Use of retinoic acid receptor (RAR) agonists to reverse, prevent, or delay aortic valve calcification

Abstract

Aortic valve calcification is a condition in which calcium deposits form on the aortic valve of the heart. These deposits can cause narrowing of the aortic valve opening. This narrowing can become severe enough to reduce blood flow through the aortic valve, a condition called aortic stenosis. The inventors have shown that retinoic acid reduces calcification and osteoblast-like phenotype in valvular interstitial cells (VICs). More specifically, RARα activation reduces calcification and osteoblast-like phenotype in VICs. Conversely, ALDH1A1 inhibition increases calcification and osteoblast-like phenotype in VICs. Therefore, these results suggest that the use of retinoic acid receptor (RAR) agonists may be suitable for reversing, preventing, or delaying aortic valve calcification.

Description

[Technical field]

[0001] Field of the invention: The present invention is in the field of medicine, in particular cardiology. [Background technology]

[0002] Background of the invention: Aortic valve calcification is a condition in which calcium deposits form on the aortic valve of the heart. These deposits can cause narrowing in the opening of the aortic valve. This narrowing can become severe enough to reduce blood flow through the aortic valve, a condition called aortic stenosis.

[0003] In particular, calcific aortic valve disease (CAVD) is the most common valvular heart disease in adults, affecting 2-6% of people over 65 years of age [1]. CAVD was first described as a passive degenerative process related to repeated high mechanical stress, but it is now clear that it is an atherosclerosis-like disease mediated by lipid deposition, inflammation, fibrosis, and calcification [2, 3]. Symptoms of CAVD vary depending on the degree of valvular stenosis. Since symptoms typically appear in patients with severe CAVD, patients with mild to moderate CAVD may lack symptoms. Symptoms may include progressive exertional shortness of breath, syncope, chest pain, and sudden death. Effective treatments are represented by valve replacement, either by transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement. In recent years, the use of bioprosthetic valves (BPVs) to treat AVS by TAVI has increased considerably compared to mechanical valves. The primary cause of long-term failure of BPV is structural deterioration of the valve due to tissue calcification. Recent studies have reported similar histological findings between stenotic AV and explanted degenerated BPV. To date, no targeted therapy has been proven to prevent, slow or treat fibrocalcified AV or prevent degeneration of BPV.

[0004] Valvular interstitial cells (VICs) are the most frequent cells found in the human aortic valve and play a major role in tissue homeostasis and valve function [4]. These cells represent a heterogeneous and dynamic cell population composed of progenitor, quiescent, activated and osteoblast-like cells [5]. Recent studies suggest that this latter cell phenotype plays a key role in valvular calcification, a hallmark of CAVD [3, 6]. A better understanding of the biology of VICs, the key components of the aortic valve and the effectors of valvular fibrocalcification may provide therapeutic targets to prevent, slow or halt the progression of fibrocalcification. The retinoic pathway has demonstrated effects on inflammation, fibrosis, angiogenesis and calcification processes in cells other than VICs. For example, retinoic acid, a bioactive metabolite of vitamin A, inhibits osteoblast mineralization (Lind, 2013) and reduces osteoprotegerin expression via activation of retinoic acid receptors in osteoblasts (Jacobson, 2004). Interestingly, retinoic acid is a negative regulator of osteoblast differentiation and inhibits mineralization in mesenchymal progenitor cells that share the same differentiation properties as VICs (Green, 2017). So far, little data exists regarding the role of retinoids and related nuclear receptors in CAVD. To our knowledge, the only published experimental data on the potential role of retinoids in aortic valve calcification suggests that excess dietary intake of vitamin A may promote heart valve calcification (Huk DJ, Hammond HL, Kegechika H, ​​Lincoln J. Increased dietary intake of vitamin A promotes aortic valve calcification in vivo. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):285-93). Summary of the Invention [Problem to be solved by the invention]

[0005] Summary of the invention: As defined by the claims, the present invention relates to the use of retinoic acid receptor (RAR) agonists for reversing, preventing, or slowing aortic valve calcification. [Means for solving the problem]

[0006] Detailed description of the invention: A first object of the present invention relates to a method for reversing, preventing or slowing aortic valve calcification in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a retinoic acid receptor (RAR) agonist. [Brief description of the drawings]

[0007] [Figure 1A] Retinoic acid reduces mineralization and osteoblast-like phenotype. A: Percentage of mineralization in VICs treated with retinoic acid (1; 10; 100 or 1000 nM) for 7 days in mineralization-promoting medium. Mineralization-promoting medium condition is set to 1. [Figure 1B] B RUNX2 and relative mRNA expression in VICs treated with retinoic acid (1; 10; 100 or 1000 nM) for 7 days in mineralization medium. Mineralization medium condition is set to 1. Data are presented as mean + SEM, *: p<0.05. [Figure 2A] Retinoids reduce mineralization and osteoblast-like phenotype in a RAR activation-dependent manner. A: Percentage of mineralization in VICs treated with retinoic acid, arotinoid acid (TTNB, a RAR agonist) or SR11237 (an RXR agonist) in mineralization-promoting medium for 7 days. Mineralization-promoting medium condition is set to 1. [Figure 2B] B and C: Relative mRNA expression of RUNX2 and MSX2 in VICs treated with retinoic acid, arotinoid acid (TTNB, a RAR agonist) or SR11237 (an RXR agonist) in mineralization medium for 7 days. Mineralization medium condition is set to 1. Data are presented as mean + SEM, *: p<0.05. [Figure 2C]B and C: Relative mRNA expression of RUNX2 and MSX2 in VICs treated with retinoic acid, arotinoid acid (TTNB, a RAR agonist) or SR11237 (an RXR agonist) in mineralization medium for 7 days. Mineralization medium condition is set to 1. Data are presented as mean + SEM, *: p<0.05. [Figure 3A] RARα activation reduces mineralization and osteoblast-like phenotype in VICs. A: Percentage of mineralization in VICs treated with arotinoid acid (TTNB, RAR agonist), AM80 (RARα agonist), CD2314 (RARβ agonist) or CD437 (RARγ agonist) in mineralization-promoting medium for 7 days. Mineralization-promoting medium condition is set to 1. [Figure 3B] B and C: Relative mRNA expression of RUNX2 and MSX2 in VICs treated with arotinoid acid (TTNB, RAR agonist), AM80 (RARα agonist), CD2314 (RARβ agonist) or CD437 (RARγ agonist) in mineralization medium for 7 days. Mineralization medium condition is set to 1. Data are presented as mean + SEM, *: p<0.05. [Figure 3C] B and C: Relative mRNA expression of RUNX2 and MSX2 in VICs treated with arotinoid acid (TTNB, RAR agonist), AM80 (RARα agonist), CD2314 (RARβ agonist) or CD437 (RARγ agonist) in mineralization medium for 7 days. Mineralization medium condition is set to 1. Data are presented as mean + SEM, *: p<0.05. [Figure 4A] Inhibition of ALDH1A1 increases mineralization and osteoblast-like phenotype in VICs. A: Percentage of mineralization in VICs treated with 25 or 50 nM 4-diethylaminobenzaldehyde (DEAB, an ALDH inhibitor) in mineralization-promoting medium for 7 days. Mineralization-promoting medium condition is set to 1. [Figure 4B] B: Relative mRNA expression of RUNX2 in VICs treated with DEAB in mineralization-promoting medium for 7 days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The term "valve" as used herein may refer to a valve that prevents the backflow of blood during rhythmic contractions. There are four main heart valves. In particular, the aortic valve separates the left ventricle from the aorta. The term "aortic valve" includes diseased aortic valves or biological valves.

[0009] As used herein, the term "bioprosthetic valve" may refer to a stented tissue heart valve, a device used to replace or supplement a defective, incompetent, or missing aortic valve. Examples of bioprostheses include TS 3fs® aortic bioprosthesis, Carpentier-Edwards PERIMOUNT Magna Ease aortic heart valve, Carpentier-Edwards PERIMOUNT Magna aortic heart valve, Carpentier-Edwards PERIMOUNT Magna mitral heart valve, Carpentier-Edwards PERIMOUNT aortic heart valve, Carpentier-Edwards PERIMOUNT Plus mitral heart valve, Carpentier-Edwards PERIMOUNT Theon aortic heart valve, Carpentier-Edwards PERIMOUNT Theon mitral valve replacement system, Carpentier-Edwards aortic porcine bioprosthesis, Carpentier-Edwards Duraflex low pressure porcine mitral valve bioprosthesis, Carpentier-Edwards Duraflex mitral valve bioprosthesis (porcine), Carpentier-Edwards mitral valve porcine bioprosthesis, Carpentier-Edwards SAV Aortic Porcine Bioprosthesis, Edwards Prima Plus Unstented Bioprosthesis, Edwards Sapien Transcatheter Heart Valve, Medtronic, Freestyle® Aortic Root Bioprosthesis, Hancock® II Stented Bioprosthesis, Hancock II Ultra® Bioprosthesis, Mosaic® Bioprosthesis, Mosaic Ultra® Bioprosthesis, St.Examples of suitable valves include, but are not limited to, Jude Medical, Biocor®, Biocor™ Supra, Biocor® Pericardia, Biocor™ Stentless, Epic™, Epic Supra™, Toronto Stentless Porcine Valve (SPV®), Toronto SPV II®, Trifecta, Sorin Group, Mitroflow Aortic Pericardial Valve®, Cryolife, Cryolife aortic Valve®, Cryolife pulmonic Valve®, Cryolife-O'Brien stentless aortic xenograft Valve®, and all variations thereof. Generally, biological valves include a tissue valve having one or more leaflets, both of which are typically mounted on a resilient frame or stent. As used herein, the term "resilient" means that the device is capable of bending, collapsing, expanding, or a combination thereof. The leaflets are typically made from mammalian tissue, including but not limited to, pigs (porcine), cows (bovine), horses, sheep, goats, monkeys, and humans.

[0010] As used herein, the phrase "aortic valve calcification" has its common meaning in the art and refers to the formation, growth or deposition of extracellular matrix hydroxyapatite (calcium phosphate) crystal deposits in aortic valves, including biological valves.

[0011] In some embodiments, the method of the present invention is particularly suitable for the primary prevention of calcification. In particular, the method of the present invention is suitable for the treatment of calcific aortic valve disease. As used herein, the term "calcific aortic valve disease" or "CAVD" has its general meaning in the art and refers to a slowly progressive disorder with a continuum of disease ranging from mild valve thickening without blood flow obstruction, termed aortic sclerosis, to severe calcification with impaired leaflet motion, or aortic valve stenosis. Thus, disease progression is generally characterized by a process of thickening of the leaflets and the formation of calcium nodules (often including actual bone formation) and new blood vessels concentrated on the aortic surface. End-stage disease, such as calcific aortic valve stenosis, is generally pathologically characterized by large nodular calcific masses in the aortic valve cusps that protrude along the aortic surface into the sinuses of Valsalva and obstruct the opening of the valve cusps. In some embodiments, the method of the present invention is particularly suitable for the treatment of calcific aortic valve stenosis.

[0012] In some embodiments, the methods of the invention are particularly suitable for secondary prevention of calcification. In particular, the methods of the invention are particularly suitable for preventing degeneration of implanted biological valves. Thus, in some embodiments, the methods of the invention are particularly suitable for delaying or preventing calcification of biological valves either after surgical valve replacement or after transcatheter aortic valve implantation (TAVI).

[0013] As used herein, the term "treatment" or "treating" refers to both preventative or prophylactic treatments and curative or disease-modifying treatments, including treatment of diseased patients or patients diagnosed with a disease or medical condition, as well as patients at risk of or suspected of having the disease, including suppression of clinical recurrence. Treatments may be administered to subjects with a medical disorder, or subjects who may eventually acquire a disorder, to prevent, cure, delay the onset, reduce the severity, or ameliorate one or more symptoms of the disorder or recurrent disorder, or to extend the subject's survival beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant a pattern of disease treatment, e.g., a dosing pattern used during treatment. Therapeutic regimens may include induction regimens and maintenance regimens. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or a portion of a therapeutic regimen) used for the initial treatment of a disease. The general goal of an induction regimen is to provide high levels of drug to the patient early in the treatment regimen. The induction regimen may use (in part or in whole) a "loading regimen" which may include administering a larger dose of the drug than the doctor would use during the maintenance regimen, administering the drug more frequently than the doctor would administer the drug during the maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a treatment regimen (or a portion of a treatment regimen) used for the maintenance of a patient during disease treatment, for example, to keep the patient in remission for an extended period of time (months or years). A maintenance regimen may use continuous therapy (e.g., administering the drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent treatment, treatment at relapse, or treatment upon the achievement of a certain predetermined criterion (e.g., disease manifestation, etc.).

[0014] In some aspects, the methods of the present invention are particularly suited for preventing stenosis. As used herein, the term "stenosis" refers to a narrowing of the aortic valve that can block or obstruct blood flow from the heart, causing backflow and pressure in the heart.

[0015] As used herein, the term "retinoic acid receptor" or "RAR" has its general meaning in the art and refers to a class of nuclear receptors that can also act as transcription factors activated by both all-trans and 9-cis retinoic acids. There are three retinoic acid receptors (RARs), RARα, RARβ, and RARγ, encoded by the RARA, RARB, and RARG genes, respectively. Each receptor isoform has ten splice variants, four alpha, four beta, and two gamma. RAR receptors, in the form of heterodimers with retinoid X receptors (known as RXR), activate transcription by binding to DNA sequence elements known as RAR response elements (RAREs).

[0016] The term "retinoic acid receptor (RAR) agonist" as used herein is intended to mean a compound recognized in the art as being capable of acting via the retinoic acid receptor and efficiently inducing RARE-dependent gene expression. Preferably, the RAR agonist is a RARα agonist. The prior art contains a large number of chemical compounds that are RAR agonists. Among the prior art documents, for example, EP 0 816 352, describing aromatic biaryl heterocyclic compounds for cosmetic use as well as for the treatment of dermatological, rheumatic, respiratory and opthalmological conditions, document WO 2005 / 056510, describing molecules comprising an aromatic ring substituted with a hydroxyalkyl group, documents WO 99 / 10308 and WO 2006 / 03374, describing substituted biphenyl derivatives, are listed. Reference may be made to US Pat. No. 6,218,128 and EP 0 879 814, which describe bicyclic and / or tricyclic compounds, document EP 0 850 909, which describes stilbene compounds, document WO 98 / 56783, which describes biaromatic compounds, and documents EP 0 776 885 and EP 0 776 881, which describe biaromatic compounds containing an adamantyl group. The RAR agonist selectivity of a compound can be determined by routine ligand binding assays known to those skilled in the art, such as those described in C. Apfel et al., Proc. Nat. Sci. Acad. (USA), 89: 7129-7133 (1992); M. Teng et al., J. Med. Chem., 40: 2445-2451 (1997); and WO 96 / 30009. For example, known RARα agonists include, but are not limited to, TTNPB, tamibarotene, 9-cis-retinoic acid, trans-retinoic acid, AGN193836, Ro 40-6055, CD666, and BMS753.In some embodiments, the RARα agonist is 4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl]benzoic acid (AM80).

[0017] By "therapeutically effective amount" is meant a sufficient amount of the agonist of the present invention to treat aortic stenosis with a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compound will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including the subject's age, weight, general health, sex, and diet; the time of administration, route of administration, rate of excretion of the particular compound employed; duration of treatment; drugs used in combination with or concomitantly with the particular polypeptide employed; and similar factors well known in medicine. For example, it is well known to those skilled in the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the product may vary over a wide range, from 0.01 to 1,000 mg per adult per day. Preferably, the composition contains 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 active ingredient to adjust the dosage symptomatically to the subject to be treated. The medicament typically contains about 0.01 mg to about 500 mg of active ingredient, preferably 1 mg to about 100 mg of active ingredient. An effective amount of the drug is usually supplied at a dosage level of 0.0002 mg / kg to about 20 mg / kg body weight, particularly about 0.001 mg / kg to 7 mg / kg body weight per day.

[0018] Typically, the agonist of the present invention may be combined with a pharma- ceutically acceptable excipient and, optionally, a sustained-release matrix, such as a biodegradable polymer, to form a pharmaceutical composition. "Pharmaceutically" or "pharma- ceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to a mammal, particularly a human, as appropriate. A pharma- ceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any kind. In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical, or rectal administration, the active agent can be administered to animals and humans, alone or in combination with another active agent, in unit dosage form, in admixture with a conventional pharmaceutical support. Suitable unit dosage forms include oral route forms such as tablets, gel capsules, powders, granules, and oral suspensions or solutions, sublingual and buccal dosage forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal dosage forms, and rectal dosage forms. The agonists of the present invention can be formulated into compositions in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, and others. Salts formed with free carboxyl groups can also be derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, and others. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

[0019] The present invention also relates to the use of the RAR agonist of the present invention for the preparation of a biological valve. In this regard, the present invention more particularly relates to a biological valve comprising an amount of an RAR agonist. Such a local biomaterial or medical delivery device can be used to treat aortic stenosis. Such a biomaterial or medical delivery device can be biodegradable. The agonist of the present invention is preferably encapsulated in the valve leaflets. The leaflets are generally made from mammalian tissues, such as, but not limited to, pigs, porcine, cows, bovine, horses, sheep, goats, monkeys, and humans. With said encapsulation, it is possible to achieve a high level of local action. According to the present invention, the valve can be a collapsible elastic valve having one or more leaflets, and the collapsible elastic valve can be mounted on an elastic stent. In some embodiments, the collapsible elastic valve can include one or more leaflets of biological origin. In some embodiments, the one or more leaflets are porcine, bovine, or human. The elastic stent portion of the valve prosthesis used in the present invention may be self-expandable or expandable via a balloon catheter. The elastic stent may comprise any biocompatible material known to those skilled in the art. Examples of biocompatible materials include, but are not limited to, ceramics; polymers; stainless steel; titanium; nickel-titanium alloys, such as Nitinol; tantalum; cobalt-containing alloys, such as Elgiloy® and Phynox®; and others. The process of disposing the coating composition containing the RAR agonist of the present invention may be any process known in the art. Local delivery according to the present invention allows high concentrations of the agonist of the present invention at diseased sites that have low concentrations of circulating compounds. For the present invention, a therapeutically effective amount will be administered.

[0020] The present invention is further illustrated by the following figures and examples, which should not, however, be construed as limiting the scope of the present invention in any way. EXAMPLES

[0021] Working Example: method Modulation of retinoic acid signaling under pro-calcification conditions VICs were treated for 7 days in medium composed of DMEM containing 10% FBS supplemented with ascorbic acid (283 μM, Sigma Aldrich), sodium phosphate (3 mM, Sigma Aldrich) and dexamethasone (100 nM, Stem Cell Technologies). VICs were treated with retinoic acid (RA: 1; 10; 100; 1000 nM), TTNPB (RAR pan-agonist, 1 μM), AM80 (RARα-specific agonist, 1 μM), CD2314 (RARβ-specific agonist, 1 μM), CD437 (RARγ-specific agonist, 1 μM) or 4-diethylaminobenzaldehyde (DEAB, ALDH inhibitor, 25, 50 nM).

[0022] Measurement of mineralization After 7 days of treatment, VICs were rinsed twice in PBS and then fixed in 4% paraformaldehyde for 15 min. After washing with deionized water, calcium deposits were stained with Alizarin Red solution (1%, pH 6.38) for 10 min. The cells were then washed with deionized water and the stain was fixed with absolute ethanol. Quantification was performed by the method of Gregory et al. Briefly, cells were incubated with 10% acetic acid for 30 min with gentle shaking. The cells were then transferred to microtubes and vortexed for 30 s. Mineral oil was added to each tube and the samples were heated at 85°C for 10 min and cooled in ice for 5 min. After centrifugation (15 min, 16,000 g), the supernatant was collected and 200 μl of ammonium hydroxide was added. The samples were then read at 405 nm in a microplate.

[0023] quantitative PCR RNA was extracted from VICs after homogenization in TRIzol reagent (Life Technologies) according to the protocol of Chomczynski and Sacchi. For gene expression analysis, 2 micrograms of extracted total RNA were reverse transcribed in a total volume of 20 μl using the High Capacity cDNA Reverse Transcription kit (Life Technologies) according to the manufacturer's procedure. Samples were incubated at 25°C for 10 min followed by 37°C for 2 h. The resulting cDNA was stored at -20°C. Quantitative PCR was performed using the ABI PRISM 7000 Detection System (Life Technologies). Four microliters of the reverse transcription product was added to a 16 μl mix consisting of 10 μl of master mix containing Taq polymerase, MgCl2, and dNTPs (Life Technologies), 1 μl of a solution containing sense primers, antisense primers and TaqMan® probes specific for the gene of interest, and 5 μl of water. Expression of the transcripts was normalized by the mRNA expression of Abelson (ABL), which was used as an endogenous reference gene. Relative quantification of transcripts was performed using the cycle threshold (Ct) comparison method and calculated using the formula: 2-ΔΔCt. Detection of PCR products was performed separately in duplicate for each sample. ABL (Hs01104728_m1), RUNX2 (Hs00231692_m1), and MSX2 (Hs00741177_m1) commercial assays were purchased from Life Technologies.

[0024] statistical analysis All data are reported as mean ± SEM. Student's t test for continuous variables was used. For all analyses, a p value of ≦0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 20.0 for Windows (SPSS, Inc., Chicago, Illinois).

[0025] result The results are shown in Figures 1-4. Figures 1A and 1B show that retinoic acid reduces mineralization and osteoblast-like phenotype. Figures 2A-2C show that retinoids reduce mineralization and osteoblast-like phenotype in a RAR activation-dependent manner. Moreover, Figures 3A-3C show that activation of RARα reduces mineralization and osteoblast-like phenotype in VICs. Finally, Figures 4A and 4B show that inhibition of ALDH1A1 increases mineralization and osteoblast-like phenotype in VICs.

[0026] References: Throughout this application, various references are referred to that describe the state of the art to which this invention pertains, the disclosures of which are hereby incorporated by reference into this disclosure.

[0027] [Table 1]

Claims

1. 1. A pharmaceutical composition for reversing, preventing, or slowing aortic valve calcification in a patient in need thereof, comprising a therapeutically effective amount of a retinoic acid receptor (RAR) agonist, A pharmaceutical composition wherein the RAR agonist is an RARα agonist, the RARα agonist being selected from the group consisting of TTNPB, trans-retinoic acid and tamibarotene (4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl]benzoic acid (AM80)).

2. 2. The pharmaceutical composition of claim 1, wherein the valve is a diseased aortic valve.

3. 3. The pharmaceutical composition of claim 2, wherein the patient is suffering from calcific aortic valve disease.

4. The pharmaceutical composition according to claim 1 , wherein the valve is a biological valve.

5. The pharmaceutical composition according to claim 4 for preventing degeneration of an implanted biological valve.

6. 5. The pharmaceutical composition according to claim 4, for delaying or preventing calcification of a biological valve either after surgical valve replacement or after transcatheter aortic valve implantation (TAVI).

7. A pharmaceutical composition for the preparation of a biological valve, comprising an RAR agonist, A pharmaceutical composition wherein the RAR agonist is an RARα agonist, the RARα agonist being selected from the group consisting of TTNPB, trans-retinoic acid and tamibarotene (4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl]benzoic acid (AM80)).

8. A biological valve comprising an RAR agonist, A biological valve, wherein the RAR agonist is an RARα agonist, and the RARα agonist is selected from the group consisting of TTNPB, trans-retinoic acid, and tamibarotene (4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl]benzoic acid (AM80)).

9. The biological valve of claim 8, wherein the RAR agonist is encapsulated in the valve leaflets.

10. The biological valve of claim 8 for the treatment of aortic stenosis.

Images