EP4734975A1 - Compositions for the treatment of cystic fibrosis - Google Patents

Compositions for the treatment of cystic fibrosis

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Publication number
EP4734975A1
EP4734975A1 EP24736383.1A EP24736383A EP4734975A1 EP 4734975 A1 EP4734975 A1 EP 4734975A1 EP 24736383 A EP24736383 A EP 24736383A EP 4734975 A1 EP4734975 A1 EP 4734975A1
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Prior art keywords
composition
dipv
cftr
mipv
cystic fibrosis
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German (de)
French (fr)
Inventor
Giorgio Cozza
Fulvio Ursini
Ilaria ARTUSI
Michela RUBIN
Valentina BOSELLO TRAVAIN
Paolo Morazzoni
Sandro SANTINELLO
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Distillerie Bonollo Umberto SpA Con Sigla "uB SPA"
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Distillerie Bonollo Umberto SpA Con Sigla "uB SPA"
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Publication of EP4734975A1 publication Critical patent/EP4734975A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine

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Abstract

A composition chosen between (4R)-5-(3'-idrossifenil)-γ-valerolactone (MIPV), (4R)-5-(3',4'-diidrossifenil)-γ-valerolactone (DIPV), and mixtures 5 thereof, in the treatment of cystic fibrosis, alone and/or in combination with CFTR protein modulators.

Description

“Compositions for the treatment of cystic fibrosis”
* * * *
FIELD OF THE INVENTION
[0001 ] The present invention relates to a composition for the treatment of cystic fibrosis. In particular, the composition according to the invention comprises (4R)-5-(3’-hydroxyphenyl)-y-valerolactone, and/or (4R)-5-(3’,4’- dihydroxyphenyl)-y-valerolactone for the treatment of cystic fibrosis.
BACKGROUND ART
[0002] Cystic fibrosis is the most common genetic disorder in Caucasians: it affects over 100.000 people in the world; in Italy, the affected people are about 6.000.
[0003] Cystic fibrosis is substantially characterized by chronic inflammation and repeated, persistent infections.
[0004] People affected by cystic fibrosis have two defective copies of the gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).
[0005] In normal conditions, CFTR protein is produced in the endoplasmic reticulum, matures in the Golgi apparatus and is transferred into cell plasmatic membrane, where it carries out its function.
[0006] CFTR is a transmembrane channel positioned inside cell membrane, allowing the passage of CF ions from the inside to the outside of cells. Said ions recall water on the outside surface of cells, so that mucus can have its physiologic consistence. The scarcity of CF ions on cells surface leads to the formation of a particularly viscous mucus, incapable of performing its physiologic functions.
[0007] Cystic fibrosis alters the secretion of many organs, which secretions being denser, dehydrated and not enough fluid contribute to the impairment of organs. Generally, the most affected organs are bronchi and lungs. Inside them, mucus tends to stagnate, leading to repeated infections. Another target organ is pancreas, which cannot carry out its normal function of secreting digestive enzymes into the intestine, leading to diarrhoea, food malabsorption, growth retardation in children and malnutrition in adults. Other affected organs are intestine, liver, nasal cavities, and vas deference in males, which can lead to infertility. Usually, sweat glands are compromised. Statistics suggest a median lifespan around 40 years for patients suffering from cystic fibrosis.
[0008] Different mutations can lead to an insufficient production of CFTR protein: the mutations known so far, over 2000, have been grouped into five classes:
1. Class 1 : protein production mutations Nonsense and splice mutations.
2. Class 2: protein processing mutations
Deletion and missense mutations.
This is the most common genetic defect in population (about 70% of mutations), due to a deletion of the phenylalanine in the 508 position of CFTR (F508del), leading to a structural defect making the protein incapable of reaching the plasmatic membrane.
For this mutation, on the market there is available a combination of drugs, Elexacaftor/Tezacaftor/Ivacaftor, enabling the correct folding of the channel and the recovery of its function.
3. Class 3: gating mutations
Mutations allowing CFTR to reach plasmatic membrane, although the protein shows a defect in the opening of the channel, so preventing the passage of CF ions through the membrane of the epithelial cells.
For this class, the drug Ivacaftor is available on the market.
4. Class 4: conduction mutations
Specific mutations of CFTR preventing the channel to transfer sufficient quantities of CF ions.
5. Class 5: insufficient protein mutations Splicing and missense mutations leading to the production of an insufficient quantity of functional protein.
For this class of mutations, Ivacaftor and a combination of Tezacaftor/Ivacaftor have been approved.
[0009] The above-quoted drugs are CFTR protein modulators. A description of such drugs can be found in the application W02021030556A1.
[0010] Briefly, there are two main types of CFTR modulators: CFTR correctors, i.e. molecules capable of binding the channel, correcting the defect and increasing the presence of the channel in the plasmatic membrane, and CFTR potentiators, i.e. molecules capable of holding the gate and increasing the efficiency of the transfer of CF ions once the channel is positioned in the membrane.
[0011] As of now, drugs for all the classes of mutations are not available, as the current therapy intercepts a CFTR channel with specific mutations, and therefore is mutation-dependent. At present, a pharmacologic therapy is available for about 11% only of cystic fibrosis patients.
[0012] Although the degree of involvement is very different among different mutations, all cystic fibrosis patients share an inflammatory condition affecting mainly digestive and respiratory apparatus, accompanied with persistent pulmonary infections tending to markedly worsen their clinic conditions over time.
[0013] The article of Mena Pedro et al: "5-(3',4'-Dihydroxyphenyl)- [gamma]valerolactone and its sulphate conjugates, representative circulating metabolites of flavan-3-ols, exhibit anti-adhesive activity against uropathogenic Escherichia coli in bladder epithelial cells", Journal of Functional Foods, Elsevier BV, NL, vol. 29, 7 January 2017 (2017-01-07), pages 275-280, XP029886736, ISSN: 1756-4646, DOI:
10.1016/J.JFF.2016.12.035 discloses that DIPV inhibits adherence ofE. coli to bladder epithelial cells. It also discloses that cranberries are a natural source of valerolactones. [0014] JP 2018 118939 A discloses that DIPV has effect in lowering blood glucose, and also discloses its use as nutraceutical and food additive.
[0015] The article of Kim Hyun Su et al: "Efficient and Divergent Enantioselective Syntheses of DHPVs and Anti-Inflammatory Effect on IEC- 6 Cells", Molecules, vol. 25, no. 9, 8 May 2020 (2020-05-08), page 2215, XP093112902, CH ISSN: 1420-3049, DOI: 10.3390/molecules 25092215, discloses that DIPV has an anti-inflammatory effect.
[0016] The article of Ruotolo Roberta et al: "Flavonoid-Derived Human Phenyl[gamma]-Valerolactone Metabolites Selectively Detoxify Amyloid[beta] Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease", Molecular Nutrition & Food Research, vol. 64, no. 5, 16 January 2020 (2020-01-16), XP093112900, DE ISSN: 1613- 4125, DOI: 10.1002/mnfr.201900890 discloses that MIPV had some effect in reducing accumulation of A- 11 -reactive amyloid oligomers in yeast cells, a model of Alzheimer's disease. MIPV was derived from catechins from plants.
[0017] US 2020/179312 Al discloses chemical compounds useful in the treatment of cystic fibrosis.
[0018] The review of Lopes-Pacheco Miqueias: "CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine", Frontiers in Pharmacology, vol. 10, 21 February 2020 (2020-02-21), XP055910442, CH ISSN: 1663-9812, DOI: 10.3389/fphar.2019.01662 discloses compounds for use in the treatment of cystic fibrosis. In particular, compounds called correctors are described, including ivacaftor.
[0019] The review of Hamed Baharara et al: "Therapeutic potential of phytochemicals for cystic fibrosis", Biofactors, Oxford University Press, Oxford, GB, vol. 49, no. 5, 16 May 2023 (2023-05-16), pages 984-1009, XP0725097 46, ISSN: 0951-6433, DOI: 10.1002/BIOF.1960 reviews various phytochemicals that may have the potential for use in the treatment of cystic fibrosis.
[0020] In view of the above-described state of the art, aim of the present invention is providing an active principle that can be used in the treatment of cystic fibrosis, independently from the underlying genetic mutation.
SUMMARY OF THE INVENTION
[0021] Such object has been achieved through the use of a composition chosen from (4R)-5-(3’-hydroxyphenyl)-y-valerolactone, (4R)- 5-(3’,4’-dihydroxyphenyl)-y-valerolactone, and mixtures thereof, as defined in the independent claim 1.
[0022] In an embodiment, the composition according to the present invention is administered alone.
[0023] In an embodiment, the composition according to the present invention is administered as adjuvant of the treatment with CFTR modulators.
[0024] In a further embodiment, the present invention relates to a composition for the administration in the form of drug, or food supplement, or nutraceutical composition, of the active principles according to the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The features and advantages of the present invention will become apparent from the following detailed description, from the embodiments provided by way of illustrative and non-limiting examples, and from the accompanying drawings, in which:
Figure 1 shows the structural formulas of the gamma-valerolactones object of the present invention, in their form with closed lactone ring.
Figure 2 shows the chart of a cell viability assay performed on HEK293T and HT1080 cells in a condition of high confluency.
Figure 3 shows a Western Blot analysis and protein quantification in presence of increasing concentrations of the gamma-valerolactones according to the present invention; CFTR and GAPDH are shown as loading markers: the treatment was performed in 16HBE (not shown) and CFBE cells.
Figure 4 shows the oxidative events occurring in vivo in the gamma- valerolactones administered according to the present invention.
Figure 5 shows the structural formulas of the gamma-valerolactones object of the present invention in their form with open lactone ring.
Figure 6 shows an Ussing Chamber measurement of CFTR chloride current functional analysis.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The invention relates to a composition chosen from (4R)-5-(3 ’- hydroxyphenyl)-y- valerolactone, (4R)-5-(3’,4’-dihydroxyphenyl)-y- valerolactone, and mixtures thereof, for use in the treatment of cystic fibrosis.
[0027] In the following description, for the sake of brevity, (4R)-5- (3 ’-hydroxyphenyl)-y- valerolactone (CAS Number 21618-91-7) is indicated as MIPV, while (4R)-5-(3’,4’-dihydroxyphenyl)-y-valerolactone (CAS Number 191666-22-5), is indicated as DIPV.
[0028] The structural formula of MIPV and DIPV is shown in Figure 1.
[0029] Surprisingly, the administration of the composition according to the present invention increases the expression of the mutated CFTR channel in the plasmatic membrane of the cells of cystic fibrosis patients in a way comparable to that of already known drugs.
[0030] The main advantage of the therapeutic proposal according to the present invention is being mutation-independent, therefore administrable even to patients affected by mutations for which at present no approved pharmacologic therapy is available. In fact, MIPV and DIPV carry out their therapeutic effect by not intercepting directly the mutated CFTR channel.
[0031] By observing the structural formula of MIPV and DIPV, shown in Figure 1, is easy to note that the y carbon atom of the lactone ring is a chiral carbon atom.
[0032] In an embodiment, the racemic mixture is administered in therapy.
[0033] In an embodiment, preferably the enantiomeric isomer R is administered.
[0034] In an embodiment, the enantiomeric isomer S is administered.
[0035] In an embodiment, a salt thereof is administered.
[0036] In an embodiment, MIPV and/or DIPV are administered with their lactone ring in open form, optionally even in an esterified formulation.
[0037] Extracts obtained from grape seeds originating from different cultivars of Vitis viniferaL. and containing polyphenols of catechetical origin have been used for a long time both as drugs for treating chronic peripheral venous insufficiency and as supplements/food supplements (nutraceuticals), in particular relating to cardiovascular well-being. Such extracts are known under the commercial name Ecovitis®, and comprise a plurality of active principles. On the market there are available food supplements based on extracts obtained from grape seeds in the form of capsules containing indicatively 300 - 600 mg of proanthocyanidins.
[0038] The application WO2022144762A1 of the same applicant describes a process for the preparation of a grape seed extract from selected unfermented marc, extracts so obtained and the use thereof in nutraceutical and pharmaceutical compositions.
[0039] The extracts from grape seeds are metabolized by human metabolome into MIPV and DIPV, or said in other words, MIPV and DIPV are contained as pro-drugs inside the extracts obtained from grape seeds. The compositions that are metabolized into MIPV and DIPV overall amount to over 80% of said extracts from grape sees in the composition prepared according to WO2022144762 Al.
[0040] Preferably, the composition according to the present invention is administered in the form of extracts obtained from grape seeds, from different cultivars of Vitis vinifera L.
[0041] Said metabolic precursors can be contained even in other kinds of plant extracts, e.g. extracts from apples, cranberries, cocoa (Theobroma cacao), maritime pine (Pinus pinaster), etc. characterized by a high titre of oligo polymeric proanthocyanidins, but also by a plurality of other active molecules.
[0042] Ecovitis® contains only proanthocyanidins mainly having an oligo polymeric character, optimal precursors of the active valerolactones MIPV and DIPV.
[0043] Preferably, the composition for the treatment of cystic fibrosis according to the present invention is administered in unit dose form. Preferably, the unit dose of composition according to the invention is administered at least once a day. For the purposes of the present invention, the term “day” means a period of 24 hours.
[0044] Preferably, said dose unit contains 0.1 mg to 1.000 mg of MIPV and/or DIPV, even more preferably 20 mg to 200 mg of MIPV and/or DIPV.
[0045] As explained in the introduction, for over 80% of mutations no specific drug is currently available. Therefore, in an embodiment, the composition according to the present invention is administered alone.
[0046] In a further aspect, the present invention relates to a pharmaceutical composition consisting essentially of MIPV and/or DIPV or mixtures thereof, or extracts of grape seeds. The term “consists essentially of means that MIPV and/or DIPV, or mixtures thereof, are the sole active ingredients present in the composition, whereas any further components or excipients do not interfere with their action.
[0047] In a further aspect, the present invention relates to a nutraceutical composition or a food supplement consisting essentially of MIPV and/or DIPV or mixtures thereof, or extracts of grape seeds. The term “consists essentially of means that MIPV and/or DIPV, or mixtures thereof, are the sole active ingredients present in the composition, whereas any further components or excipients do not interfere with their action.
[0048] In a further aspect, the present invention relates to the administration of the composition according to the present invention as adjuvant in the treatment with CFTR modulators, in particular Elexacaftor, Tezacaftor, Ivacaftor. Said combined administration can occur simultaneously, separately, or sequentially.
[0049] The composition according to the present invention is administered through a systemic route, preferably oral route. For oral administration, the components can be, e.g. mixed with one or more excipients, in the form of capsules, tablets, soft-gel capsules, granules, microgranules, pellets, multi particulate, micronized particulate, powder, solution, suspension, dispersion. As known in the art, suitable physiologically acceptable excipients are added to the composition.
[0050] Said physiologically acceptable excipients include acidifiers, acidity regulators, anti-caking agents, antioxidants, bulking agents, resistance agents, gelling agents, coating agents, modified starches, sequestering agents, thickeners, sweeteners, diluents, solvents, disaggregating agents, glidants, colorants, binders, lubricants, stabilisers, adsorbents, preservatives, humectants, flavourings, film- forming agents, emulsifiers, wetting agents, release retardants, and mixtures thereof.
[0051] Preferably, said excipients comprise starch, modified starch, cellulose, modified cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, pectin, tragacanth gum, mannitol, dicalcium phosphate, xanthan gum, carrageenan, sodium alginate, guar gum, maltodextrin, silicon dioxide, or mixtures thereof.
[0052] As the electronic charge present on the y carbon atom is influenced by the carboxylic group of the lactone ring, it is plausible that in vivo such ring is present even in its open form; as the active portion of the molecule is the phenyl ring, it is plausible that even the form of MIPV and DIPV with open lactone ring (MIPVa and DIPVa, respectively) maintains a clinical activity in vivo.
[0053] In the following there are provided examples of the present invention, which are provided for illustrative, non-limiting aims, showing the lack of toxicity and the efficacy of MIPV and DIPV in the treatment of cystic fibrosis.
EXAMPLES
Example 1.
Cell viability assay
[0054] MIPV e DIPV were studied in human cell lines HT1080 (fibrosarcoma) and HEK293T (human embryonic kidney cells). After a step of evaluation of the cell viability obtained through the resazurin assay with wide-ranging concentrations of the compositions (100 nM-50 pM), the range of non-toxic concentrations of the composition was estimated, to be used in the cell tests.
[0055] The viability assays were concentrated on the two cell lines potentially more sensitive to a possible toxic effect of the compositions, HT1080 and HEK293T. Cells were treated with dimethyl sulfoxide (indicated as DMSO in figures) as control, and with increasing quantities of MIPV and DIPV (100 nM, 200 nM, 375 nM, 1,5 pM, 3 pM, 6 pM, 12 pM, 25 pM and 50 pM). The treatment was performed for 24 hours.
[0056] In both cases, the non-toxicity of MIPV and DIPV even at particularly high concentrations is observed, as can be seen in Figure 2.
Example 2.
Western Blot analysis on CFBE cells
[0057] Successively, the capacity of said compositions for intervening directly on the CFTR defect in models of cystic fibrosis was investigated.
[0058] Said tests were performed on CFBE cells (CF Bronchial Epithelial with delF508 CFTR mutation), i.e. a model of cystic fibrosis with the most common mutation.
[0059] In fact, although today an approved therapy proposed by Vertex is available, consisting in a combination of three drugs (among which the VX445 used as control in the experiments), all drugs being directed against the defective channel, as explained above a therapy capable of intervening in a large part of mutations is lacking, in particular a therapy capable of recovering the CFTR channel in the membrane, re-balancing cell redox status.
[0060] As explained above, in normal conditions the CFTR channel is produced in the endoplasmic reticulum, matures in the Golgi apparatus and is transferred into cell plasmatic membrane, where it carries out its function. Its maturation coincides with the degree of glycosylation of the channel. In the case of the delF508CFTR mutation, as in other mutations, the structural defect of the channel prevents its maturation in the Golgi apparatus and its transferring into the membrane. Its direct consequence is visible in Western Blot. In fact, in normal conditions, the CFTR shows a partially glycosylated band B (150kDa), residing mainly in the endoplasmic reticulum, and a completely glycosylated band C (180 kDa), representing a channel positioned in the plasmatic membrane. In the case of CFTR mutations there is a marked accumulation of band B while band C is substantially absent. All this means that Western Blot represents an efficient screening technique for compositions directly in cystic fibrosis models, with particular reference to the capability of such compositions of recovering the mutated CFTR in plasmatic membrane.
[0061] The specific experiments are shown in Figure 3. CFBE cells have been treated for 24 hours with MIPV and DIPV at different concentrations (100 nM, 500 nm and 1 pM). Controls are represented by dimethyl sulfoxide (DMSO), VX445, (a CFTR modulator currently used in therapy) and R08 (a synthetic composition having an anti-oxidant action). The results clearly show the effect of VX445 (drug currently in clinical use) in recovering band C (around 180 kDa), but at the same time shows also a positive effect by MIPV and DIPV at concentrations of 100 nM and 500 nM with the first and 500 nM and IpM with the second composition. Moreover, the increase of band B is to be noted, which is a sign that the intervention of MIPV and DIPV decreased the degradation of CFTR, increasing its share in the endoplasmic reticulum. This is a very interesting result, paving the way to combinations of MIPV and DIPV with VX445 or analogous drugs in clinic, as the compositions already used in clinic can lead to the maturation of the very band B. As a consequence, increasing the pool of band B can increase the efficacy of the therapy actually used in clinic.
[0062] In conclusion, in the considered cystic fibrosis models, MIPV and DIPV are active already from low concentrations; in particular, MIPV and DIPV at concentrations of 100 e 500 nM e IpM can recover band C of the delF508CFTR channel in Western Blot, therefore allowing the localization of said channel in the plasmatic membrane.
Example 3.
Representation of the oxidative events involving DIPV and MIPV
[0063] The in vivo action of the two molecules MIPV and DIPV undergoes an oxidative event involving the hydroxy groups on the phenyl ring of the two molecules DIPV and MIPV. Such oxidative event allows to shift the equilibrium of the enol/s toward its/their ketone form.
[0064] In particular, schematizing the oxidation of the hydroxy groups of DIPV passing to its ortho-quinone form is easy, through an ortho-diphenol intermediate (Figure 4A). This oxidation is quite common in the poly-hydroy phenols. The oxidation of MIPV, presenting just one hydroxy group (Figure 4B), is much more complex. The event involves the single-electron oxidation of the phenyl anion with consequent generation of the phenoxy radical, which successively reacts with a molecular oxygen in order to produce the para- peroxy-cycloexadienone derivative; finally, the loss of a water molecule generates the para-benzo-quinone derivative
[0065] Finally, Figure 5 shows the two gamma-valerolactones MIPVa and DIPVa with their open lactone ring. As the electronic charge present on the y carbon atom is affected by the electron-attractive effect of the carboxylic group of the lactone ring, it is plausible that such ring in vivo is present even in its open form. As the active portion of the molecule is the phenyl ring (see Figure 5), even MIPVa and DIPVa with open lactone ring might maintain a clinical activity in vivo.
[0066] In this regard, the administration of the open form of MIPVa (CAS number 31129-95-0) and DIPVa (CAS number 31129-94-9), both shown in Figure 5, is conceivable, even in their esterified form. Preferably, the esters of MIPVa and DIPVa comprise a methyl ester or esters comprising alkyl chains of 2 to 5 carbon atoms.
Example 4.
Functional analysis of CFTR channel in Ussing Chamber
[0067] In order to strengthen the data obtained with the abovedescribed tests, Ussing chamber experiments were performed, whose results are shown in Figure 6. In particular, A shows the summary of short-circuit currents (AIscinhi72) of polarized CFBE-delF monolayers treated for 24h with 25 pM, 50 pM of MIPV or DIPV in combination with VX445 (2 pM) and VX661 (5 pM). Error bars are mean ± SD (number of tissues). One-way ANOVA multiple comparison vs. VX445+VX661 was performed (*p <0,05;***p <0,001). B shows representative traces of Ussing chamber measurements on CFBE-delF epithelia treated with VX445 + VX661 compared to the combination of correctors with 50 pM DIPV.
[0068] Briefly, CFBE-delF508 cells were seeded at high density on porous membranes (Coming® Costar® Snapwell inserts, 3801) coated with collagen type IV (C7521, Sigma). Cells were cultured in liquid-liquid conditions in complete MEM (10% FBS, 1% PSG, 2 pg/ml puromycin). After 6-7 days, polarized epithelia with resistances above 400 Ohm*cm2 were used for Ussing chamber experiments. 24 h before the analysis, epithelia were treated with correctors VX445 and VX661 alone or combined with MIPV, DIPV (25 or 50 pM).
[0069] Snapwell inserts were mounted in an Ussing chamber filled on the apical hemichamber with a Ringer solution containing: 30 mM NaCl, 0,4 mM KH2PO4, 1,6 mM K2HPO4*3H2O, 5 mM glucose, 1 mM MgCl2*6H2O, 1,5 mM CaC12*2H2O, 90 mM Na-gluconate, 25 mM NaHCCE. In the basal compartment, NaCl concentration was increased up to 120 mM. Solutions were kept at 37°C and continuously bubbled with a 5% CO2-95% O2 mixture. During an Ussing experiment, CFTR activity was elicited by applying to the apical hemichamber the activator of adenylyl cyclase forskolin (FSK, 2 pM) and the phosphodiesterase inhibitor IBMX (100 pM). Both promote the activation of PKA (Protein Kinase A) and subsequent CFTR phosphorylation, ultimately triggering channel opening. A further, prolonged CF ion flux through the activated CFTR channel is then induced with the potentiator VX770 (1 pM). Finally, the selective CFTRinh-172 (10 pM) was added to inhibit CFTR-mediated currents. For each epithelium, the amplitude of the current drop caused by Inh- 172 is comparable to the total activity of the CFTR channel in the epithelium.
[0070] The analysis of CFTR channel functionality was performed on bronchial epithelial cells, permanently transfected with delF508 CFTR mutation (CFBE-delF508). This technique is performed on polarized epithelia expressing the mature CFTR channel on cell membrane surface, and allows to measure, in Ussing chambers, CF ion flux from the basolateral side to the apical side upon CFTR activation.
[0071] The data obtained on CFBE-delF508 epithelia treated for 24h with MIPV and DIPV show that such compositions elicit, in a statistically significant way, the activity of CFTR when combined with the correctors used in the current therapy (VX445 and VX661). In particular, an increase in the current is observed after treatment with DIPV 50 pM, indicating a greater number of open CFTR channels in the plasmatic membrane. Therefore, cotreatment with DIPV and correctors enhances the activity of CFTR-delF508 channel compared to treatment with the correctors alone.

Claims

1. A composition chosen between (4R)-5-(3’-idrossifenil)-y- valerolactone
(MIPV), (4R)-5-(3’,4’-diidrossifenil)-y- valerolactone (DIPV), and mixtures thereof, for use in the treatment of cystic fibrosis.
2. The composition according to claim 1, wherein said composition is a racemate, a R enantiomer, a S enantiomer, or a salt thereof.
3. The composition according to claim 2, wherein said composition is a R enantiomer.
4. The composition according to any of claims 1-3, wherein said medicament comprises metabolic precursors releasing said composition, preferably an extract of Vitis vinifera L. grape seeds.
5. The composition according to any of claims 1-4, wherein said composition is administered as adjuvant of other medicaments for the treatment of cystic fibrosis.
6. The composition according to claim 5, wherein said other medicaments are CFTR modulators, in particular Elexacaftor, Tezacaftor, Ivacaftor, or combinations thereof.
7. The composition according to any of claims 1-6, wherein said composition is in its form with open lactone ring, optionally in the form of an esterified open lactone ring.
8. Food supplement comprising the composition according to claim 1, and suitable food excipients.
9. Pharmaceutical or nutraceutical composition comprising the composition according to any of claims 1-8, and at least one physiologically acceptable excipient.
EP24736383.1A 2023-06-28 2024-06-21 Compositions for the treatment of cystic fibrosis Pending EP4734975A1 (en)

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IT102023000013374A IT202300013374A1 (en) 2023-06-28 2023-06-28 “COMPOUNDS FOR THE TREATMENT OF CYSTIC FIBROSIS”
PCT/EP2024/067425 WO2025003000A1 (en) 2023-06-28 2024-06-21 Compositions for the treatment of cystic fibrosis

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JP6855263B2 (en) * 2017-01-27 2021-04-07 三井農林株式会社 Dipeptidylpeptidase-IV inhibitor
EP3656381A1 (en) * 2018-11-23 2020-05-27 I.E.R.F.C. European Institute for Cystic Fibrosis Research Analogues of cysteamine as therapeutic agents for cystic fibrosis
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