[go: up one dir, main page]

WO2022196609A1 - Composition destinée à la prévention de la dégénérescence rétinienne - Google Patents

Composition destinée à la prévention de la dégénérescence rétinienne Download PDF

Info

Publication number
WO2022196609A1
WO2022196609A1 PCT/JP2022/011209 JP2022011209W WO2022196609A1 WO 2022196609 A1 WO2022196609 A1 WO 2022196609A1 JP 2022011209 W JP2022011209 W JP 2022011209W WO 2022196609 A1 WO2022196609 A1 WO 2022196609A1
Authority
WO
WIPO (PCT)
Prior art keywords
pba
pharmaceutical composition
phenylbutyric acid
salt
retina
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2022/011209
Other languages
English (en)
Japanese (ja)
Inventor
洋子 小澤
栄之 岡野
一男 坪田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Keio University
Original Assignee
Keio University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Keio University filed Critical Keio University
Publication of WO2022196609A1 publication Critical patent/WO2022196609A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition for suppressing retinal degeneration including retinitis pigmentosa.
  • Retinitis pigmentosa is a hereditary retinal disease in which rod photoreceptors, which are photoreceptors that recognize the brightness of light, are degenerated due to genetic mutations. is a disease that can lead to blindness. At present, there is no effective treatment, and clinically, vitamin preparations have been administered for the purpose of neuroprotection, but the effects are poor. In addition, research on gene transfer therapy using viruses has been advanced so far, and clinical trials are being conducted worldwide. In addition, visual cycle modulator (Visual Cycle Modulator) is being researched as drug therapy (Non-Patent Document 1), which protects the retina by not using visual function, and maintains visual function.
  • Visual Cycle Modulator Visual Cycle Modulator
  • PBA phenylbutyric acid
  • Patent Documents 1 and 2 phenylbutyric acid
  • an object of the present invention is to provide a pharmaceutical composition for suppressing retinal degeneration including retinitis pigmentosa.
  • the present inventors conducted studies to solve the above problems, found that PBA suppresses progressive retinal photoreceptor death and suppresses deterioration of visual function, and completed the present invention.
  • a pharmaceutical composition for suppressing retinal degeneration containing phenylbutyric acid (PBA), a salt thereof, or a derivative thereof.
  • a pharmaceutical composition for treating or preventing retinal degenerative diseases containing phenylbutyric acid (PBA) or a salt thereof or a derivative thereof.
  • PBA phenylbutyric acid
  • a pharmaceutical composition for treating or preventing retinal degenerative diseases containing phenylbutyric acid (PBA) or a salt thereof or a derivative thereof.
  • the pharmaceutical composition of [2] wherein the retinal degenerative disease is a disease in which retinal photoreceptors are degenerated.
  • the retinal degenerative disease is one or more selected from retinitis pigmentosa, diabetic retinopathy, age-related macular degeneration, and retinal degeneration associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes)
  • the pharmaceutical composition according to any one of [1] to [5] which is a tablet, granule, suspension, injection or eye drop.
  • a pharmaceutical composition for promoting endoplasmic reticulum stress-related degradation in the retina comprising phenylbutyric acid (PBA) or a salt thereof or a derivative thereof.
  • a pharmaceutical composition for activating mitochondrial biosynthesis in the retina and/or for improving metabolic function of mitochondria in the retina comprising phenylbutyric acid (PBA) or a salt thereof or a derivative thereof.
  • a method of inhibiting retinal degeneration in a subject comprising administering phenylbutyric acid (PBA) or a salt thereof or a derivative thereof to the subject.
  • a method of treating or preventing retinal degeneration in a subject comprising administering phenylbutyric acid (PBA) or a salt or derivative thereof to the subject.
  • PBA phenylbutyric acid
  • a method of promoting endoplasmic reticulum stress-related degradation in the retina in a subject comprising administering phenylbutyric acid (PBA) or a salt or derivative thereof to the subject.
  • a method of activating mitochondrial biogenesis in the retina and/or improving metabolic function of mitochondria in the retina in a subject comprising administering phenylbutyric acid (PBA) or a salt thereof or a derivative thereof to the subject
  • PBA phenylbutyric acid
  • a method comprising: [13] Phenylbutyric acid (PBA) or a salt or derivative thereof for use in inhibiting retinal degeneration.
  • PBA phenylbutyric acid
  • phenylbutyric acid (PBA) or a salt thereof or a derivative thereof in the manufacture of a medicament for use in promoting endoplasmic reticulum stress-related degradation in the retina.
  • PBA phenylbutyric acid
  • PBA phenylbutyric acid
  • a salt thereof or a derivative thereof in the manufacture of a medicament for use in activating mitochondrial biogenesis in the retina and/or improving metabolic function of mitochondria in the retina.
  • the present invention has found that PBA promotes the maintenance of visual function in retinitis pigmentosa models, and can provide an agent for suppressing retinal degeneration including retinitis pigmentosa, which is effective even with a diagnosis.
  • Fig. 10 shows the maintenance and promotion of visual function in P23H rhodopsin knock-in heterozygous retinitis pigmentosa model mice (also referred to simply as P23H knock-in heterozygous mice and P23H RP model mice in the present disclosure) by PBA.
  • WT indicates wild-type mice
  • Hetero indicates P23H knock-in heterozygous mice.
  • A is a micrograph of a mouse retina stained with hematoxylin and eosin.
  • B is a graph showing the number of nuclei in the outer nuclear layer (ONL).
  • * indicates P ⁇ 0.05 and ** indicates P ⁇ 0.01.
  • FIG. 10 shows the maintenance and promotion of visual function in P23H rhodopsin knock-in heterozygous retinitis pigmentosa model mice (also referred to simply as P23H knock-in heterozygous mice and P23H RP model mice in the present disclosure) by PBA.
  • WT indicates wild-type mice
  • FIG. 10 shows the maintenance and promotion of visual function maintenance in P23H knock-in heterozygous mice by PBA.
  • a to E are dark adaptation ERG result diagrams, A shows the waveform of electroretinogram, B to C show the amplitude and latency of a-wave, respectively, and D to E show the amplitude and latency of b-wave, respectively. indicate.
  • F to H are the results of photopic ERG, F shows the waveform of the electroretinogram, and G to H show the amplitude and latency, respectively. In the figure, * indicates P ⁇ 0.05.
  • FIG. 2 shows PBA-induced endoplasmic reticulum stress-related degradation and increased expression of mitochondrial markers in the retina of P23H knock-in heterozygous mice.
  • FIG. 2 shows improvement of mitochondrial metabolism in cell lines by PBA.
  • AB respectively show that the mRNA expression levels of Pgc1- ⁇ and Tfam are increased in a PBA dose-dependent manner.
  • C is an electron micrograph showing improvement in membrane potential before and after administration of BAM15, a mitochondrial protonophore uncoupler.
  • D is a graph showing mitochondrial membrane potential improvement.
  • E to F are graphs showing enhancement of the electron transport chain complex IV (CoX IV) activity by PBA and an increase in ATP expression level, respectively.
  • CoX IV electron transport chain complex IV
  • Fig. 10 shows changes in body weight of P23H knock-in heterozygous mice by oral administration of PBA.
  • Fig. 10 shows elevation of mitochondrial marker expression in the retina of P23H knock-in heterozygous mice by oral administration of PBA.
  • Graphs AB respectively show changes in the expression level of each gene marker by real-time reverse transcription-polymerase chain reaction (RT-PCR).
  • * indicates P ⁇ 0.05 and ** indicates P ⁇ 0.01.
  • One embodiment of the present invention is a pharmaceutical composition for suppressing retinal degeneration or a pharmaceutical composition for treating or preventing retinal degenerative diseases, containing phenylbutyric acid (PBA) or a salt thereof or a derivative thereof.
  • PBA phenylbutyric acid
  • phenylbutyric acid is not limited as long as it does not interfere with the effects of the present invention, and includes 4-phenylbutyric acid, 3-phenylbutyric acid, 2-phenylbutyric acid, 2-phenylisobutyric acid, 3-phenylisobutyric acid and the like. , preferably 4-phenylbutyric acid. It can be obtained as a reagent, an industrial raw material, etc., and can also be synthesized according to a conventional method. Phenylbutyric acid salts are not limited as long as they do not interfere with the effects of the present invention, and examples thereof include sodium salts, potassium salts, magnesium salts, calcium salts and the like, preferably sodium salts.
  • the derivative of phenylbutyric acid or phenylbutyrate is not limited as long as it does not interfere with the effects of the present invention.
  • saturated hydrocarbon group with 3 or less carbon atoms such as an alkyl group of 3, unsaturated hydrocarbon group with 3 or less carbon atoms, halogen, etc.
  • Any hydrogen on the hydrocarbon chain of is any substituent (e.g., a saturated hydrocarbon group having 3 or less carbon atoms such as an alkyl group having 1 to 3 carbon atoms, an unsaturated hydrocarbon group having 3 or less carbon atoms, a halogen etc.).
  • the derivative of phenylbutyrate may be an ester or ether of phenylbutyrate, such as methyl ester, ethyl ester, n-propyl ester, isopropyl ester, or the like.
  • retinal degeneration is not particularly limited to diseases, and refers to a state in which degeneration of retinal cells has occurred. Preferably, it is a state in which degeneration of retinal photoreceptors has occurred. Degeneration of retinal photoreceptors may be degeneration of rod photoreceptors or degeneration of cone photoreceptors.
  • inhibition of retinal degeneration means that administration of the pharmaceutical composition of the present embodiment, for example, inhibits the progress of degeneration, delays the progress of degeneration, degenerates is improved, and the denatured state is completely eliminated.
  • the degradation of abnormal proteins caused by degeneration in the retina is promoted, the mitochondrial function is improved or enhanced, and/or the protective function of retinal photoreceptors is improved. Or, retinal degeneration is suppressed by being improved or the like.
  • the index for judging suppression of retinal degeneration is not particularly limited. It may be determined that retinal degeneration is suppressed by increasing the number of retinal cells, particularly the number of retinal photoreceptors, and by increasing the amplitude and / or shortening the latency in the electroretinogram You may judge that retinal degeneration was suppressed. A statistically significant difference is preferred, but not necessarily a significant difference.
  • the retinal degenerative disease to be treated by the present sample is not particularly limited as long as it causes degeneration of retinal cells, regardless of the cause of retinal degeneration. is preferred. Specifically, but not particularly limited, for example, retinitis pigmentosa, diabetic retinopathy, age-related macular degeneration, and retinal degeneration associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) One or more diseases are included.
  • treatment also includes prevention of disease occurrence.
  • the content of phenylbutyric acid or a salt thereof or a derivative thereof in the pharmaceutical composition, or the dosage or administration method of the pharmaceutical composition containing it is particularly limited as long as the therapeutic effect of the pharmaceutical composition can be obtained. However, it can be appropriately determined according to the type of disease, degree of disease, symptoms, patient's age, body weight, and the like.
  • the content of phenylbutyric acid or a salt thereof or a derivative thereof in the pharmaceutical composition may be 10 to 1000 mg, preferably 100 to 1000 mg, per 1 g of the pharmaceutical composition. good.
  • the content of phenylbutyric acid or a salt thereof or a derivative thereof in the pharmaceutical composition may be, for example, 0.001 ⁇ g/mL to 1000 mg/mL, and may be 0.001 ⁇ M to 1000 mM. .
  • the dosage form of the pharmaceutical composition of this embodiment can be appropriately selected according to the administration method.
  • solid preparations such as powders, granules, tablets and capsules
  • liquid preparations such as solutions, syrups, suspensions and emulsions
  • parenteral administration it can be formulated into injections, liquids, suspensions, and the like.
  • the route of administration is not particularly limited as long as a therapeutic effect is obtained, and may be oral administration, ocular administration, intravenous administration, topical administration, or the like.
  • it may be administered orally in dosage forms such as tablets, granules, or suspensions, may be administered topically to the eye as an injection, or may be administered to the eye as eye drops.
  • the dosage of the pharmaceutical composition of the present embodiment is 0 per day for a human weighing 60 kg, for example, when oral administration, intravenous administration, or the like is performed.
  • .001-100.0 g/m 2 (body surface area), 0.01-50.0 g/m 2 (body surface area), 0.1-30.0 g/m 2 (body surface area) ), may be 1.0 to 20.0 g/m 2 (body surface area), may be 9.9 to 13.0 g/m 2 (body surface area), may be 0.1 to 10 0 g/m 2 (body surface area), 0.1 to 1.0 g/m 2 (body surface area).
  • the above dosage of the pharmaceutical composition may be administered once a day, or may be administered in several divided doses per day.
  • a pharmaceutical composition having a concentration of 0.001 ⁇ g/mL to 1000 mg/mL or 0.001 ⁇ M to 1000 mM is applied once per eye, once a day.
  • multiple doses may be administered.
  • the pharmaceutical composition of this embodiment may contain additional active ingredients as long as they do not interfere with the effects of the present invention. Additionally, it may be used in combination with additional disease treatment methods.
  • the pharmaceutical composition of this embodiment may contain carriers and additives.
  • carriers include pharmacologically acceptable solvents, diluents, excipients, binders, etc.
  • examples include water, physiological saline, buffers, etc. is used.
  • Additives include stabilizers, pH adjusters, thickeners, antioxidants, tonicity agents, buffers, solubilizers, suspending agents, preservatives, antifreeze agents, cryoprotectants, and lyophilization.
  • Protective agents, bacteriostatic agents and the like can be mentioned.
  • Another embodiment of the present invention is a pharmaceutical composition for promoting endoplasmic reticulum stress-related degradation in the retina, comprising phenylbutyric acid (PBA) or a salt or derivative thereof.
  • PBA phenylbutyric acid
  • promotion of endoplasmic reticulum stress-related degradation in the retina is not particularly limited, but for example, endoplasmic reticulum stress-related degradation of XBP1s (XBP1 spliced form), VCP (valosin-containing protein), Derlin1 (degradation in endoplasmic reticulum protein 1), etc. is that the gene expression level or protein expression level of a molecular marker associated with is enhanced. By enhancing the expression level of this molecular marker, it is possible to promote the degradation of abnormal proteins occurring in the retina. In particular, promotion of endoplasmic reticulum stress-related degradation promotes degradation of abnormal P23H rhodopsin, thereby suppressing retinal degeneration.
  • the enhancement of the expression level of various molecular markers is not particularly limited, but in a subject administered the pharmaceutical composition of the present embodiment, compared with a control subject not administered the pharmaceutical composition, the marker It may mean that the gene or protein expression level of is increased. Alternatively, it may be determined that the expression level is enhanced when the gene or protein expression level of the marker exceeds a preset cutoff value in subjects administered with the pharmaceutical composition of the present embodiment.
  • the type of phenylbutyric acid salt or derivative, the content of phenylbutyric acid or its salt or its derivative in the pharmaceutical composition, or the dosage, administration method, dosage form, additional ingredients, etc. of the pharmaceutical composition are It is not particularly limited, and the description of the pharmaceutical composition for suppressing retinal degeneration can be applied mutatis mutandis.
  • Another embodiment of the present invention is a pharmaceutical composition for activating mitochondrial biogenesis in the retina and/or improving the metabolic function of mitochondria in the retina, comprising phenylbutyric acid or a salt thereof or a derivative thereof. be.
  • Activating mitochondrial biogenesis in the retina is not particularly limited, but for example, mitochondrial fission markers such as Fis1 (Mitochondrial fission 1 protein), autophagy markers such as LC3 (microtubule-associated protein light chain 3), or Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), or the like, or Pgc1- ⁇ (peroxisome proliferators-activated receptor- ⁇ co-activator), which is a regulator of mitochondrial biogenesis -1 ⁇ ) or Tfam (mitochondrial transcription factor A), which is a mitochondrial transcription factor, or the expression level of genes or proteins is enhanced.
  • mitochondrial fission markers such as Fis1 (Mitochondrial fission 1 protein), autophagy markers such as LC3 (microtubule-associated protein light chain 3), or Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), or the like
  • Pgc1- ⁇ peroxisome proliferators-activated
  • Enhanced gene or protein expression levels of these molecules can activate mitochondrial biogenesis in the retina and promote mitophagy of damaged mitochondria. Improving the metabolic function of mitochondria in the retina is not particularly limited, but includes, for example, enhancement of mitochondrial membrane potential and enhancement of cytochrome c oxidase IV (COX IV) activity. Activation of mitochondrial biogenesis and improved mitochondrial metabolic function can result in increased ATP levels in mitochondria, leading to protection of photoreceptors. That is, retinal degeneration can be suppressed by using the pharmaceutical composition of this embodiment.
  • enhancement of expression levels of various molecular markers, enhancement of mitochondrial membrane potential, and enhancement of COX IV activity are not particularly limited. It may mean increased gene or protein expression of the marker, enhanced mitochondrial membrane potential, or enhanced COX IV activity compared to a control subject without the marker. Alternatively, in subjects administered the pharmaceutical composition of the present embodiment, the gene or protein expression level of the marker, the measured value of mitochondrial membrane potential, or the measured value of COX IV activity exceeds a preset cutoff value In some cases, it may be determined that the gene or protein expression level of the marker is increased, the mitochondrial membrane potential is enhanced, or the activity of COX IV is enhanced.
  • Kinds of phenylbutyric acid salts and derivatives, content of phenylbutyric acid or its salts or derivatives thereof in the pharmaceutical composition, dosage, administration method, dosage form, additional ingredients, etc. of the pharmaceutical composition in the present embodiment is not particularly limited, and the description of the pharmaceutical composition for suppressing retinal degeneration can be applied mutatis mutandis.
  • mice P23H knock-in heterozygous mice (+/-, 2 weeks old, male) obtained by a method known to those skilled in the art (Non-Patent Document 2) were placed in a temperature-controlled room at the animal experiment facility of Keio University School of Medicine. The mice were reared at (22° C.) with a 12-hour light-dark cycle (lights on from 8:00 am to 8:00 pm) under an environment in which food and water were available ad libitum. All animal experiments were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the guidelines of the Keio University Animal Care and Use Committee.
  • RNA concentration was measured using a NanoDrop 1000 (Thermo Fisher Scientific) and 1 ⁇ g of RNA was reverse transcribed using SuperScript VILO master mix (Life Technologies, Carlsbad, Calif., USA) according to the manufacturer's instructions. Primers with the following sequences were used.
  • Glyceraldehyde 3-phosphate dehydrogenase forward primer 5′-ACTTTCGGCCCATCTCTCA-3′ (SEQ ID NO: 1) and reverse primer 5′-GATGACCCCTTTTGGCTCTCCAC-3′ (SEQ ID NO: 2).
  • Pgc1- ⁇ forward primer 5′-GATGATACCGCAAAGAGCA-3′ (SEQ ID NO:3) and reverse primer 5′-AGATTTACGGTGCATTCCT-3′ (SEQ ID NO:4).
  • Fis1 forward primer 5′-ATATGCCTGGTGCCTGGTTC-3′ (SEQ ID NO:5) and reverse primer 5′-AGTCCCGCTGTTCCTCTTTG-3′ (SEQ ID NO:6).
  • Mfn1 forward primer 5′-GATGTTCCACCAGAGCTGGGA-3′ (SEQ ID NO:7) and reverse primer 5′-AGGAGCCGCTCATTCACCCTTTTA-3′ (SEQ ID NO:8).
  • Mfn2 forward primer 5'-CCCCTCCTCAAGCACTTTGGTTC-3' (SEQ ID NO: 9) and reverse primer 5'-ACCCTGCTCTCTCTCCGTGTTGTAAAC-3' (SEQ ID NO: 10).
  • Xbp1s forward primer 5′-CTGAGTCCGCAGCAGGTG-3′ (SEQ ID NO: 11) and reverse primer 5′-TGCCCAAAAGGATATCAGACT-3′ (SEQ ID NO: 12).
  • VCP forward primer 5'-AAGTCCCCAGTTGCCAAGGATG-3' (SEQ ID NO: 13) and reverse primer 5'-AGCCGATGGATTTGTCTGCCTC-3' (SEQ ID NO: 14).
  • Derl1 forward primer 5′-CGCGATTTAAGGCCTGTTAC-3′ (SEQ ID NO: 15) and reverse primer 5′-GGTAGCCAGCGGTACAAAAAA-3′ (SEQ ID NO: 16).
  • Tfam forward primer 5′-AGTCAGCTGATGGGTATGGAGAA-3′ (SEQ ID NO: 17) and reverse primer 5′-TGCTGAACGAGGTCTTTTTG-3′ (SEQ ID NO: 18).
  • LC3b Mm00782868 (Taqman).
  • Taqman probes (Applied Biosystems, Thermo Fisher Scientific) were combined with Kir2.1 (also known as Kcnj2, potassium inward rectifying channel, subfamily J, member 2; Mm00434616), Aqp4 (Mm00802131), Kir4.1 (as Kcnj10 Potassium inward rectifying channel, subfamily J, member 10; Mm00445028), Kcnv2 (potassium channel, subfamily V, member 2 (Mm00807577), and BCL2-associated X protein (Bax; Mm00432050), also known as BCL2, were used.
  • Real-time PCR was performed using the StepOnePlus TM PCR system (Applied Biosystems, Thermo Fisher Scientific) and gene expression was quantified using the ⁇ CT method All mRNA levels were normalized to Gapdh.
  • mice were dark adapted for at least 12 hours and then placed under dim red light before performing ERGs (7-8).
  • Mice were injected intraperitoneally with a compound anesthetic [Midazolam 4 mg/kg body weight (Sand Japan Co., Ltd., Tokyo, Japan), medetomidine 0.75 mg/kg body weight (Nippon Zenyaku Kogyo Co., Ltd., Fukushima, Japan), and butorphanol tartrate 5 mg/kg. kg body weight (Meiji Seika Pharma Co., Ltd., Tokyo, Japan)] and remained on a heating pad during the experiment.
  • a compound anesthetic [Midazolam 4 mg/kg body weight (Sand Japan Co., Ltd., Tokyo, Japan), medetomidine 0.75 mg/kg body weight (Nippon Zenyaku Kogyo Co., Ltd., Fukushima, Japan), and butorphanol tartrate 5 mg/kg. kg body weight (Meiji Seika Pharma Co., Ltd
  • An active gold wire electrode was placed on the cornea, and ground and reference electrodes were placed on the tail and in the mouth, respectively. Electroretinogram recordings were performed using a PowerLab system 2/25 (AD Instruments, New South Wales, Australia).
  • the full-field scotopic ERG measured responses to flash stimuli at stimulus intensities ranging from ⁇ 2.1 to 2.9 log cd s/m 2 . Photopic ERG was measured 10 minutes after light adaptation.
  • HEK293 cells ATCC CRL-1573 were added to Dulbecco's modified Eagle's medium (#08456-65; Nacalai Tesque, Kyoto, Japan) supplemented with 10% fetal bovine serum (Life technologies, Carlsbad, CA, USA), and maintained with 100 units/ml penicillin and 100 ⁇ g/ml streptomycin (Sigma-Aldrich, St. Louis, MO, USA).
  • Phenylbutyric acid (PBA) suppressed photoreceptor loss in P23H knock-in heterozygous mice (P23H RP model mice)> Previously, in P23H knock-in heterozygous mice, there was no change in the thickness of the photoreceptor layer until postnatal day 12, and the inner segment (IS) and outer segment (OS) lengths differed from wild-type (WT). It is reported that retinitis pigmentosa progresses gradually thereafter (Non-Patent Document 9). In this study, continuous administration of PBA was started from 2 weeks of age.
  • sodium phenylbutyrate sodium 4-phenylbutyrate (the same applies to each example below); Sigma-Aldrich, 10 mg/kg body weight) is administered intraperitoneally every day from 2 weeks of age five times a week. gone.
  • PBA was prepared in an amount of body weight (g) ⁇ 10 ⁇ L and administered in one dose for one day.
  • the number of remaining photoreceptors (photoreceptor nuclei) in the retinas of P23H RP model mice administered with PBA was significantly higher than that of mice administered with vehicle ( 1A, B).
  • PBA was prepared in an amount of body weight (g) ⁇ 10 ⁇ L and administered in one dose for one day.
  • body weight g
  • 10-week-old PBA-treated P23H RP model mice showed greater amplitude of a-waves, which reflects the function of rod photoreceptors, compared to vehicle-treated mice.
  • B-wave amplitudes, which reflect function, were shown to be greater and latency to be shorter.
  • continued PBA treatment was shown to preserve the visual function of the rod system.
  • the latency of the b-wave which mainly indicates the function of cone photoreceptors, was shortened after PBA treatment. was done.
  • ERAD is also activated by the conversion of IRE1-associated XBP1 to XBP1s, leading to the induction of VCP (also known as Cdc48 or p97) that interacts with Derlin 1, exploiting its ATPase activity to It has been previously shown that certain misfolded proteins are transported from the ER to the cytoplasm (Non-Patent Document 18), and that proteins are degraded via the ubiquitin proteasome system (UPS) ( Non-Patent Documents 16-17).
  • UPS ubiquitin proteasome system
  • Non-Patent Documents 18-19 (19-20), while the fusion-associated protein mitofusin protein has been shown to induce degradation via the UPS (18-19).
  • This system maintains cellular homeostasis (Non-Patent Document 21) and has also been shown to maintain neuronal plasticity and survival (Non-Patent Document 22).
  • intraperitoneal administration of PBA described in Examples 1 and 2 resulted in mitochondrial fission marker Fis1 (Fig. 3D) and autophagy marker LC3 (Fig. 3E).
  • Non-Patent Documents 19, 23 mRNA levels of Pgc1- ⁇ , which is known to regulate mitochondrial biogenesis (Non-Patent Document 24), and Tfam (Non-Patent Document 25), a transcription factor that induces mitochondrial DNA encoding molecules involved in respiration. was shown to be increased by PBA as described in Examples 1 and 2 ( Figures 3H and I). These results indicated that PBA treatment activates mitochondrial biogenesis.
  • Example 4 PBA activated oxidative phosphorylation (OXPHOS) in mitochondria in vitro> Furthermore, in order to analyze the voltage effect caused by PBA, a study using HEK293 cell line was performed. Cells were treated with 0-2.5 ⁇ M PBA 12 or 24 hours before each measurement. Mitochondrial membrane potential was determined by incubating cells with tetramethylrhodamine methyl ester (TMRE) (10 ⁇ M) at 37° C.
  • TMRE tetramethylrhodamine methyl ester
  • the luminescence signal was analyzed by Cytation 5 system (BioTek, Winooski, VT, USA).
  • Cytation 5 system BioTek, Winooski, VT, USA.
  • ATP ATP Bioluminescence Assay Kit CLSII (Sigma-Aldrich)
  • the luminescence signal was analyzed using the Cytation 5 system (BioTek). was measured using As a result, PBA dose-dependently expressed Pgc1- ⁇ (FIG. 4A) and Tfam (FIG. 4B) in the HEK293 cell line.
  • the mitochondrial membrane potential is essential for ATP synthesis in mitochondria, and BAM15, a mitochondrial protonophore uncoupler, counteracts this potential.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Il a été découvert que l'acide phénylbutyrique (PBA) peut empêcher la mort cellulaire progressive de photorécepteurs rétiniens et peut empêcher la détérioration d'une fonction visuelle. Sur la base de ces découvertes, une composition pharmaceutique destinée à prévenir la dégénérescence rétinienne y compris la rétinite pigmentaire peut être fournie.
PCT/JP2022/011209 2021-03-16 2022-03-14 Composition destinée à la prévention de la dégénérescence rétinienne Ceased WO2022196609A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021042005A JP2024069730A (ja) 2021-03-16 2021-03-16 網膜変性抑制用組成物
JP2021-042005 2021-03-16

Publications (1)

Publication Number Publication Date
WO2022196609A1 true WO2022196609A1 (fr) 2022-09-22

Family

ID=83320371

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/011209 Ceased WO2022196609A1 (fr) 2021-03-16 2022-03-14 Composition destinée à la prévention de la dégénérescence rétinienne

Country Status (2)

Country Link
JP (1) JP2024069730A (fr)
WO (1) WO2022196609A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013525451A (ja) * 2010-04-28 2013-06-20 ザ・チャイニーズ・ユニバーシティ・オブ・ホンコン 高眼圧症及び緑内障を予防及び治療する方法及び薬物
WO2015064768A1 (fr) * 2013-10-31 2015-05-07 京都府公立大学法人 Médicament thérapeutique pour des maladies associées à la mort cellulaire du réticulum endoplasmique dans l'endothélium de la cornée
JP2017529344A (ja) * 2014-09-19 2017-10-05 ユニバーシティ インダストリー コオペレイション グループ オブ キョンヒ ユニバーシティ ボタンの根皮、アンジェリカ・ダフリカの根、及びミシマサイコの根又はそれらの画分を有効成分として含有する神経変性障害の治療及び予防のための医薬組成物
WO2018164113A1 (fr) * 2017-03-06 2018-09-13 学校法人 慶應義塾 Modèle murin d'induction de la myopie et inhibiteur de stress du réticulum endoplasmique pour prévenir ou supprimer la myopie
JP2019112338A (ja) * 2017-12-22 2019-07-11 国立大学法人 熊本大学 ミトコンドリア病治療薬

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013525451A (ja) * 2010-04-28 2013-06-20 ザ・チャイニーズ・ユニバーシティ・オブ・ホンコン 高眼圧症及び緑内障を予防及び治療する方法及び薬物
WO2015064768A1 (fr) * 2013-10-31 2015-05-07 京都府公立大学法人 Médicament thérapeutique pour des maladies associées à la mort cellulaire du réticulum endoplasmique dans l'endothélium de la cornée
JP2017529344A (ja) * 2014-09-19 2017-10-05 ユニバーシティ インダストリー コオペレイション グループ オブ キョンヒ ユニバーシティ ボタンの根皮、アンジェリカ・ダフリカの根、及びミシマサイコの根又はそれらの画分を有効成分として含有する神経変性障害の治療及び予防のための医薬組成物
WO2018164113A1 (fr) * 2017-03-06 2018-09-13 学校法人 慶應義塾 Modèle murin d'induction de la myopie et inhibiteur de stress du réticulum endoplasmique pour prévenir ou supprimer la myopie
JP2019112338A (ja) * 2017-12-22 2019-07-11 国立大学法人 熊本大学 ミトコンドリア病治療薬

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LI S., SAMARDZIJA M., YANG Z., GRIMM C., JIN M.: "Pharmacological Amelioration of Cone Survival and Vision in a Mouse Model for Leber Congenital Amaurosis", THE JOURNAL OF NEUROSCIENCE, SOCIETY FOR NEUROSCIENCE, US, vol. 36, no. 21, 25 May 2016 (2016-05-25), US , pages 5808 - 5819, XP055939751, ISSN: 0270-6474, DOI: 10.1523/JNEUROSCI.3857-15.2016 *
MENDES HUGO F, CHEETHAM M E: "Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa.", HUMAN MOLECULAR GENETICS, OXFORD UNIVERSITY PRESS, GB, vol. 17, no. 19, 1 October 2008 (2008-10-01), GB , pages 3043 - 3054, XP002554593, ISSN: 0964-6906, DOI: 10.1093/hmg/ddn202 *
SHRUTHI KARNAM; REDDY SINGAREDDY SREENIVASA; REDDY GEEREDDY BHANUPRAKASH: "Ubiquitin-proteasome system and ER stress in the retina of diabetic rats", ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, ACADEMIC PRESS, US, vol. 627, 9 June 2017 (2017-06-09), US , pages 10 - 20, XP085113965, ISSN: 0003-9861, DOI: 10.1016/j.abb.2017.06.006 *
YAO, JINGYU; QIU, YAOYAN; JIA, LIN; FEATHERS, KECIA; THOMPSON, DEBRA A.; ZACKS, DAVID N. : "Protective effect of shifting protein degradation from autophagy to proteasome on retinal degeneration in P23H mice", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, US, vol. 60, no. 9, 1 July 2019 (2019-07-01), US , pages 288, XP009539721, ISSN: 0146-0404 *

Also Published As

Publication number Publication date
JP2024069730A (ja) 2024-05-22

Similar Documents

Publication Publication Date Title
Rezaie et al. Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration
US10583125B2 (en) Method for treating neurodegenerative diseases
JP2024010082A (ja) オートファジーおよびリポファジーを調節するためのβ－ヒドロキシ－β－メチルブチレート（ＨＭＢ）の組成物および使用方法
WO2006033734A2 (fr) Procedes de combinaison, compositions et therapies permettant de traiter des etats opthalmiques par des derives de 13-cis-retinyle
Vianello et al. Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy
EP2600862B1 (fr) Inhibiteurs de l'erk destinés à traiter des troubles du développement de la connectivité neuronale
US12220391B2 (en) Compositions and methods of use of β-hydroxy-β-methylbutyrate (HMB) for modulating autophagy and lipophagy
JP7668998B2 (ja) 神経疾患の処置
IL259381A (en) Mirabgron for the treatment of retinal diseases
WO2022196609A1 (fr) Composition destinée à la prévention de la dégénérescence rétinienne
WO2015042821A1 (fr) Composé servant à l'activation de l'ampk et ses utilisations
Sakuma et al. Molecular mechanisms controlling skeletal muscle mass
TWI481406B (zh) 活化ａｍｐｋ之化合物及其使用
US20250177335A1 (en) Compositions and methods of use of beta-hydroxy-beta-methylbutyrate (hmb) for modulating autophagy and lipophagy
JP2016183111A (ja) Ｎｒｆ２活性化剤
JP6153838B2 (ja) 血管透過性抑制剤
Millet-Boureima et al. Empowering Melatonin Therapeutics with Drosophila Models. Diseases 2021, 9, 67
HK40079403A (en) Compositions and methods of use of beta-hydroxy-beta-methylbutyrate (hmb) for modulating autophagy and lipophagy
TW202327566A (zh) 包含藻褐素及小分子褐藻醣膠之組合物用於製備治療或改善慢性腎病之醫藥品的用途及包含藻褐素、小分子褐藻醣膠及左旋肉鹼之組合物及包含其的醫藥品
Barakat Diabetes and depression: unveiling a potential biological link

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22771355

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22771355

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP