JP6145667B2 - アロディニア、痛覚過敏、自発痛、及び幻痛の治療 - Google Patents
アロディニア、痛覚過敏、自発痛、及び幻痛の治療 Download PDFInfo
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- JP6145667B2 JP6145667B2 JP2014528860A JP2014528860A JP6145667B2 JP 6145667 B2 JP6145667 B2 JP 6145667B2 JP 2014528860 A JP2014528860 A JP 2014528860A JP 2014528860 A JP2014528860 A JP 2014528860A JP 6145667 B2 JP6145667 B2 JP 6145667B2
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Description
i. 配列番号7のアミノ酸配列と、
ii. 配列番号7に対して少なくとも70%の配列同一性を有する、配列番号7のアミノ酸配列の生物活性配列変異体と、
iii. 配列番号7に対して少なくとも70%の同一性を有する、a)又はb)の少なくとも50個の隣接アミノ酸の生物活性フラグメント。
i. 配列番号7のアミノ酸配列と、
ii. 配列番号7に対して少なくとも70%の配列同一性を有する、配列番号7のアミノ酸配列の生物活性配列変異体と、
iii. 配列番号7に対して少なくとも70%の同一性を有する、a)又はb)の少なくとも50個の隣接アミノ酸の生物活性フラグメント。
i. 生体適合性の外膜及び内核を含み、かつ、
ii. 前記内核が、本発明による細胞を含む、カプセルに関する。
i. 本発明による単離ポリペプチド、又は
ii. 本発明による単離核酸、又は
iii. 本発明による発現ベクター、又は
iv. 本発明による株化細胞、又は
v. 本発明による移植可能な生体適合性カプセルを含む、アロディニア、痛覚過敏、自発痛、及び/又は幻痛の治療方法において使用するための組成物に関する。
●機械的アロディニア(接触性アロディニアとしても知られる)
- 静的機械的アロディニア-軽い接触/圧力に対する痛み
- 動的機械的アロディニア-撫でることに対する痛み
●温熱性(温感又は冷感)アロディニア-通常は温和である患部の皮膚温度による痛み
皮下、静脈内、動脈内、筋肉内、髄腔内、又は他の適切な部位への注射、
連続注入(髄腔内カテーテル)、
マイクロカプセル化、又は徐放性ポリマーインプラント、
カプセル化細胞及び非カプセル化細胞グラフト(例えば、生体外遺伝子治療)、及び
吸入。
i)配列番号10に記載のアミノ酸配列を有するポリペプチド、及び1乃至5個の余分なアミノ酸を有するポリペプチドと、
ii)配列番号11に記載のアミノ酸配列を有するポリペプチド、及び1乃至5個の余分なアミノ酸を有するポリペプチドと、
iii)配列番号12に記載のアミノ酸配列を有するポリペプチド、及び1乃至5個の余分なアミノ酸を有するポリペプチドと、
iv)前記ポリペプチドの変異体と、からなる群から選択され、ここで、選択された配列において指定された任意のアミノ酸が異なるアミノ酸へ変化するのは、このように変化する配列内のアミノ酸残基が20個以内の場合である。
-STA、NEQK、NHQK、NDEQ、QHRK、MILV、MILF、HY、FYW
-CSA、ATV、SAG、STNK、STPA、SGND、SNDEQK、NDEQHK、NEQHRK、VLIM、HFY
a)配列番号7から選択されるアミノ酸配列と、
b)配列番号7に対して少なくとも70%の配列同一性を有する、配列番号7のアミノ酸配列の配列変異体と、
c)配列番号7に対して少なくとも70%の配列同一性を有する、a)乃至b)の何れかの少なくとも50個の隣接アミノ酸の生物活性フラグメント。
a)配列番号1、13、及び16からなる群から選択されるヌクレオチド配列と、
b)配列番号1、13、及び16からなる群から選択されるヌクレオチド配列に対して少なくとも70%の配列同一性を有するヌクレオチド配列と、
c)配列番号1、13、及び16からなる群から選択される配列の少なくとも150個の隣接ヌクレオチドの核酸配列と、からなる群から選択されるヌクレオチド配列を含む。
配列リスト番号
配列番号1:ヒトコメチンcDNA
配列番号2:ヒトコメチンタンパク質(シグナルペプチドを含む)
配列番号3:マウスコメチンcDNA
配列番号4:マウスコメチンタンパク質(シグナルペプチドを含む)
配列番号5:ラットコメチンcDNA
配列番号6:ラットコメチンタンパク質(シグナルペプチドを含む)
配列番号7:ヒト成熟コメチンタンパク質
配列番号8:マウス成熟コメチンタンパク質
配列番号9:ラット成熟コメチンタンパク質
配列番号10:ヒトコメチンコアフラグメント
配列番号11:マウスコメチンコアフラグメント
配列番号12:ラットコメチンコアフラグメント
配列番号13:hコメチンオープンリーディングフレーム
配列番号14:mコメチンオープンリーディングフレーム
配列番号15:rコメチンオープンリーディングフレーム
配列番号16:ヒトCDS成熟コメチン
配列番号17:マウスCDS成熟コメチン
配列番号18:ラットCDS成熟コメチン
配列番号19:ウシコメチンタンパク質(シグナルペプチドを含む)
配列番号20:ニワトリコメチンタンパク質(シグナルペプチドを含む)
配列番号21:カエルコメチンタンパク質(シグナルペプチドを含む)
配列番号22:ゼブラフィッシュコメチンタンパク質(シグナルペプチドを含む)
配列番号23:ヒトMETRNタンパク質(シグナルペプチドを含む)
配列番号24:マウスMETRNタンパク質(シグナルペプチドを含む)
配列番号25:ラットMETRNタンパク質(シグナルペプチドを含む)
Kupers,R., Yu,W., Persson,J.K., Xu,X.J., and Wiesenfeld-Hallin,Z. (1998). Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain. Pain 76, 45-59.
Storkson,R.V., Kjorsvik,A., Tjolsen,A., and Hole,K. (1996). Lumbar catheterization of the spinal subarachnoid space in the rat. J. Neurosci. Methods 65, 167-172.
Human: ヒト
Cow: ウシ
Mouse: マウス
Rat: ラット
Chicken: ニワトリ
Zenopus: アフリカツメガエル
Zebrafish: ゼブラフィッシュ
[図4]
Paw withdrawal threshold: 足引っ込め閾値
Days: 日数
Cometin: コメチン
Vehicle: ビヒクル
[図5]
Cold score: 冷感スコア
Days: 日数
Cometin: コメチン
Vehicle: ビヒクル
[図6]
Body weight: 体重
Days: 日数
Cometin: コメチン
Vehicle: ビヒクル
Claims (42)
- 以下の群から選択されるアミノ酸配列を含む単離ポリペプチドを含有する、アロディニア、痛覚過敏、自発痛、及び/又は幻痛の治療方法において使用するための医薬:
i. 配列番号7のアミノ酸配列と、
ii. 配列番号7に対して少なくとも90%の配列同一性を有する、配列番号7のアミノ酸配列の生物活性配列変異体。 - 前記ポリペプチドは、配列番号7の配列を有するタンパク質に対して少なくとも95%、又は少なくとも98%の配列同一性を有する、請求項1に記載の医薬。
- 本明細書に記載の変異体ポリペプチドであり、アミノ酸置換のいずれもが保存的置換である、請求項1又は2に記載の医薬。
- 配列番号7の保存システインを配列番号7と同じ位置に含む、請求項1〜3の何れかに記載の医薬。
- 前記ポリペプチドは、少なくとも1つの分子内システイン架橋を形成することが可能である、請求項1〜4の何れかに記載の医薬。
- 医薬的に許容可能な担体、希釈剤、又は賦形剤を含む、請求項1〜5の何れかに記載の医薬。
- 無菌且つ等張性である、請求項1〜6の何れかに記載の医薬。
- 徐放性剤形での投与用に調製される、請求項1〜7の何れかに記載の医薬。
- 有痛性糖尿病神経障害、帯状疱疹後神経痛、又は坐骨神経痛と診断された患者への投与用である、請求項1〜8の何れかに記載の医薬。
- 温熱性アロディニアの治療用である、請求項1〜9の何れかに記載の医薬。
- 冷感アロディニアの治療用である、請求項10記載の医薬。
- 機械的アロディニアの治療用である、請求項1〜11の何れかに記載の医薬。
- 自発痛の治療用である、請求項1〜12の何れかに記載の医薬。
- 痛覚過敏の治療用である、請求項1〜13の何れかに記載の医薬。
- 前記痛覚過敏は、温熱性痛覚過敏である、請求項14記載の医薬。
- 前記温熱性痛覚過敏は、冷感痛覚過敏である、請求項15記載の医薬。
- 前記痛覚過敏は、機械的痛覚過敏である、請求項14記載の医薬。
- 治療対象の前記患者は、体重が低下しない、請求項1〜17の何れかに記載の医薬。
- 治療対象の前記患者は、哺乳類、霊長類、又はヒトである、請求項1〜18の何れかに記載の医薬。
- 全身投与、静脈注射又は皮下注射用である、請求項1〜19の何れかに記載の医薬。
- 非経口注射、皮下注射又は髄腔内投与により施される、請求項1〜20の何れかに記載の医薬。
- 体重に対して1μg/kg乃至10,000μg/kg、又は1μg/kg乃至7,500μg/kg、又は1μg/kg乃至5,000μg/kg、又は1μg/kg乃至2,000μg/kg、又は1μg/kg乃至1,000μg/kg、又は1μg/kg乃至700μg/kg、又は5μg/kg乃至500μg/kg、又は10μg/kg乃至100μg/kgの投与量で投与される、請求項1〜21の何れかに記載の医薬。
- 前記投与は、毎日繰り返される、請求項1〜22の何れかに記載の医薬。
- 前記投与は、少なくとも週に1乃至3回、又は週に2乃至5回、又は週に3乃至6回繰り返される、請求項1〜23の何れかに記載の医薬。
- アロディニア及び/又は痛覚過敏の治療方法において使用するためのものである、請求項1〜24の何れかに記載の医薬。
- 以下の群から選択されるアミノ酸配列を含むポリペプチドをコードする単離核酸分子を含む、アロディニア、痛覚過敏、自発痛、及び/又は幻痛の治療方法において使用するための核酸医薬:
i. 配列番号7のアミノ酸配列と、
ii. 配列番号7に対して少なくとも90%の配列同一性を有する、配列番号7のアミノ酸配列の生物活性配列変異体。 - 前記コードされたポリペプチドは、配列番号7の配列に対して少なくとも95%、又は少なくとも98%の配列同一性を有する、請求項26記載の核酸医薬。
- 前記単離核酸分子は、
i. 配列番号1、13、及び16からなる群から選択されるヌクレオチド配列と、
ii. 配列番号1、13、及び16からなる群から選択されるヌクレオチド配列に対して少なくとも90%の配列同一性を有するヌクレオチド配列と、からなる群から選択されるヌクレオチド配列を含む、請求項26又は27に記載の核酸医薬。 - アロディニア及び/又は痛覚過敏の治療方法において使用するためのものである、請求項26〜28の何れかに記載の核酸医薬。
- 以下の群から選択されるアミノ酸配列を含むポリペプチドをコードする単離核酸分子を含む、アロディニア、痛覚過敏、自発痛、及び/又は幻痛の治療方法において使用するための遺伝子治療ベクター:
i. 配列番号7のアミノ酸配列と、
ii. 配列番号7に対して少なくとも90%の配列同一性を有する、配列番号7のアミノ酸配列の生物活性配列変異体。 - 更に、前記単離核酸分子に作動可能となるように連結されたプロモーターを含む、請求項30記載の遺伝子治療ベクター。
- 前記プロモーターは、CAG、CMV、ヒトUbiC、JeT、RSV、EF-1α、SV40、及びMt1からなる群から選択される構成的プロモーター、又は、Tet-On、Tet-Off、Mo-MLV-LTR、Mx1、プロゲステロン、RU486、及びラパマイシン誘導性プロモーターからなる群から選択されるような誘導性プロモーターである、請求項31記載の遺伝子治療ベクター。
- 前記遺伝子治療ベクターは、アデノ随伴ウイルス、アルファウイルス、アデノウイルス、バキュロウイルス、HSV、コロナウイルス、ウシパピローマウイルス、及びMo-MLVからなる群から選択される、請求項30〜32の何れかに記載の遺伝子治療ベクター。
- 前記遺伝子治療ベクターは、アロディニア及び/又は痛覚過敏の治療方法において使用するためのものである、請求項30〜33の何れかに記載の遺伝子治療ベクター。
- 請求項30〜34記載の遺伝子治療ベクターにより形質転換又は形質導入された単離株化細胞を含む、アロディニア、痛覚過敏、自発痛、及び/又は幻痛の治療方法において使用するための細胞医薬。
- 前記単離株化細胞は、哺乳類細胞、霊長類細胞、又はヒト細胞である、請求項35記載の細胞医薬。
- 前記単離株化細胞は、ARPE-19細胞、不死化網膜色素上皮細胞、不死化ヒト線維芽細胞、及び不死化ヒト星状細胞からなる群から選択される、請求項36記載の細胞医薬。
- 前記単離株化細胞は、幹細胞、ヒト神経幹細胞又はヒト神経前駆細胞、ヒトグリア幹細胞又はヒトグリア前駆細胞、及び胎生幹細胞からなる群から選択される、請求項36記載の細胞医薬。
- ヒト胚に由来していない、請求項36〜38の何れかに記載の細胞医薬。
- 分泌される生物活性コメチンの患者への送達による、アロディニア、痛覚過敏、自発痛、及び/又は幻痛の治療方法において使用するための移植可能な生体適合性カプセルであって、当該カプセルは、
i. 生体適合性の外膜及び内核を含み、
ii. 前記内核は、請求項35〜39何れかに記載の細胞医薬を含む。 - 前記生体適合性の膜は、前記分泌される生物活性コメチンを通過させる半透性外膜である、請求項40のカプセル。
- 前記内核は、マトリクスを含む、請求項40又は41記載のカプセル。
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