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NON-HUMAN MAMMAL MODEL FOR NORMAL TENSION GLAUCOMA

Foreign code F130007328
File No. S2011-0498-C0
Posted date Apr 26, 2013
Country WIPO
International application number 2012JP056627
International publication number WO 2012124752
Date of international filing Mar 15, 2012
Date of international publication Sep 20, 2012
Priority data
  • P2011-057926 (Mar 16, 2011) JP
Title NON-HUMAN MAMMAL MODEL FOR NORMAL TENSION GLAUCOMA
Abstract The present invention provides a genetically modified non-human mammal where a mutation, substituting Asp or Glu for the Ser that is the Cdk5 phosphorylation site of the c-Src protein, has been introduced into the Src gene. Provided thereby is a novel non-human mammal and the like which can be used as a model for normal tension glaucoma.
Outline of related art and contending technology BACKGROUND ART
Glaucoma, optic nerve is damaged for some reason, the field of progressive disease and are damaged, is left as it is, ultimately leading to a high possibility that the blindness.
1 A high intraocular pressure glaucoma is one of glaucoma, the anterior chamber is deteriorated and the excretion of aqueous humor in the eye pressure (intraocular pressure) by the increase in the optic nerve atrophy and is pressed, visual function so that fluid is damaged, a field of view is narrowed disease.
Normal tension glaucoma is, from a height of prevalence, are of particular interest in the recent disease. And about 400 million Japanese glaucoma patients, of which about 3 one-half the normal tension glaucoma patient 2. Is normal tension glaucoma, normal intraocular pressure (in humans usually 10-21mmHg) even though not, finding similar to that of the high intraocular pressure glaucoma (optic nerve atrophy and loss of vision) and exhibits a disease state, specifically, not accompanied by inflammation of the nerve can be (a), (b) lesion is retinal ganglion cell (RGC: retinal ganglion cell) be restrictive, (c) a nervous disorder to proceed over time, the optic papilla (d) characteristic findings have (recessed), (e) maintained in a normal eye pressure, which is characteristic of the such as. Is normal tension glaucoma, slow the progress of the subjective symptom is small, early detection is difficult, also at present, other than to lower eye pressure further, and therapy is not determined.
Normal tension glaucoma model non-human mammal is obtained, useful in the treatment of normal tension glaucoma therapeutic agent for the development of, the establishment of a method for the treatment, and a cause of the disease and also for elucidation of the pathogenesis, expected to be extremely valuable.
Here, as a model mouse normal tension glaucoma, the anterior chamber and the ablation laser exhaust path (non-patent document 1), placing a bead the anterior chamber (non-patent document 2), the vein is solidified so that the discharge of aqueous (non-patent document 3) as, and the like are known. However, any of the model, it is difficult to adjust in intraocular pressure, can be associated with inflammation, can be a contradiction in the pathogenesis, such as a problem.
In addition, GLAST gene were deleted normal tension glaucoma also known model mouse (non-patent document 4, patent document 1). Is GLAST, nerve information possibly because the collecting mechanism known as metabotropic glutamate transporter in.
As normal tension glaucoma model mouse, the progress of a condition including is gradual, actual human normal tension glaucoma in the same manner as of the onset of symptoms similar to mechanism is demanded.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 c-Srcタンパク質のCdk5リン酸化部位であるSerをAsp又はGluに置換する変異をSrc遺伝子に導入した遺伝子改変非ヒト哺乳動物。

[請求項2]
 前記Serが、c-Srcタンパク質のN末端から74番目のアミノ酸残基である、請求項1記載の非ヒト哺乳動物。

[請求項3]
 前記SerがAspと置換された、請求項1又は2記載の非ヒト哺乳動物。

[請求項4]
 前記非ヒト哺乳動物が、変異型Src遺伝子をホモ接合で有する、請求項1~3のいずれか1項記載の非ヒト哺乳動物。

[請求項5]
 前記非ヒト哺乳動物が次の条件:
 1)その眼圧が正常範囲にあり、かつ
 2)その網膜神経節の細胞数が、野生型非ヒト哺乳動物に比べて減少している、
 を満たしている、請求項1~4のいずれか1項記載の非ヒト哺乳動物。

[請求項6]
 前記非ヒト哺乳動物がマウスである、請求項1~5のいずれか1項記載の非ヒト哺乳動物。

[請求項7]
 前記非ヒト哺乳動物が正常眼圧緑内障モデルとして用いられる、請求項1~6のいずれか1項記載の非ヒト哺乳動物。

[請求項8]
 請求項1~7のいずれか1項記載の非ヒト哺乳動物を用いた、正常眼圧緑内障の予防及び/又は治療剤のスクリーニング方法。

[請求項9]
 前記方法が、
 1)請求項1~7のいずれか1項記載の非ヒト哺乳動物及び対照非ヒト哺乳動物に候補物質を投与すること、
 2)前記各非ヒト哺乳動物において、投与前、及び投与してから一定期間後に、生存する視神経細胞の数量を検査すること、及び
 3)前記各非ヒト哺乳動物の検査結果を比較して、候補物質の有効性を評価すること、
 を含む、請求項8記載の方法。

[請求項10]
 前記生存する視神経細胞の数量の検査が、網膜神経節の神経細胞数を計数することである、請求項9記載の方法。

[請求項11]
 前記対照非ヒト動物が、野生型非ヒト動物及び/又はc-Srcタンパク質のCdk5リン酸化部位であるSerをAlaに置換する変異をSrc遺伝子に導入した遺伝子改変非ヒト哺乳動物である、請求項9又は10記載の方法。

[請求項12]
 c-Srcタンパク質のCdk5リン酸化部位であるSerをAlaに置換する変異をSrc遺伝子に導入した遺伝子改変非ヒト哺乳動物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • UNIVERSITY OF YAMANASHI
  • Inventor
  • KASHIWAGI Kenji
  • KATO Goro
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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