or splicing abnormalities (e.g. 2789+5G->A, A455E) (19). Class VI mutations destabilize the channel in post-ER compartments and/or at the plasma membrane (PM), by reducing its conformational stability (20) and/or generating additional internalization signals (21). This results in accelerated plasma-membrane turnover and reduced apical CFTR expression (20-21). (e.g. c. 120dell23, rPhe580del).

Examples of CFTR mutations include, but are not limited to 124del23bp CFTR, CFTRdelel CFTR, Ml V CFTR, Q2X CFT, S4X CFTR, P5L CFTR, S13F CFTR, L15P CFTR, 182delT CFTR, CFTRdele2 CFTR, CFTRdele2-4 CFTR, 185+1G->T CFTR, CFTRdele2,3 CFTR, W19X CFTR, G27R CFTR, G27X CFTR, Q30X CFTR, R31C CFTR, R31L CFTR, Q39X CFTR, A46D CFTR, 296+lG->A CFTR, 296+lG->T CFTR, CFTRdele3-10,14b-16 CFTR, 296+28A->G CFTR, 296+2T->C CFTR, 296+3insT CFTR, 297-3C->T CFTR, 297- 1G->A CFTR, E56K CFTR, W57G CFTR, W57X CFTR, 306insA CFTR, 306delTAGA CFTR, E60X CFTR, P67L CFTR, R74W CFTR, R75X CFTR, R75Q CFTR, 365-366insT CFTR, G85E CFTR, 394delTT CFTR, L88X CFTR, G91R CFTR, CFTRdele4-7 CFTR, CFTRdele4-l l CFTR, CFTR50kbdel CFTR, 405+lG->A CFTR, 405+3 A->C CFTR, 406-2A- >G CFTR, 406-lG->A CFTR, E92K CFTR, E92X CFTR, Q98X CFTR, Q98R CFTR, P99L CFTR, L102R CFTR, 442delA CFTR, 444delA CFTR, 457TAT->G CFTR, D110H CFTR, D110E CFTR, R117C CFTR, R117G CFTR, R117H CFTR, R117H;5T CFTR, R117H;7T CFTR, 541 del C CFTR, L138ins CFTR, H139R CFTR, 574delA CFTR, I148T CFTR, 602dell4 CFTR, Y161D CFTR , 621+1G->T CFTR, 621+3A->G CFTR, L165S CFTR, R170H CFTR, 663delT CFTR, G178R CFTR, 675del4 CFTR, E193X CFTR, 711+1G->T CFTR, 711+3 A- >G CFTR, 711+5G->A CFTR, 712-1G-+T CFTR, H199Y CFTR, V201M CFTR, P205S CFTR, L206W CFTR, W216X CFTR, Q220X CFTR, L227R CFTR, V232D CFTR, 849delG CFTR, 852del22 CFTR, CFTRdup6b-10 CFTR, M265R CFTR, 935delA CFTR, Y275X CFTR, C276X CFTR, 977insA CFTR, 991del5 CFTR, F311L CFTR, 1078delT CFTR, L320V CFTR, 1119delA CFTR, G330X CFTR, R334W CFTR, R334Q CFTR, R334L CFTR, 1138insG CFTR, I336K CFTR, T338I CFTR, S341P CFTR, 1154insTC CFTR, 1161delC CFTR, R347H CFTR, R347P CFTR, A349V CFTR, R352W CFTR, R352Q CFTR, Q359K/T360K CFTR, 1213delT CFTR, 1248+1G-+A CFTR, 1249-1G-+A CFTR, 1259insA CFTR, 1288insTA CFTR, W401X CFTR, 1341+1G-+A CFTR, 5T CFTR, 5T;TG11 CFTR, 5T;TG12 CFTR, 5T;TG13 CFTR, 7T CFTR, 9T CFTR, 1343delG CFTR, Q414X CFTR, 1429del7 CFTR, D443Y CFTR, 1461ins4 CFTR, 1471delA CFTR, L453S CFTR, A455E CFTR, 1497delGG CFTR, V456A CFTR, 1504delG CFTR, 1525- 1G->A CFTR, 1525-2A-+G CFTR, S466X CFTR, L467P CFTR, M470V CFTR, 1548delG CFTR, E474K CFTR, S489X CFTR, S492F CFTR, 1609delCA CFTR, Q493X CFTR, W496X CFTR, I502T CFTR, I507del CFTR, F508del CFTR, F508C CFTR, D513G CFTR, 1677delTA CFTR, V520F CFTR, C524X CFTR, Q525X CFTR, 1716+1G->A CFTR, CFTRdelel l CFTR, 1717-1G->A CFTR, 1717- 8G->A CFTR, G542X CFTR, S549R CFTR, S549N CFTR, G550X CFTR, 1782delA CFTR, G551 S CFTR, G551D CFTR, Q552X CFTR, R553X CFTR, 1802delC CFTR, L558S CFTR, A559T CFTR, 1811+1G->C CFTR, R560K CFTR, R560T CFTR, 1811+1G->A CFTR, 1811+1634A->G or 181 l+1.6kbA->G CFTR, 1811+1643G->T CFTR, 1812-1G->A CFTR, R560S CFTR, A561E CFTR, V562I CFTR, Y563N CFTR, Y563D CFTR, 1824delA CFTR, 1833delT CFTR, Y569D CFTR , P574H CFTR , F575Y CFTR, G576A CFTR, D579G CFTR, E585X CFTR, E588V CFTR, 1898+1G->A CFTR, 1898+1G->C CFTR, 1898+1G->T CFTR, CFTRdelel3,14a CFTR, 1898+3A->G CFTR, 1898+5G->T CFTR, 1924del7 CFTR, H609R CFTR, A613T CFTR, D614G CFTR, G622D CFTR , 2055del9->A CFTR, 2075delA CFTR, 2105-2117dell3insAGAAA CFTR, 2118del4 CFTR, R668C CFTR, 2143delT CFTR, G673X CFTR, 2183AA->G CFTR, 2184insA CFTR, 2184delA CFTR, 2185insC CFTR, Q685X CFTR, R709X CFTR, K710X CFTR, Q715X CFTR, Q720X CFTR, 2307insA CFTR, L732X CFTR, 2347delG CFTR, 2372del8 CFTR, P750L CFTR, V754M CFTR, R764X CFTR, R785X CFTR, R792X CFTR, I807M CFTR, 2556insAT CFTR, 2585delT CFTR, 2594delGT CFTR, E822X CFTR, 2622+lG->A CFTR, E831X CFTR, D836Y CFTR, W846X CFTR Y849X CFTR, R851X CFTR, T854T CFTR, 2711delT CFTR, 2721dell l CFTR, 2732insA CFTR, CFTRdelel4b-17b CFTR, 2752-26A->G CFTR, W882X CFTR, 2789+2insA CFTR, 2789+5G->A CFTR, 2790-lG->C CFTR, Q890X CFTR, S912X CFTR, S912L CFTR, 2869insG CFTR, Y913X CFTR, 2896insAG CFTR, L927P CFTR, 2942insT CFTR, 2957delT CFTR, S945L CFTR, 2991del32 CFTR, 3007delG CFTR, 3028delA CFTR, L967S CFTR, G970R CFTR, CFTRdelel6-17b CFTR, G970D CFTR, S977F CFTR, D979V CFTR, 3120G- >A CFTR, CFTRdelel7a,17b CFTR, CFTRdelel7a-18 CFTR, 3120+1G->A CFTR, 3121-1 G- >A CFTR, 3121-2A->G CFTR, 3121-977_3499+248del2515 CFTR, L997F CFTR, 3132delTG CFTR, A1006E CFTR, 3143del9 CFTR, 3171delC CFTR, 3171insC CFTR, Y1014C CFTR, F1016S CFTR, I1027T CFTR, Y1032C CFTR, Q1042X CFTR, 3271delGG CFTR, 3272-26A->G CFTR, FI 052V CFTR, T 10531 CFTR, H1054D CFTR, G1061R CFTR, L1065P CFTR, R1066C CFTR, R1066H CFTR, G1069R CFTR, R1070W CFTR, R1070Q CFTR, 3349insT CFTR, F1074L CFTR, L1077P CFTR, W1089X CFTR, Y1092X CFTR, W1098X CFTR, W1098C CFTR, F1099L CFTR, M1101K CFTR, R1102X CFTR, E1104X CFTR, S1118F CFTR, CFTRdelel8 CFTR, 3500-2A->G CFTR, W1145X CFTR, D1152H CFTR, V1153E CFTR, 3600G->A CFTR, CFTRdelel9 CFTR, CFTRdelel9-21 CFTR, 3600+2insT CFTR, 3600+5G->A CFTR, R1158X CFTR, S1159P CFTR, S1159F CFTR, R1162X CFTR, R1162L CFTR, 3659delC CFTR, 3667ins4 CFTR, S1196X CFTR, 3737delA CFTR, W1204X CFTR, 3791delC CFTR, Y122X CFTR, 3821delT CFTR, I1234V CFTR, S1235R CFTR, 3849G->A CFTR, 3849+4A->G CFTR, 3849+5G->A CFTR, 3849+40A->G CFTR, 3849+10kbC->T CFTR, 3850-lG->A CFTR, 3850-3T->G CFTR, V1240G CFTR, G1244E CFTR, T 12461 CFTR, 3876delA CFTR, 3878delG CFTR, S 125 IN CFTR, L1254X CFTR, S1255P CFTR, S1255X CFTR, 3905insT CFTR, D1270N CFTR, W1282X CFTR, R1283M CFTR, Q1291R CFTR, 4005+lG->A CFTR, CFTRdele21 CFTR, 4005+2T->C CFTR, 4010del4 CFTR, 4015delA CFTR, 4016insT CFTR, 4022insT CFTR, 4040delA CFTR, N1303K CFTR, Q1313X CFTR, CFTRdele22-24 CFTR, CFTRdele22,23 CFTR, L1324P CFTR, Q1330X CFTR, L1335P CFTR, 4168delCTAAGCC CFTR, G1349D CFTR, 4209TGTT->AA CFTR, 4218insT CFTR, E1371X CFTR, H1375P CFTR, 4259del5 CFTR, Q1382X CFTR, 4279insA CFTR, 4326delTC CFTR, Q1411X CFTR, Q1412X CFTR, 4374+lG->T CFTR, 4374+lG->A CFTR, 4382delA CFTR, 4428insGA CFTR (see, e.g., https://www.cftr2.org/mutations_history, for CFTR mutations).

In one embodiment, the subject harbors at least one allelic mutation selected from class

I, class II, class III, class IV, class V or VI class.

In one embodiment, the subject harbors at least one mutation selected from class I, class

II, class III, class IV, class V or class VI in the first allele and at least one mutation selected from class I, class II, class III, class IV, class V or class VI in the second allele. In a particular embodiment, the subject harbors at least a mutation of class I in the first allele and at least a mutation of class II in the second allele. In a particular embodiment, the subject harbors at least a mutation of class II in the first allele and at least a mutation of class II in the second allele.

In a particular embodiment, the subject harbors at least one allelic mutation in the CFTR gene including, but not limited to F508del-CFTR, R117H CFTR, 2184delA CFTR, W1282X CFTR, 2183AA>G CFTR or G551D CFTR.

In one embodiment, the subject harbors at least a F508del mutation in the CFTR gene. In one embodiment, the subject harbors at least a 2183AA>G mutation in the CFTR gene. In one embodiment, the subject harbors at least a F508del mutation in the first allele and at least a 2183AA>G mutation in the second allele.

As used herein, the term“resolvin D1 compound” refers to one of the potent lipid mediators derived from both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Resolvin D1 (RvDl) is produced physiologically from the sequential oxygenation of DHA by 15- and 5 -lipoxygenase. In addition to being anti-inflammatory, resolvins promote the resolution of the inflammatory response back to a non-inflamed state. In the context of the invention, RvDl is able to have anti-inflammatory effects which are not immunosuppressive. More particularly, RvDl is able to stimulate the bacteria clearance by increasing airway surface liquid (ASL) and the alveolar macrophage-mediated phagocytosis activity. RvDl has the following structure (Formula I) and CAS number: 872993-05-0:

Formula I

As used herein the terms "administering" or "administration" refer to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., resolving Dl) into the subject, such as by, intravenous, intramuscular, enteral, subcutaneous, parenteral, systemic, local, spinal, nasal, topical or epidermal administration (e.g., by injection or infusion). When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof. In a particular embodiment, the RvDl compound is administered by nasal administration.

A“therapeutically effective amount” is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject. For example, a "therapeutically effective amount" to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.

In a particular embodiment, the i) RvDl compound as described above and ii) a classical treatment as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

As used herein the terms "administering" or "administration" refer to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., RvDl alone or in a combination with at least one classical treatment of CF airways) into the subject, such as by, intravenous, intramuscular, enteral, subcutaneous, parenteral, systemic, local, spinal, nasal, topical or epidermal administration (e.g., by injection or infusion). When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof. In a particular embodiment, the administration is performed by inhalation.

As used herein, the term“administration simultaneously” refers to administration of 2 active ingredients by the same route and at the same time or at substantially the same time. The term“administration separately” refers to an administration of 2 active ingredients at the same time or at substantially the same time by different routes. The term “administration sequentially” refers to an administration of 2 active ingredients at different times, the administration route being identical or different.

As used herein, the term“classical treatment” refers to the treatments used or will be used to treat cystic fibrosis airways. Typically, the classical treatment includes, but is not limited to: antibiotics, aerosolized medications (e.g. dornase alfa, hypertonic saline, Denufosol), chest physiotherapy, expiratory pressure physiotherapy, anti-inflammatory compounds (Lenabasum also known as Corbus, Celtaxis), Lung transplantation, lumacaftor, ivacaftor, tezacaftor, elexacaftor or trikafta.

In a particular embodiment, i) RvDl compound as described above and ii) tezacaftor as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

As used herein the term“tezacaftor” also called“l-(2,2-difluoro-2H-l,3-benzodioxol- 5-yl)-N-{ l-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH- indol-5-yl}cyclopropane-l-carboxamide” has its general meaning in the art and refers to the compound characterized by the formula of:

Formula II

In another embodiment, i) RvDl compound as described above and ii) lumacaftor as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

As used herein the term “lumacaftor” also called “3-{6-[l-(2,2-difluoro-2H-l,3- benzodioxol-5-yl)cyclopropaneamido]-3-methylpyridin-2-yl}benzoic acid” or“VX809” has its general meaning in the art and refers to the compound characterized by the formula of:

Formula III

In another embodiment, i) RvDl compound as described above and ii) ivacaftor as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

As used herein the term“ivacaftor” also called“N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 4-oxo- l,4-dihydroquinoline-3 -carboxamide” or“VX770” has its general meaning in the art and refers to the compound characterized by the formula of: Formula IV

In further embodiment, the combination of Lumacaftor/ivacaftor is already commercially available under the brand name Orkambi® in the form of 200 mg of /125 mg tablets (Lumacaftor/ivacaftor) for the treatment of cystic fibrosis.

Accordingly, in a particular embodiment, i) RvDl compound as described above and ii) Orkambi® as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

In a further embodiment, the i) RvDl compound as described above and ii) an anti- inflammatory compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.

In a particular embodiment, the i) RvDl compound as described above and ii) Lenabasum, as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

As used herein, the Lenabasum developed by Corbus, also called “6H-

Dibenzo(b,d)pyran-9-carboxylic acid, 3 -( 1 , 1 -dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro- 1 - hydroxy-6, 6-dimethyl-, (6aR,10aR)” is a candidate drug ongoing in phase 2 study. Lenabasum has general meaning in the art and refers to the compound characterized by the formula of:

Formula V In a particular embodiment, the i) RvDl compound as described above and ii) acebilusta as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.

As used herein, the acebilustat developed by celaxis, also called“Benzoic acid, 4- (((1 S,4S)-5-((4-(4-(2-oxazolyl)phenoxy)phenyl)methyl)-2,5-diazabicyclo(2.2. l)hept-2- yl)methyl)-“ is a candidate drug ongoing in phase 2 study. Acebilustat has its general meaning in the art and refers to the compound characterized by the formula of:

In a particular embodiment, i) RvDl compound as described above and ii) elexacaftor as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

As used herein the term“elexacaftor” also called“N-[(l,3-dimethyl-lH-pyrazol-4- yl)sulfonyl]-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-lH-pyrazol-l-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-l-yl]pyridine-3 -carboxamide” or“VX-445” has its general meaning in the art and refers to the compound characterized by the formula of:

Formula VII

In further embodiment, the combination of elexacaftor/tezacaftor/ivacaftor is already commercially available under the brand name Trikafta™ in the form of 100mg/50mg/75mg and

150mg tablets (elexacaftor/tezacaftor/ivacaftor and ivacaftor) for the treatment of cystic fibrosis. Accordingly, in a particular embodiment, i) RvDl compound as described above and ii) trikafta as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

In a second aspect, the invention relates to a pharmaceutical composition for use in the treatment of cystic fibrosis.

The resolvin D1 alone and/or with a classical treatment as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual , buccal, and inhalation administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms. Typically, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The resolving D1 compound can be formulated into a composition in a neutral or salt form. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

In a particular embodiment, the compound RvDl according to the invention wherein said compound is used by inhalation administration.

As used herein, the term“inhalation administration” when the compound RvDl enters to the lungs by breathing it.

The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

FIGURES:

Figure 1: Resolvin D1 effects on airway surface liquid (ASL) height in polarised, differentiated CF Bronchial Epithelial Cells. ASL height in pm was measured by live cell confocal fluorescence microscopy using Texas red®-dextran to stain the ASL. (A) Primary cultures of human CF Bronchial Epithelial Cells were stimulated with either vehicle control (Cont) or RvDl (1 nM) for 30min prior to image acquisition. Representative images of the ASL are presented with quantification of the ASL height measured in inserts prepared from bronchial epithelium derived from 2 separate children with CF (***P<0.001, n=7, Wilcoxon). (B) CF bronchial epithelial monolayers were stimulated with either vehicle control (Cont), amiloride (10pM), human neutrophil elastase (NE) alone or followed by RvDl (InM-lOOnM) 30min prior to image acquisition. (*P<0.05, **P<0.01, ***P<0.001, n=6, ANOVA). (C) CF bronchial epithelial cells were treated with either vehicle control (Cont) or with Boc2 (10 pM) for 20 min followed by RvDl (1 nM) for 30 min (*P<0.05, **P<0.01, n=6). (D) CF cells were treated with either vehicle control (Cont) or with BAPTA-AM (10 pM) (intracellular calcium chelator) for 20 min followed by RvDl (1 nM) for 30 min (**P<0.01, ***P<0.001, n=5, ANOVA). (E) Primary cultures of human CF Bronchial Epithelial Cells from 3 subjects, one non-CF (subject 1), one CF patient homozygous for the mutation F508del mutation (subject 2) and one CF patient with the F508del/394delTT mutation (subject 3) were studied. Bronchial epithelial cells from the CF patients were exposed to either vehicle control (NT) or RvDl for 30min prior to image acquisition. The effect of RvDl on ASLh of Bronchial epithelial cells from subject 2 was compared to the effect of the combination of CFTR corrector (VX809) and potentiator (VX770). (**p<0.01)

Figure 2. Effect of RvDl on nasal potential in WT and F508del-CFTR mice. (A) Representative nasal potential (VTE) recordings obtained in F508del-CFTR mice. Amiloride (10 mM) and low Cl- solution were perfused at the time indicated on the graph. (B) Baseline VTE measured during nasal perfusion in a normal Cl- solution with or without RvDl (lOnM), in F508del-CFTR (n=10) and WT mice (n=4). (C) Effect of RvDl on the amiloride- sensitive nasal potential difference (AVTE amiloride) in F508del-CFTR and WT mice. (D) Effect of RvDl on nasal Cl- secretion measured by the nasal potential difference change generated by removal of Cl- in the perfusion solution (D VTE low C1-) in F508del-CFTR and WT mice. Each mice treated with RvDl had its own untreated control. (*P<0.05 / **P<0.01, Wilcoxon).

Figure 3: Resolvin D1 decreases TNFa-induced IL8 secretion via preservation of

IKB. A significant induction of IL8 secretion was observed in CF airway epithelial cells following treatment with TNFa (80 ng/ml), (546±39 ng/ml, P<0.001, n=6), compared to the baseline IL8 secretion (169±54 ng/ml). Treatment with RvDl (100 nM) prevented the stimulation of IL8 secretion induced by TNFa in CF epithelial cells (283±44 ng/ml, P<0.01, n=6), (figure 3A). TNFa treatment of CF cells resulted in a significant degree of IKB degradation (0.67±0.06; in TNFa cells compared to untreated cells (1.07±0.04, P<0.01, n=6). Co-treatment with RvDl significantly prevented IKB degradation (0.93±0.05, in TNFa + RvDl compared to 0.67±0.06 in TNFa alone, P<0.05, n=5), (figure 3B).

Figure 4. Resolvin D1 effect on the phagocytic capacity and bacterial killing of primary alveolar macrophages from children with CF (CFAM). (A) Fluorescence intensity of phagocytosed FITC-labelled beads were quantified using a fluorescence plate reader (n=9). (B) CFAM were treated with either vehicle control (Cont) or RvDl (100 nM) for 3h and then exposed to PAOl bacteria. After 30 min, the non-engulfed bacteria were removed and CFAM were treated with gentamicin to kill residual extracellular and membrane-bound bacteria. CFAM were then lysed and the bacterial load within the lysate was quantified (n=9 from 3 patient samples for phagocytosis and n=4 preparations from 2 patients for bacterial killing **P<0.01, *P<0.05, Wilcoxon).

EXAMPLE:

Material & Methods

Clinical samples

Bronchoalveolar lavage fluid (B AL) and bronchial brushings were collected through the Study of Host Immunity and Early Lung Disease in CF (11). Studies were carried out in accordance with European community guidelines and approved by the Research Ethics Committee of Our Lady’s Children’s Hospital Crumlin (Dublin). Human airway epithelial cell culture

Primary cultures of bronchial epithelial cells were grown from bronchial brushings or biopsies obtained from 5 healthy donors and 6 children with CF (4 F508del-CFTR homozygous and 2 F508del-CFTR heterozygous (F508del/2789+5G>A and F508del/H199Y). The CF epithelia showed similar electrophysiological profiles in untreated conditions. Humna bronchial epithelial cell lines were also used; Non-CF NuLi-1 and CF (F508del homozygous) CuFi-1 (22). Epithelial cells were cultured on permeable supports under an air-liquid interface until reaching a high trans-eithelial electrical resistance, (TEER >700 W/ah2) (23).

Airway surface liquid (ASL) height measurements

Texas red (2mg/ml, Invitrogen) was applied to the ASL of bronchial epithelial cells 24h prior imaging and Perfluorocarbon-72 (3M, St. Paul, USA) was added before acquisition to prevent evaporation. The ASL images were captured with a Zeiss LSM 510 Meta microscope (40X) and analysed using Zeiss LSM Image Browser. Each biological repeat represents the mean of 27 ASL height measurements per culture insert.

Nasal potential difference measurements

Nasal potential difference measurements were performed on homozygous F508del- CFTR mice (FVB/N) and their wild-type normal homozygous littermates (WT) as previously described (24) and approved by the ethics committee of Necker Hospital (Paris, France) and conformed to European Community regulations for the use of animals in research (authorization no. P2.AE.092.09). Changes in nasal VTE obtained after amiloride IOOmM and low Cl- solution perfusion reflect the ionic current contribution of Na+ absorption via ENaC and Cl- secretion, respectively.

Short - circuit current (ISC) recordings

Differentiated HBE cells were mounted in Ussing chambers and short-circuit-current SCC was measured under voltage clamp conditions and a Cl- gradient across the epithelium (see online Supplement). The SCC decreased after amiloride (IOOmM) and increased after forskolin (IOmM) /IBMX (IOOmM) treatment. The use of these drugs served as an indicator of SCC changes reflecting ENaC and CFTR activity, respectively.

Enriching Primary Alveolar Macrophages

Alveolar macrophages (AM) were isolated from the BAL of 3 CF female children (<6y, F508del homozygous), re-suspended in primary AM medium (online data), plated in 96 well plates and incubated (humidified, 37.2 °C, 21% oxygen, 5% C02) overnight. The following morning, non-adherent cells were aspirated and discarded. The adherent cells were washed twice with pre-warmed Ca2+ and Mg2+ free PBS. Alveolar Macrophage Phagocytosis Assay

The phagocytic capacity of Alveolar Macrophages (AM) was measured by their ability to engulf IgG & FITC labelled beads (Cayman Chemical, Ann Arbour, MI). Phagocytosis was quantified by the fluorescence intensity of engulfed FITC labelled complexes using a plate reader (Synergy MX Biotek Instruments, Winooski, VT).

Bactericidal assay against Pseudomonas aeruginosa

Alveolar Macrophages were washed twice with antibiotic-free medium and incubated with PAOl (2c10^L14 CFU/ml) for 3 h. AM were then washed and gentamicin (400 pg/ml) was applied for 1 h. After 2 washing AM were lysed with Triton-X 100 (0.4% v/v) for 15 min to release internalised bacteria. Quantification of the viable intracellular bacterial load was performed and expressed as colony forming units per ml.

Statistical Analysis

Results are presented as mean and standard error of the mean (SEM). The non- parametric Wilcoxon-Mann-Whitney rank sum test was used when comparing two groups. The one-way analysis of variance (ANOVA) was used in the cases of multiple comparisons.

Results

Resolvin D1 restores ASL height in CF bronchial epithelial cells

We investigated the effect of RvDl on ASL height in CF airway epithelia. Under vehicle control conditions, the ASL height was low and the hydrated layer overlaying the epithelium was discontinuous in primary cultures of CF bronchial epithelial cells derived from F508del CFTR homozygous patients, (3.7±0.2 pm, n=7), (figure 1A). A similar low and disrupted ASL was observed in CuFi-1 cells, a cell line derived from bronchial epithelium of a patient homozygote for F508del mutation (5.7±0.3 pm, n=8), (figure IB, 1C and ID). After exposure of CF bronchial epithelial cells to RvDl, the ASL height was higher with a more continuous hydrated layer (data not shown). Exposure to RvDl (1 nM, 30 min) produced an increase in ASL height to 6.8±0.3 pm (P<0.001, n=7) in CF bronchial epithelial primary cultures (figure 1A) and to 7.1±0.15 pm (PO.01, n=6), in CuFi-1 cells (figure IB, 1C, ID). As shown in the dose-response figure, treatment of CuFi-1 cells with higher concentrations of RvDl resulted in a further increase in ASL height compared to vehicle control conditions (figure IB). In CuFi- 1 cells, the ASL height increased to 7.7±0.2 pm (P<0.01, n=5) and to 8.3±0.3pm (P<0.001, n=5) with RvDl 10 nM and lOOnM, respectively (figure IB). We compared the ASLh increase induced by RvDl (O. lnM-lOOnM) to the effect of a combination of CFTR modulators (VX809+VX770) used to restore CFTR function (figure IE). The effect of RvDl was dose dependent. RvDl (O. lnM-lOOnM) produced a similar or more potent response than the combination of corrector and potentiator (Orkambi, VX809 10pm + VX770 10 pm) in the same cell cultures (figure IE). Furthermore, RvDl induced an ASLh increase in primary culture of bronchial epithelial from CF patients with different genotypes.

ENaC activity contributes to the increased ASL height induced by Resolvin D1

The possible role of ENaC in causing an ASL height increase in response to RvDl was tested in CuFi-1 cells by either inhibiting or stimulating ENaC activity using amiloride or human neutrophil elastase, respectively (figure IB). Apical amiloride (10 pm) exposure of the CF epithelial cells produced an ASL height increase from 5.5±0.1 to 6.6±0.1 pm, P<0.001, n=6. The ASL height increase (8.2±0.2 pm, PO.OOl, n=6) induced by RvDl (lOOnM) was larger than that produced by amiloride alone, however, when cells were exposed to both RvDl and amiloride, no additive effects were observed (7.9±0.1 pm, P>0.5, n=6). Conversely, ENaC stimulation by apical exposure to neutrophil elastase induced a small but significant reduction in ASL height (5.1±0.1 pm, PO.05, n=6). RvDl treatment reversed the ASL height decrease induced by human neutrophil elastase by restoring the ASL height above basal values (7.1±0.16 pm, P<0.001, n=6). This latter result, which is consistent with a greater stimulatory ASL response to RvDl compared to amiloride alone, suggests that the ASL height increase induced by RvDl involves both inhibition of ENaC and regulation of another ion transport pathway.

ALX/FPR2 receptor and intracellular calcium mediate Resolvin D1 effects on ASL height

Exposure of CF CuFi-1 cells under basal conditions to the ALX/FPR2 receptor antagonist, Boc2, did not significantly alter ASL height (Boc2 (10 pM): 5.9±0.6 pm vs control: 5.7±0.3 pm, n=6). In contrast, pre-treatment of CuFi-1 cells with Boc2 completely prevented the increase in ASL height produced by RvDl (5.7±0.5 pm in RvDl + Boc2 compared with 7.1±0.2 pm in RvDl alone (P<0.05, n=6), (figures 1C). Incubation of CuFi-1 cells with the intracellular calcium chelator BAPTA-AM (10 pM) did not significantly affect the basal ASL height (5.2±0.4 pm vs 5.7±0.3 pm, n=5), (figure 1C). However, the RvDl mediated increase in ASL height was abolished by co-treatment with BAPTA-AM. Under these conditions the ASL height remained low in the combined presence of RvDl and BAPTA-AM (4.9±0.2 pm, n=5) compared to the enhanced ASL height in the presence of RVD1 alone (7.1±0.2 pm, PO.OOl, n=5), (figure ID). These data indicate that the ASL height increase induced by RvDl in CF airway epithelia is transduced by the ALX/FPR2 receptor and involves the mobilization of intracellular calcium.

Resolvin D1 decreases TNFa-induced IL8 secretion via preservation of IKB We investigated whether RvDl can modulate inflammatory responsiveness in CF airway epithelia. A significant induction of IL8 secretion was observed in CF airway epithelial cells following treatment with TNFa (80 ng/ml), (546±39 ng/ml, P<0.001, n=6), compared to the baseline IL8 secretion (169±54 ng/ml). Treatment with RvDl (100 nM) prevented the stimulation of IL8 secretion induced by TNFa in CuFi-1 cells (283±44 ng/ml, P<0.01, n=6), (figure 3 A). TNFa treatment of CuFi-1 cells resulted in a significant degree of IKB degradation (0.67±0.06; in TNFa cells compared to untreated cells (1.07±0.04, P<0.01, n=6). Co-treatment with RvDl significantly prevented IKB degradation (0.93±0.05, in TNFa + RvDl compared to 0.67±0.06 in TNFa alone, P<0.05, n=5), (figure 3B).

Resolvin D1 restores nasal potential difference in CF and non-CF mice

We investigated the impact of RvDl in regulating ion transport in CF airway in vivo, by testing the effects of this SPM on the nasal transepithelial electrical potential difference (VTE) in mice homozygous for F508del-CFTR (FVB/N) and in their wild-type CFTR litter- mates. In agreement with previously published studies, F508del-CF mice displayed a raised (more negative) baseline nasal transepithelial potential (VTE = -14.2±1.1 mV, n=10) compared to WT mice (-6.1±1.3 mV, n=4), (Figure 2A and 2B). The baseline VTE was significantly depolarised (shifted to less negative potentials) with RvDl (10 nM) treatment in the CF mice (-9.0±2.1 mV, P<0.005, n=10), whereas it was unaltered in WT mice (-5.7±1.4 mV, P>0.5, n=4), (figure 2A and 2B). The relative contribution of Na+ absorption and Cl- secretion to the VTE response to RvDl was tested using amiloride (lOOpm) and low Cl- solutions, respectively. RvDl reduced the amiloride-sensitive VTE in CF mice (AVTE 10.1±1.0 mV with amiloride alone compared to a AVTE of 6.3±1.1 mV with combined amiloride and RvDl treatment, P<0.05, n=10). In contrast, RVDl treatment did not affect the AVTE changes induced by amiloride in WT mice (AVTE 3.5±0.36 mV with amiloride alone compared to AVTE 3.1±1.1 mV with amiloride and RvDl, P>0.5, n=4), (figure 2A and 2C). As already reported, perfusion of the nasal cavity with low Cl- solutions induced a small VTE change in CF mice (-1.1±0.4 mV) while producing a significantly larger VTE change in WT mice (-3.9±0.6 mV). This latter response was not significantly affected by RvDl treatment of WT mice (-3.2±0.5, P > 0.1, n=4). In contrast, when RvDl was added to the nasal infusion fluid of CF mice, the VTE response to low Cl- solution was significantly increased (-3.1±0.8 mV, P<0.05, n=10) to levels obtained in WT mice (without RvDl) (figure 2A and 2D). These data are consistent with an inhibitory effect of RvDl on ENaC and a stimulation of a non-CFTR dependent Cl- secretion in the CF airway. Resolvin D1 enhances the phagocytic capacity of CF Primary Alveolar Macrophages

The phagocytic activity of CF (F508del) alveolar macrophages was measured after treatment with either vehicle control or RvDl (100 nM) and incubation with fluorescently latex beads. A greater proportion of alveolar macrophages treated with RvDl was observed to have engulfed labelled beads. In addition, the fluorescence intensity measured from RvDl treated macrophage samples was significantly higher compared to vehicle control samples (7490±950, in RvDl compared to 4420±1020, in untreated cells, P<0.01, n=9), (figure 4 A). In order to quantify the bacterial killing capacity of RvDl treatment, CF alveolar macrophages were pre treated with either vehicle control or RvDl (100 nM) and exposed to P. aeruginosa lab strain PAOl (2x1014 CFU/ml) for 3 h. The intracellular viable bacterial load of PAOl was significantly decreased in preparations treated with RvDl compared to vehicle control conditions (1.7±0.6 xl06 CFU/ml, in RvDl and 6.0±1.4 xl06 CFU/ml in vehicle control, P<0.05, n=4) (figure 4B).

In conclusion, inventors report that RvDl has multiple roles in reversing CF airway epithelial dysfunction by synergistically correcting abnormalities in airway epithelial ion transport and airway surface liquid dynamics; airway epithelial cell IL8 production; and bacterial killing capacities of CF alveolar macrophages. RvDl thus displays high therapeutic potential in CF lung disease.

REFERENCES:

Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

[1] R. C. Boucher, "Evidence for airway surface dehydration as the initiating event in CF airway disease," (in eng), J Intern Med, vol. 261, no. 1, pp. 5-16, Jan 2007.

[2] J. Emerson, M. Rosenfeld, S. McNamara, B. Ramsey, and R. L. Gibson, "Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis," (in ENG), Pediatr Pulmonol, vol. 34, no. 2, pp. 91-100, Aug 2002.

[3] M. Leveque, S. Le Trionnaire, P. Del Porto, and C. Martin-Chouly, "The impact of impaired macrophage functions in cystic fibrosis disease progression," (in eng), J Cyst Fibros, Nov 2016. [4] B. S. Scales, R. P. Dickson, and G. B. Huffnagle, "A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs," (in eng), J Leukoc Biol, vol. 100, no. 5, pp. 943-950, Nov 2016.

[5] C. J. Wagner, C. Schultz, and M. A. Mall, "Neutrophil elastase and matrix metalloproteinase 12 in cystic fibrosis lung disease," (in eng), Mol Cell Pediatr, vol. 3, no. 1, p. 25, Dec 2016.

[6] R. A. Caldwell, R. C. Boucher, and M. J. Stutts, "Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport," (in eng), Am J Physiol Lung Cell Mol Physiol, vol. 288, no. 5, pp. L813-9, May 2005.

[7] C. Margaroli et ah,“Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis”, Am J Respir Crit Care Med, vol 199, no.7, p.873-881, 2018.

[8] C. N. Serhan, "Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms," (in eng), FASEB J, Jan 2017.

[9] CL Karp et al.,“Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway”, Nat Immunol, 5(4):388-92, 2004

[10] S. D. Freedman, J. C. Shea, P. G. Blanco, and J. G. Alvarez, "Fatty acids in cystic fibrosis," (in ENG), Curr Opin Pulm Med, vol. 6, no. 6, pp. 530-2, Nov 2000.

[11] F. C. Ringholz et al., "Reduced 15 -lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis," (in ENG), Eur Respir J, Apr 2014.

[12] O. Eickmeier et al., "Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis," (in eng), PLoS One, vol. 12, no. 2, p. e0171249, 2017.

[13] G. Fredman and C. N. Serhan, "Specialized proresolving mediator targets for RvEl and RvDl in peripheral blood and mechanisms of resolution," (in eng), Biochem J, vol. 437, no. 2, pp. 185-97, Jul 2011.

[14] M. Codagnone et ak, "Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection," (in eng), Mucosal Immunol, Apr 2017.

[15] RC Boucher, “Cystic fibrosis: a disease of vulnerability to airway surface dehydration”, Trends Mol Med., 13(6):231-240, 2007

[16] PM Farrell et al,“Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report”, J Pediatr., 153(2):S4-S14, 2008

[17] GS Sawicki et al, “High treatment burden in adults with cystic fibrosis: challenges to disease self-management”, J Cyst Fibros, 8(2);91-96, 2008. [18] AS Verkman et al,“Chloride channels as drug targets”, Nat Rev Drug Discov, 8(2): 153-71, 2009.

[19] H Corvol et al,“Translating the genetics of cystic fibrosis to personalized medicine”, Transl Res. 168:40-49, 2016.

[20] M Haardt et al, “C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation. J Biol Chem, 274(31):21873-7, 1999

[21] MR Silvis et al,“A mutation in the cystic fibrosis transmembrane conductance regulator generates a novel internalization sequence and enhances endocytic rates”, J Biol Chem, 278(13): 11554-60, 2003.

[22] J. Zabner et al., "Development of cystic fibrosis and noncystic fibrosis airway cell lines," (in eng), Am J Physiol Lung Cell Mol Physiol, vol. 284, no. 5, pp. L844-54, May 2003.

[23] V. Verriere et al., "Lipoxin a(4) stimulates calcium-activated chloride currents and increases airway surface liquid height in normal and cystic fibrosis airway epithelia.," (in eng), PLoS One, vol. 7, no. 5, p. e37746, 2012.

[24] E. L. Saussereau, D. Roussel, S. Diallo, L. Debarbieux, A. Edelman, and I. Sermet-Gaudelus, "Characterization of nasal potential difference in cftr knockout and F508del- CFTR mice," (in eng), PLoS One, vol. 8, no. 3, p. e57317, 2013.

[25] G. Higgins et al., "Activation of P2RY11 and ATP Release by Lipoxin A4 Restores the Airway Surface Liquid Layer and Epithelial Repair in Cystic Fibrosis," (in eng), Am J Respir Cell Mol Biol, vol. 51, no. 2, pp. 178-90, Aug 2014.

[26] M. Al-Alawi et al., "Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium," (in ENG), Physiol Rep, vol. 2, no. 8, Aug 2014.

[27] C. Bonnans, B. Mainprice, P. Chanez, J. Bousquet, and V. Urbach, "Lipoxin A(4) stimulates a cytosolic Ca2+ increase in human bronchial epithelium," Journal of Biological Chemistry, vol. 278, no. 13, pp. 10879-10884, Mar 28 2003.

[28] F. Antigny, C. Norez, F. Becq, and C. Vandebrouck, "CFTR and Ca Signaling in Cystic Fibrosis," Front Pharmacol, vol. 2, no. 67, p. 25, 2011.

[29] J. P. Winpenny, L. L. Marsey, and D. W. Sexton, "The CLCA gene family: putative therapeutic target for respiratory diseases," (in ENG), Inflamm Allergy Drug Targets, vol. 8, no. 2, pp. 146-60, Jun 2009. [30] J. Ousingsawat, J. R. Martins, R. Schreiber, J. R. Rock, B. D. Harfe, and K. Kunzelmann, "Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport," (in ENG), J Biol Chem, vol. 284, no. 42, pp. 28698-703, Oct 2009.

[31] T. Yamagata et al., "Modulation of Na+ transport and epithelial sodium channel expression by protein kinase C in rat alveolar epithelial cells," (in eng), Can J Physiol Pharmacol, vol. 83, no. 11, pp. 977-87, Nov 2005.

[32] M. Uddin and B. D. Levy, "Resolvins: natural agonists for resolution of pulmonary inflammation," (in ENG), Prog Lipid Res, vol. 50, no. 1, pp. 75-88, Jan 2011.

[33] H. M. Hsiao et al., "A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation," (in ENG), PLoS One, vol. 8, no. 3, p. e58258, 2013.

[34] F. Simiele et al., "Epigenetic regulation of the formyl peptide receptor 2 gene," (in ENG), Biochim Biophys Acta, vol. 1859, no. 10, pp. 1252-8, Oct 2016.

[35] C. N. Serhan, "Pro-resolving lipid mediators are leads for resolution physiology," (in eng), Nature, vol. 510, no. 7503, pp. 92-101, Jun 2014.

[36] Q. Wang et al., "Resolvin D 1 stimulates alveolar fluid clearance through alveolar epithelial sodium channel, Na,K-ATPase via ALX/cAMP/PI3K pathway in lipopolysaccharide- induced acute lung injury," (in ENG), J Immunol, vol. 192, no. 8, pp. 3765-77, Apr 2014.

[37] J. R. de Oliveira et al., "AT-RvDl modulates CCL-2 and CXCL-8 production and NF-kB, STAT-6, SOCS1, and SOCS3 expression on bronchial epithelial cells stimulated with IL-4," (in eng), Biomed Res Int, vol. 2015, p. 178369, 2015.

[38] R. W. Vandivier et al., "Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis," (in ENG), J Clin Invest, vol. 109, no. 5, pp. 661-70, Mar 2002.

[39] P. Del Porto et al., "Dysfunctional CFTR alters the bactericidal activity of human macrophages against Pseudomonas aeruginosa," (in eng), PLoS One, vol. 6, no. 5, p. el9970, 2011

[40] A. A. Pezzulo et al., "Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung," (in ENG), Nature, vol. 487, no. 7405, pp. 109-13, Jul 2012.

Claims

CLAIMS:

1. A resolvin D1 (RvDl) compound for use in the treatment of cystic fibrosis airways.

2. The compound for use according to claim 1, wherein the RvDl compound is used by inhalation administration.

3. The compound for use according to claim 1 and ii) a classical treatment as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.

4. The compound for use according to claim 1 and ii) tezacaftor as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.

5. The compound for use according to claim 1 and ii) ivacaftor as a combined preparation for simultaneous, separate or sequential use in in the treatment of cystic fibrosis airways.

6. The compound for use according to claim 1 and ii) lumacaftor as a combined preparation for simultaneous, separate or sequential use in the in the treatment of cystic fibrosis airways.

7. The compound for use according to claim 1 and ii) Orkambi® as a combined preparation for simultaneous, separate or sequential use in in the treatment of cystic fibrosis airways.

8. The compound for use according to claim 1 and ii) lenabasum, as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.

9. The compound for use according to claim 1 and ii) acebilusta as a combined preparation for simultaneous, separate or sequential use in the method for in the treatment of cystic fibrosis airways.

10. The compound for use according to claim 1 and ii) trikafta as a combined preparation for simultaneous, separate or sequential use in the treatment of cystic fibrosis airways.

11. A pharmaceutical composition comprising RvDl compound for use in the treatment of cystic fibrosis airways.