WO2022057234A1 - 巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用 - Google Patents

巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用 Download PDF

Info

Publication number
WO2022057234A1
WO2022057234A1 PCT/CN2021/083739 CN2021083739W WO2022057234A1 WO 2022057234 A1 WO2022057234 A1 WO 2022057234A1 CN 2021083739 W CN2021083739 W CN 2021083739W WO 2022057234 A1 WO2022057234 A1 WO 2022057234A1
Authority
WO
WIPO (PCT)
Prior art keywords
myopia
lipid
drug
lipid metabolism
scleral
Prior art date
Application number
PCT/CN2021/083739
Other languages
English (en)
French (fr)
Inventor
周翔天
潘妙珍
瞿佳
Original Assignee
温州医科大学
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 温州医科大学 filed Critical 温州医科大学
Publication of WO2022057234A1 publication Critical patent/WO2022057234A1/zh

Links

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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the invention specifically relates to the technical field of myopia treatment, in particular to the application of a lipid metabolism pathway intervention regulator in the sclera or a lipid metabolism regulating drug as a drug for inhibiting the negative diopter of myopia and prolonging the eye axis.
  • Human myopia is mainly characterized by axial extension, and the main part of axial extension is at the posterior pole of the eyeball.
  • Early studies have found that there are significant differences in collagen bundle structure, fiber diameter distribution, and fiber morphology between normal human eyes and myopic eyes.
  • scleral thinning, scleral collagen fibers thinning, and the disappearance of the gradient in the diameter of the inner, middle and outer layers of scleral fibers in myopic eyes have also been found in mammals (tree rats, marmosets, guinea pigs) for a long time in experimental myopia.
  • mammals tree rats, marmosets, guinea pigs
  • the sclera is currently considered to be the target tissue for the occurrence and progression of myopia.
  • Our mouse RNA-seq experiments found that the scleral lipid metabolism pathway in myopia was significantly down-regulated, and the expression of several key enzyme genes in the lipid metabolism pathway was down-regulated.
  • Electron microscope observation of myopic sclera found lipid droplet deposition, which further explained the abnormal lipid metabolism in myopic sclera. It has been widely reported that the intake of polyunsaturated fatty acids is closely related to metabolic diseases. Endogenous omega-3 PUFA increase and fish oil supplementation reduced the transcription and protein expression of acute alcohol-induced upregulation of SREBP-1c in the liver.
  • SREBP-1c upregulates the expression of lipogenesis-related genes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1), thereby promoting fat biosynthesis. Therefore, omega-3 polyunsaturated fatty acids can regulate lipid metabolism, but there is no research on the regulation of omega-3 on scleral lipids and myopia.
  • ACLY ATP-citrate lyase
  • ACC acetyl-CoA carboxylase
  • FAS fatty acid synthase
  • SCD-1 stearoyl-CoA desaturase-1
  • the present invention provides the application of a lipid metabolism pathway intervention regulator or lipid metabolism regulating drug in the sclera as a drug for inhibiting the negative diopter of myopia and the prolongation of the eye axis.
  • the technical solution adopted in the present invention is: the application of the lipid metabolism pathway intervention regulator in the sclera as a drug for inhibiting the negative diopter of myopia and the prolongation of the eye axis.
  • the sclera lipid metabolism pathway intervention regulator is omega-3.
  • lipid metabolism-regulating drugs in sclera as drugs to inhibit myopia from negative diopter and axial lengthening.
  • the drug for regulating lipid metabolism in the sclera is omega-3.
  • the present invention provides the application of a lipid metabolism pathway intervention regulator or lipid metabolism regulating drug in the sclera as a drug for inhibiting the negative refraction of myopia and prolonging the axial length of the eye.
  • the metabolic pathway was significantly down-regulated, and the expression of several key enzyme genes in the lipid metabolism pathway was down-regulated. Electron microscope observation of myopic sclera found lipid droplet deposition, further indicating that lipid metabolism in myopic sclera is abnormal, and regulating scleral lipid metabolism through ⁇ -3 can effectively inhibit myopic diopter negative and axial lengthening.
  • Figure 1 is a sequence map of the sclera transcriptome of form deprivation myopia mice.
  • Figure 2 is an electron microscope image of the sclera of form deprivation myopia mice.
  • Figure 3 is a graph of the diopter difference between the experimental eye and the contralateral eye.
  • Figure 4 is a graph of the difference in the depth of the vitreous cavity between the experimental eye and the contralateral eye.
  • Figure 5 is a graph of the difference in axial length between the experimental eye and the contralateral eye.
  • difference refers to the difference between the experimental eye and the contralateral eye diopter or axial parameters; the comparison between the solvent group and the drug group was performed by one-way analysis of variance (ANOVA): "*” means P ⁇ 0.05; “* *” means P ⁇ 0.01; “* * *” means P ⁇ 0.001.
  • FIG. 1 The present invention will now be further described with reference to FIG. 1 , FIG. 2 , FIG. 3 , FIG. 4 , and FIG. 5 .
  • RNA-seq experiments in myopic mice found that the scleral lipid metabolism pathway was significantly down-regulated, and the expression of several key enzyme genes in the lipid metabolism pathway was down-regulated. Electron microscope observation of myopic sclera found lipid droplet deposition, which further explained the abnormal lipid metabolism in myopic sclera. A large number of experiments have confirmed the effect of ⁇ -3 in reducing lipid concentration in severe hypertriglyceridemia, but there is no result of the regulation of ⁇ -3 on scleral lipid regulation and myopia.
  • Part 1 The experimental animals were 3-week-old C57/BL6 mice, which were subjected to monocular form deprivation by the blindfold method. After 2 weeks of the experiment, the animals were anesthetized and sacrificed, and the sclera of both eyes were taken for transcriptome sequencing analysis and electron microscope observation.
  • the experimental animals were 3-week-old British tricolor short-haired guinea pigs. Monocular form deprivation (FD) was performed using the mask method, and deprived guinea pigs were gavaged with omega-3. Animals were randomly divided into 2 groups: form deprivation + solvent control group (FD + vehicle) (the solvent here refers to olive oil), form deprivation + drug group (FD + omega-3 (DHA 300mg, EPA 60mg)) Group. Oral gavage was performed at 9 am every day for 2 weeks.
  • FD + solvent control group FD + vehicle
  • FD + drug group FD + omega-3 (DHA 300mg, EPA 60mg)
  • Oral gavage was performed at 9 am every day for 2 weeks.
  • EIR eccentric infrared photorefractor

Landscapes

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

Abstract

巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用，通过近视眼小鼠RNA-seq实验发现巩膜脂代谢通路明显下调，脂代谢通路中多个关键酶基因表达下调。近视眼巩膜电镜观察发现脂滴沉积，进一步说明近视眼巩膜中脂代谢异常，并通过ω-3调节眼巩膜脂质代谢，可以有效地抑制近视屈光度变负和眼轴延长。

Description

巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用 技术领域
本发明具体涉及近视治疗技术领域，具体涉及巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用。
 背景技术
人类近视眼以眼轴延长为主要特征，眼轴延长的主要部位在眼球的后极部。早期的研究发现正常人眼与近视眼两者在胶原束结构、纤维直径分布以及纤维形态等方面都有明显差别。目前已发现哺乳类动物（树鼠，绒猴，豚鼠）长时间的实验性近视眼中也出现巩膜变薄，巩膜胶原纤维变细，以及近视眼中巩膜内、中、外层纤维直径梯度性变化消失的现象。这些都提示：在近视的发展过程中，近视眼的巩膜结构变化经历了一个主动重塑的过程。
综上所述，巩膜目前已被认为是近视发生和进展的靶组织。我们小鼠RNA-seq实验发现近视眼巩膜脂代谢通路明显下调，脂代谢通路中多个关键酶基因表达下调。近视眼巩膜电镜观察发现脂滴沉积，进一步说明近视眼巩膜中脂代谢异常。据广泛报道，多不饱和脂肪酸的摄入与代谢性疾病密切相关。内源性ω-3多不饱和脂肪酸增加和补充鱼油可以降低肝脏中急性酒精诱导上调的SREBP-1c的转录和蛋白表达。SREBP-1c通过上调脂肪生成相关基因的表达，包括ATP-柠檬酸裂解酶(ACLY)、乙酰辅酶A羧化酶(ACC)、脂肪酸合成酶(FAS)和硬脂酰辅酶A脱饱和酶-1(SCD-1)，从而促进脂肪的生物合成。因此，ω-3多不饱和脂肪酸可调控脂质代谢，但目前尚无ω-3对巩膜脂质调控以及近视调控作用的研究。
 技术问题
为了解决现有技术存在的技术缺陷，本发明提供了巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用。
 技术解决方案
本发明采用的技术解决方案是：巩膜中脂代谢通路干预调节剂作为抑制近视的屈光度变负和眼轴延长药物的应用。
所述的巩膜中脂代谢通路干预调节剂为ω-3。
巩膜中脂代谢调节药物作为抑制近视的屈光度变负和眼轴延长药物的应用。
所述的巩膜中脂代谢调节药物为ω-3。
 有益效果
本发明的有益效果是：本发明提供了巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用，通过近视眼小鼠RNA-seq实验发现巩膜脂代谢通路明显下调，脂代谢通路中多个关键酶基因表达下调。近视眼巩膜电镜观察发现脂滴沉积，进一步说明近视眼巩膜中脂代谢异常，并通过ω-3调节眼巩膜脂质代谢，可以有效地抑制近视屈光度变负和眼轴延长。
 附图说明
图1是形觉剥夺性近视小鼠巩膜转录组测序图。
图2是形觉剥夺性近视小鼠巩膜电镜图。
图3是实验眼和对侧眼屈光度差值图。
图4是实验眼和对侧眼玻璃体腔深度差值图。
图5是实验眼和对侧眼眼轴长度差值图。
附图中，“差值”指实验眼与对侧眼屈光度或眼轴参数的差值；溶剂组和给药组之间比较采用单因素方差分析（ANOVA）：“*” 表示P< 0.05； “* *” 表示P<0.01； “* * *”表示P<0.001。
 本发明的实施方式
现结合图1、图2、图3、图4、图5对本发明进行进一步说明。
我们近视眼小鼠RNA-seq实验发现巩膜脂代谢通路明显下调，脂代谢通路中多个关键酶基因表达下调。近视眼巩膜电镜观察发现脂滴沉积，进一步说明近视眼巩膜中脂代谢异常。已有大量实验证实ω-3在降低严重高甘油三酯血症中脂质浓度方面的效果，但是目前尚无ω-3对巩膜脂质调控和近视的调控作用的结果。
因此我们进行实验以验证ω-3的作用。
实验内容
第一分部：实验动物为3周龄C57/BL6小鼠，采用眼罩法进行单眼形觉剥夺，实验2周后麻醉处死动物，取双眼巩膜进行转录组测序分析和电镜观察。
第二部分：实验动物为3周龄英国种三色短毛豚鼠。采用面罩法进行单眼形觉剥夺（FD），并对剥夺豚鼠灌胃ω-3。动物随机分为2组：形觉剥夺+溶剂对照组（FD+vehicle）（这里的溶剂是指食用橄榄油），形觉剥夺+药物组（FD+ω-3（DHA 300mg，EPA 60mg））组。每天上午9点进行灌胃，连续给药2周。分别于实验前、给药1周、给药2周用红外偏心摄影验光仪（EIR）测量屈光度、A超（11MHz）测量玻璃体腔深度和眼轴长度等眼轴参数。
比较实验前后测量参数，发现给药组的形觉剥夺眼，屈光近视程度和玻璃体腔及眼轴延长程度均小于形觉剥夺对照组和给予溶剂组，和溶剂对照组比较具有统计学意义。因此，喂食ω-3可以抑制豚鼠形觉剥夺性近视的形成。
由图1可知，形觉剥夺2周后，小鼠近视眼巩膜脂代谢通路整理下调，脂代谢关键酶肉碱脂酰转移酶2明显减少，说明近视眼脂代谢通路下调。
由图2可知，形觉剥夺2周后，小鼠近视眼巩膜脂质沉积增加，说明近视眼巩膜脂代谢异常。
由图3可知，实验2周后，给药组形成近视量小于溶剂组，且具有时间效应，说明ω-3能抑制形觉剥夺性近视的形成。
由图4可知，实验2周后，给药组玻璃体腔延长显著小于溶剂组，且具有时间效应，说明ω-3能抑制形觉剥夺玻璃体腔的延长。
由图5可知，实验2周后，给药组眼轴延长显著小于溶剂组，且具有时间效应，说明ω-3能抑制形觉剥夺后眼轴的延长。
实验结论
上述实验，证明ω-3可明显起到延缓屈光度变负和眼轴延长的作用。
各位技术人员须知：虽然本发明已按照上述具体实施方式做了描述，但是本发明的发明思想并不仅限于此发明，任何运用本发明思想的改装，都将纳入本专利专利权保护范围内。
以上所述仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (4)

  1. 巩膜中脂代谢通路信号干预调节剂作为抑制近视的屈光度变负和眼轴延长药物的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的巩膜中脂代谢通路信号干预调节剂为ω-3。
  3. 巩膜中脂代谢调节药物作为抑制近视的屈光度变负和眼轴延长药物的应用。
  4. 根据权利要求3所述的应用，其特征在于，所述的巩膜中脂代谢调节药物为ω-3。
PCT/CN2021/083739 2020-09-17 2021-03-30 巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用 WO2022057234A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010976517.X 2020-09-17
CN202010976517.XA CN112057444A (zh) 2020-09-17 2020-09-17 巩膜脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光变负和眼轴延长药物的应用

Publications (1)

Publication Number Publication Date
WO2022057234A1 true WO2022057234A1 (zh) 2022-03-24

Family

ID=73696986

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/083739 WO2022057234A1 (zh) 2020-09-17 2021-03-30 巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用

Country Status (2)

Country Link
CN (1) CN112057444A (zh)
WO (1) WO2022057234A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114053407B (zh) * 2020-09-17 2023-08-29 极目峰睿(上海)生物科技有限公司 一种通过调节眼巩膜脂代谢来抑制近视的应用
CN112057444A (zh) * 2020-09-17 2020-12-11 温州医科大学 巩膜脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光变负和眼轴延长药物的应用
CN114533716A (zh) * 2022-03-03 2022-05-27 三维医疗科技有限公司 含有不饱和脂肪酸的组合物及在抑制近视产品中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015165507A1 (en) * 2014-04-29 2015-11-05 Georgiou Tassos Treatment of eye diseases using omega 3 fatty acids and aa/epa blood ratio
JP2020138964A (ja) * 2019-02-25 2020-09-03 株式会社坪田ラボ 近視進行抑制剤、機能性食品及び眼科用組成物
CN112057444A (zh) * 2020-09-17 2020-12-11 温州医科大学 巩膜脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光变负和眼轴延长药物的应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101142947A (zh) * 2007-09-24 2008-03-19 张国浩 一种含鱼油或多烯鱼油的营养均衡调和油及其生产方法
CN102696790A (zh) * 2012-06-28 2012-10-03 世纪润和品牌管理(北京)有限公司 一种平衡能量配方油
WO2016171282A1 (ja) * 2015-04-24 2016-10-27 学校法人慶應義塾 近視予防剤及び近視進行抑制剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015165507A1 (en) * 2014-04-29 2015-11-05 Georgiou Tassos Treatment of eye diseases using omega 3 fatty acids and aa/epa blood ratio
JP2020138964A (ja) * 2019-02-25 2020-09-03 株式会社坪田ラボ 近視進行抑制剤、機能性食品及び眼科用組成物
CN112057444A (zh) * 2020-09-17 2020-12-11 温州医科大学 巩膜脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光变负和眼轴延长药物的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WU, JING-RUI ET AL.: "The Combined Effect of ω-3 Fatty Acid and Lutein on the Vision of Young Children", ACTA NUTRIMENTA SINICA, vol. 40, no. 5, 31 December 2018 (2018-12-31), pages 503 - 505, XP055912913 *

Also Published As

Publication number Publication date
CN112057444A (zh) 2020-12-11

Similar Documents

Publication Publication Date Title
WO2022057234A1 (zh) 巩膜中脂代谢通路干预调节剂或脂代谢调节药物作为抑制近视屈光度变负和眼轴延长药物的应用
Joffre et al. N-3 polyunsaturated fatty acids and the resolution of neuroinflammation
US10792269B2 (en) Glyceryl 3-hydroxybutyrates for migraine symptom management
Assisi et al. Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders
Horrobin et al. The membrane hypothesis of schizophrenia
Katzenschlager et al. Treatment of Parkinson's disease: levodopa as the first choice
Sinclair Docosahexaenoic acid and the brain-what is its role?
US20100048705A1 (en) Methods of treating and preventing neovascularization with omega-3 polyunsaturated fatty acids
US20100105773A1 (en) Use of resolvins and docosatrienes and analogues thereof for the treatment of angiogenesis and ocular neovascularization
Tani et al. Autoregulation of retinal blood flow in response to decreased ocular perfusion pressure in cats: comparison of the effects of increased intraocular pressure and systemic hypotension
JPH06199663A (ja) 精神分裂病治療法
CA2589797A1 (fr) Utilisation d&#39;acide(s) gras omega-3 pour le traitement de l&#39;hypercholesterolemie causee par un traitement anti-retroviral chez les patients infectes par le vih
US9962355B2 (en) Mixture of fatty acids and palmitoylethanolamide for use in the treatment of inflammatory and allergic pathologies
JP6062362B2 (ja) Ｐｋｃ活性化剤を使用した、異常な樹状突起棘に関連した認知障害の治療
CN114053407B (zh) 一种通过调节眼巩膜脂代谢来抑制近视的应用
Sartini et al. Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring
JP2018008991A (ja) 医薬組成物及びその用途
Neves et al. Use of linseed oil to treat experimentally induced keratoconjunctivitis sicca in rabbits
Li et al. Mfsd2a attenuated hypoxic-ischemic brain damage via protection of the blood–brain barrier in mfat-1 transgenic mice
JP5584316B2 (ja) 近視の抑制方法及び近視を抑制する薬物とするアデニル酸シクラーゼ抑制剤の応用
Kolko et al. Is fat the future for saving sight? Bioactive lipids and their impact on glaucoma
US20220409688A1 (en) Pharmaceutical composition for use in increasing hair, modifying scalp or skin, healing a wound, promoting osteogenesis, or modifying hair
Hurley et al. Energy metabolism in the vertebrate retina
Tian et al. Extraocular source of oligodendrocytes contribute to retinal myelination and optokinetic responses in zebrafish
RU2652342C1 (ru) Композиция для лечения ретинальной неоваскуляризации в эксперименте и способ лечения с ее использованием

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: 21868072

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: 21868072

Country of ref document: EP

Kind code of ref document: A1