TW202408563A - 治療視神經病變的方法 - Google Patents
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Abstract
本揭露提供一種用於治療視神經病變之醫藥組成物,其包含長效顆粒性白血球集落刺激因子及其藥學上可接受之賦形劑。本揭露亦提供於有其需要之個體中治療視神經病變之方法,其包含將該長效顆粒性白血球集落刺激因子給藥至該個體。
Description
本揭露整體上關於視神經病變之治療,尤係關於以長效顆粒性白血球集落刺激因子(granulocyte-colony stimulating factor,G-CSF)治療視神經病變之方法。
視神經(optic nerve,ON)包含自視網膜出現的神經細胞軸突,自眼睛的視神經盤離開,進入大腦的視覺皮質區,於此處將來自眼睛的輸入處理成視覺。視神經病變係指任何原因所導致之視神經損傷。神經細胞的損傷與死亡為視神經病變之主要特徵。主要症狀為視覺受損及受到影響之眼睛所見顏色呈隱約地褪色。
創傷性視神經病變(traumatic optic neuropathy,TON)表示外傷後繼發的視神經損傷,根據創傷部位(例如ON頭、眼眶內、小管內或顱內創傷)或取決於創傷的類型(例如直接或間接創傷)[1,2]進行識別。直接創傷性視神經病變顯現對視神經解剖構造的嚴重破壞,例如高速穿透眼眶的拋射物,或為視神經撕脫(avulsion)的結果[3]。自遠處向視神經傳遞力道可導致間接創傷性視神經病變而無明顯可見的創傷。創傷後,視網膜神經節細胞(retinal ganglion cells,RGCs)的軸突會立即減少,這是導致神經元減少的不可逆作
用[4]。於直接物理性創傷與血管缺血後,可觀察到繼發的視神經管狹小範圍內之視神經腫脹[5]。接續出現的症狀進一步破壞供給倖存視網膜神經節細胞之已受損的血液供給,繼而發展凋亡性細胞死亡[6]。
創傷性視神經病變為鈍性或穿刺性頭部創傷後視力喪失之原因,發生率為0.7%至2.5%。英國的一項全國性創傷性視神經病變流行病學調查發現,一般人群中的最低盛行率為1,000,000分之一。絕大多數受影響的患者為年輕成年男性(79%至85%)。車輛及腳踏車事故(49%)、跌倒(27%)、攻擊(13%)則是最常導致創傷性視神經病變的原因[7,8],在兒科人群中,跌倒(50%)和道路交通事故(40%)繼發之創傷性視神經病變病例佔大多數[9]。
由於創傷性視神經病變的確切病理生理學尚不清楚,其處置方式仍有爭議[10]。三種常見的處置為住院觀察、給予皮質類固醇及/或視神經管減壓手術。在文獻中,相較於住院觀察,皮質類固醇與視神經管減壓手術未顯示任何顯著較佳的視覺結果[11]。然而,統合分析所得出的結論為皮質類固醇、視神經管減壓手術或兩者,相較於完全沒有治療來的好[12]。這些醫療或手術介入的結果尚不確定,且可能有嚴重副作用或併發症[13-15]。迄今,沒有研究能夠證實創傷性視神經病變之特定處置方法的有效性。
是以,目前尚缺乏對於創傷性視神經病變病患的有效治療建議,而開發針對創傷性視神經病變病患之替代療法迫在眉睫。
有鑑於此,本揭露提供之長效顆粒性白血球集落刺激因子(G-CSF)能對視神經提供神經保護,從而防止視力受損、阻止視力受損的進展、
改善視力受損與其伴隨的視神經病變。於至少一個方面,本揭露提供治療有其需要之個體之視神經病變的醫藥組成物,其中,該醫藥組成物包括有效量的長效白血球集落刺激因子及其藥學上可接受的賦形劑。
於本揭露之至少一個具體態樣中,視神經病變可能是缺血性視神經病變、視神經炎、壓迫性視神經病變、浸潤性視神經病變、創傷性視神經病變、粒線體視神經病變、營養性視神經病變、中毒性視神經病變、放射性視神經病變、遺傳性視神經病變或其任意之組合。
於本揭露之至少一個具體態樣中,該長效白血球集落刺激因子係選自由重組白血球集落刺激因子、複合白血球集落刺激因子、白血球集落刺激因子融合蛋白或其任意之組合所組成群組的至少一者。在一些具體態樣中,該複合白血球集落刺激因子是連接至白血球集落刺激因子的非免疫原性親水聚合物。在一些具體態樣中,該非免疫原性親水聚合物共價連接該白血球集落刺激因子。在一些具體態樣中,該白血球集落刺激因子融合蛋白包括融合至選自白蛋白及IgG免疫球蛋白片段的蛋白質之白血球集落刺激因子。在一些具體態樣中,該白血球集落刺激因子與IgG免疫球蛋白Fc片段融合。
於本揭露之至少一個具體態樣中,該非免疫原性親水聚合物係選自由聚乙二醇(polyethylene glycol,PEG)、聚氧丙烯(polyoxypropylene)、聚氧乙烯-聚氧丙烯嵌段共聚物(polyoxyethylene-polyoxypropylene block copolymer)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、聚丙烯醯嗎啉(polyacyloylmorpholine)、多醣、胺羰聚乙二醇(aminocarbamyl polyethylene glycol)或其任意之組合所組成之組的至少一者。於一些具體態樣中,該長效白血球集落刺激因子為聚乙基化白血球集落刺激因子(PEG-GCSF)。
於本揭露之至少一個具體態樣中,該醫藥組成物係經由口服、玻璃體內注射、腹膜內注射、靜脈注射、皮內注射、肌肉注射、皮下注射或經皮給藥。在一些具體態樣中,該醫藥組成物經由玻璃體內注射給藥。
於本揭露之至少一個具體態樣中,該長效白血球集落刺激因子的給藥有效量範圍為約1μg至約2μg,例如約1.1μg至約1.9μg、約1.2μg至約1.8μg、約1.3μg至約1.7μg、約1.4μg至約1-6μg及約1μg至約1.5μ8。於一些具體態樣中,長效白血球集落刺激因子的給藥有效量為約1μg、約1.1μg、約1.2μg、約1.3μg、約1.4μg、約1.5μg、約1.6μg、約1.7μg、約1.8μg、約1.9μg或約2.0μg。在一些具體態樣中,該長效白血球集落刺激因子給藥至人類的有效量範圍為約1μg至2μg。
於本揭露之至少一個具體態樣中,該長效白血球集落刺激因子的給藥有效量範圍為約10ng至100ng,例如約15ng至約95ng、約20ng至約80ng、約25ng至約75ng、約30ng至約60ng、約35ng至約55ng。在一些具體態樣中,該長效白血球集落刺激因子的給藥有效量為約10ng、約15ng、約20ng、約25ng、約26ng、約27ng、約28ng、約29ng、約30ng、約31ng、約32ng、約33ng、約34ng、約35ng、約36ng、約37ng、約38ng、約39ng、約40ng、約45ng、約50ng、約60ng、約70ng、約80ng、約90ng或約100ng。在一些具體態樣中,該長效白血球集落刺激因子給藥至大鼠的有效量範圍為約1μg至約2μg。
於本揭露之至少一個具體態樣中,該醫藥組成物於治療期間給藥至個體1至4次,例如於治療期間給藥2次及於治療期間給藥3次。於一些具體態樣中,該醫藥組成物於治療期間僅給藥1次至個體。於一些具體態
樣中,本揭露的方法包括在發生視神經病變後例如一個月內,以單次注射給藥該醫藥組成物至個體。
顆粒性白血球集落刺激因子係藉由視網膜神經節細胞抗細胞凋亡和抗視神經發炎的雙重作用,對視神經擠壓傷(optic nerve crush,ONC)模型和前部缺血性視神經病變(anterior ischemic optic neuropathy,rAION)之大鼠模型具有神經保護效果。此外,白血球集落刺激因子及其受體在中樞神經系統(CNS)和視網膜神經元中為內生性配體。於一些具體態樣中,使用白血球集落刺激因子治療可藉由自分泌保護機制來活化創傷性視神經損傷的大鼠模型中之PI3K/AKT促存活訊息傳遞,從而保護視網膜神經節細胞不讓其死亡。然而,有些白血球集落刺激因子的治療為每日經皮下注射白血球集落刺激因子一次,總共五日,這會突然地誘發白血球增多症的副作用。此外,有些藉由玻璃體內注射白血球集落刺激因子的治療需要重複注射,會有害地提高發炎和感染的機率。於本揭露之至少一個具體態樣中,顯示在治療視神經病變中給予長效白血球集落刺激因子並無副作用。例如,單一劑PEG-GCSF玻璃體內注射展現對創傷性視神經病變的良好神經保護效果。
由下列實施例的描述結合圖式,此等和彼等態樣係顯而易見者,儘管於不悖離本揭露範圍下可能影響其中之變更與修飾。
結合圖式閱讀以下實施例之描述,可更充分地理解本揭露。
圖1A和1B顯示PEG-GCSF在正常大鼠中對閃光視覺誘發電位(FVEP)的影響。各組P1-N2的振幅表示為平均值±SD。
圖2顯示PEG-GCSF在視神經擠壓傷(ONC)模型中對白血球增多症的影響,其白血球(WBC)數在玻璃體內注射PEG-GCSF(PG)後第7天測定。各組數據表示為平均值±SD。
圖3A和3B顯示PEG-GCSF在視神經擠壓傷(ONC)模型中對閃光視覺誘發電位(FVEP)的影響。各組P1-N2振幅表示為平均值±SD。採用Mann-Whitney U檢驗且星號(*)表示p<0.05。ONC:視神經擠壓;PBS:磷酸鹽緩衝生理食鹽水。
圖4顯示各組藉由FluoroGold逆向標定的平貼中央視網膜和視網膜神經節細胞的型態測量之代表圖。各組數據表示為平均值±SD。使用Mann-Whitney U檢驗且星號(*)表示p<0.05。ONC:視神經擠壓傷;PBS:磷酸鹽緩衝生理食鹽水。
圖5A至5C顯示在視神經擠壓傷(ONC)模型中PEG-GCSF對發炎性浸潤與小膠質細胞活化的評估。圖5A顯示在ON縱向切片中的ED1和離子化鈣結合銜接分子1(ionized calcium binding adaptor molecule 1,IBA1)的染色。ED1陽性細胞標定為紅色,且IBA1陽性細胞標定為綠色。視神經的細胞核由4',6-二脒基-2-苯基吲哚(4’,6-diamidino-2-phenylindole,DAPI)染為藍色。圖5B和5C顯示每個高倍視野(HPF)中ED1陽性(ED1+)細胞和IBA1陽性(IBA1+)細胞的數量。各組數據表示為平均值±SD。使用Mann-Whitney U檢驗且星號(*)表示p<0.05。ONC:視神經擠壓傷;PBS:磷酸鹽緩衝生理食鹽水。
圖6顯示PEG-GCSF在ONC模型中對視網膜神經節細胞凋亡的影響,由TUNEL測定分析視網膜神經節細胞層中視網膜神經節細胞的死
亡。綠色的凋亡細胞(TUNEL陽性細胞)由TUNEL染色所染,藍色的視網膜神經節細胞細胞核是由DAPI染色所染。呈現每個高倍視野(HPF)的TUNEL陽性(TUNEL+)細胞的數量。各組數據表示為平均值±SD。使用Mann-Whitney U檢驗且星號(*)表示p<0.05。ONC:視神經擠壓傷;PBS:磷酸鹽緩衝生理食鹽水;GCL:神經節細胞層;INL:內核層。
圖7A顯示受試者在Neulasta治療介入前、第1天、第7天、第30天與第90天的logMAR BCVA。
圖7B顯示受試者的Neulasta治療之穩定的結果、改善的結果與降低的結果之比例。
圖8顯示受試者在Neulasta治療介入前、第1天、第7天、第30天與第90天的logMAR BCVA。
圖9顯示受試者在治療介入前、第30天和第90天的眼壓。
圖10顯示受試者在治療介入前、第30天和第90天的視野MD(-dB)。
圖11顯示受試者在治療介入前、第1天、第7天、第30天、第90天的WBC數量。
圖12顯示受試者初始BCVA、初始視野(db)、治療後90天的BCVA與治療後90天的視野(dB)。
使用下揭實例以例示及說明本揭露內容。基於本說明書所揭露內容,所屬領域中具有通常知識者可輕易地推及本揭露之其他優點與效果。
本揭露亦可依不同示例描述之作法加以實施或應用。於不悖離本揭露範圍下,可修飾或變更下揭實例,俾供不同方面及應用。
須留意的是,本揭露所使用的單數冠詞「一」、「一個」與「該」,除非明確地與無疑義地表達僅限於單一個指示物,否則亦包括複數個指示物。除非上下文另外明確指出,否則用語「或」與用語「及/或」可交替使用。
在本文中,用語「包括」或「包含」用於指包括在本揭露中之組成物、方法與其各自的組分,但對納入未指定的元素也是開放的。
本揭露有關在有其需要之個體中治療視神經病變之方法。於本揭露中,令人驚訝地發現經玻璃體內注射長效白血球集落刺激因子,如PEG-GCSF,能在視神經病變發生後保留視覺功能及視網膜神經節細胞密度。還發現經玻璃體內注射長效白血球集落刺激因子能抑制巨噬細胞浸潤視神經及視網膜神經節細胞凋亡。因此,本揭露提供一種藉由將有效量之長效白血球集落刺激因子給藥至有其需要的個體以治療視神經病變之方法。
於一些具體態樣中,視神經病變可選自但不限於:創傷性神經病變(可由任意類型的對視神經之創傷所引起)、缺血性神經病變(如非動脈炎性前部缺血性視神經病變(nonarteritic anterior ischemic optic neuropathy,NAION)、前部缺血性視神經病變(anterior ischemic optic neuropathy,AION)、後部缺血性視神經病變(posterior ischemic optic neuropathy)、放射性視神經病變(radiation optic neuropathy,RON)、視神經炎、壓迫性視神經病變、浸潤性視神經病變、粒線體視神經病變、營養性視神經病變、中毒性視神經病變、遺傳性視神經病變及類似者。
在本文中,用語「長效白血球集落刺激因子」旨在指具生理活性之白血球集落刺激因子相較天然形式白血球集落刺激因子,具有延長的作用持續時間的蛋白質構建體。在本文中,用語「長效」係指相較天然形式有較長的作用時間。
為了本揭露所使用,白血球集落刺激因子具有人類白血球集落刺激因子胺基酸序列或密切相關的類似物。可用於本揭露中的白血球集落刺激因子可為天然存在的蛋白質或重組蛋白質。此外,白血球集落刺激因子可為經歷胺基酸添加、刪除或插入的突變體,只要該突變對其原始生物活性沒有顯著的影響。
於本揭露之至少一個具體態樣中,長效白血球集落刺激因子可以是重組白血球集落刺激因子、複合白血球集落刺激因子或白血球集落刺激因子融合蛋白。用語「複合白血球集落刺激因子」或「白血球集落刺激因子複合物」係指其中白血球集落刺激因子與一種或多種非免疫原性親水聚合物共價連接的構建體。用語「白血球集落刺激因子融合蛋白」係指一種構建體,其中白血球集落刺激因子與一種或多種蛋白質或其片段、模體或結構域,例如白蛋白和IgG免疫球蛋白Fc片段,透過使用重組技術進行融合。
於本揭露之至少一個具體態樣中,長效白血球集落刺激因子可藉由將白血球集落刺激因子與聚乙二醇相連接形成聚乙基化白血球集落刺激因子(PEG-GCSF)來製備。
在本文中,用語「給藥」或「投藥」係指透過將有效藥劑(例如長效白血球集落刺激因子)經由至少能夠部分送達所欲部位的方法或途徑,將該有效藥劑置於個體體內,從而產生所欲之效果。本文所述的有效藥劑可經
由所屬領域中具通常知識者習知的合適途徑投藥,但不限於:口服或非消化道給藥途徑,如玻璃體內注射、腹膜內注射、靜脈注射、皮內注射、肌肉注射、皮下注射或經皮給藥途徑。
於本揭露之至少一個具體態樣中,長效白血球集落刺激因子可配製為用於給藥的醫藥組成物。該醫藥組成物包括例如有效量的上述長效白血球集落刺激因子作為有效藥劑及其藥學上可接受的載體。
在本文中,用語「藥學上可接受的賦形劑」係指藥學上可接受的物質、組成物或載體,例如稀釋劑、崩解劑、黏合劑、潤滑劑、助流劑與界面活性劑,其不會阻礙有效藥劑的生物活性或特性,且相對無毒性,意即,可以將該物質施用於個體,但不會引起不欲之生物學效應,或以有害方式與包含它的藥物組成物的任何組分交互作用。
在本文中,用語「有效量」係指賦予治療對象所欲治療效果(例如保留視覺功能)所需的有效藥劑(例如長效白血球集落刺激因子)的量。如本領域中具有通常知識者所習知者,有效量會根據給藥途徑、賦形劑的使用、與其他治療藥劑共同使用的可能性以及待治療的病狀而有所不同。
在本文中,用語「治療」係指使用有效藥劑於有其需要之個體,目的是治癒、減輕、緩解、補救、改善、降低或預防疾病、其症狀或其傾向。
在本文中,用語「個體」係指哺乳動物,例如人類,但也可以是其他動物,例如家畜(如犬、貓等)、農畜(如牛、羊、豬、馬等)或是實驗動物(如猴子、齧齒動物、鼠、兔、天竺鼠等)。用語「受試者」或「病患」係指被懷疑患有或患有疾病或病症的「個體」。此外,用語「受試者」、「病患」、「個體」可互換使用。
許多示例已被用於闡明本揭露。下揭實施例不應視為本揭露範圍之限制。
實施例
下面詳細描述實施例1至6中使用的材料與方法。本揭露中所使用但未加以註釋之材料係可商購而得者。
(1)研究用動物
研究使用之重量為150至180g的Wistar大鼠(公鼠;7至8週齡),購自台灣BioLASCO公司的繁殖群。動物照護和實驗流程遵循視覺與眼科研究協會(Association for Research in Vision and Ophthalmology,ARVO)關於在眼科和視覺研究中使用動物的聲明。將大鼠飼養於受控的12小時切換的明暗循環中,且在恆溫(23%)和恆濕(55%)的受控環境中可自由取得食物和水。所有手術在動物全身麻醉下執行,由肌肉注射K他命(100mg/kg體重)和甲苯噻嗪(10mg/kg體重;Sigma,St.Louis,MO,USA)混合物來達成。花蓮慈濟醫院實驗動物照護及使用委員會(Institutional Animal Care and Use Committee at Hualien Tzu-Chi Hospital)(台灣)核准所有動物實驗。
(2)視神經擠壓傷實驗
ONC是由前述方法所導致[16]。簡言之,經過特定麻醉和局部點Alcaine眼藥水,裸露且分離右眼的視神經。小心地執行手術以避免損害視神經周圍小血管。隨後將血管夾(60-g微血管夾,World Precision Instruments,FL,USA)標準ONC應用至距離眼球後面2mm處的視神經30秒。手術過後,投予Tobradex眼藥膏(Alcon,Puurs,Belgium)。最後將大鼠置於37℃電熱
毯上康復。假手術組的大鼠接受假的右眼手術,即裸露視神經但不經歷擠壓傷手術。
(3)研究設計
將視神經擠壓傷大鼠進一步分配為四組。第一組大鼠在ONC後第0天時經玻璃體內注射一劑(5μL)PEG-GCSF(Neulasta,Amgen,Inc.)(n=36)。第二組大鼠在ONC後第0天和第14天時經玻璃體內注射共兩劑(5μL*2)的PEG-GCSF(n=36)。第三組大鼠在ONC後第0、14、28天時經玻璃體內注射共三劑(5μL*3)的PEG-GCSF。第四組大鼠經歷過手術但不投予任何治療(n=12)。另外12隻未經歷手術的大鼠為假手術組。透過使用FluoroGold逆行標記測量視網膜神經節細胞密度,並在ONC後2、4、6和8週透過閃光視覺誘發電位(FVEP)評估視覺功能。還進行視網膜神經節細胞層中的末端去氧核苷酸轉移酶dUTP切口末端標記(TUNEL)測定。透過免疫組織化學(IHC)研究視神經切片中的外源性巨噬細胞(ED1)標記和小膠質細胞標記(IBA1)。
(4)PEG-GCSF的玻璃體內注射
如前面所述執行PEG-GCSF的玻璃體內注射(Neulasta,Amgen,Inc.)[17]。簡言之,以肌肉注射K他命-甲苯噻嗪(分別是40mg/kg和4mg/kg)混和物麻醉大鼠。於顯微鏡底下將單次3μL之30ng PEG-GCSF經玻璃體內注射至視神經擠壓傷的大鼠眼睛,以避免晶狀體損傷。使用33-G針(Hamilton7747-01與Gastight注射筒;IA2-1701RN 10-1L SYR;Hamilton Co.,Hamilton,KS,USA)執行玻璃體內注射。玻璃體內注射一天後使用Tono-Pen(Reichert Technologies,Depew,NY,USA)測量眼壓(IOP)。
(5)利用FluoroGold逆向標記測量存活的視網膜神經節細胞
實驗流程如先前研究所述[16-19]。簡言之,在大鼠犧牲前一週使用逆向標記視網膜神經節細胞,以避免因混合已標記的視網膜神經節細胞和被染劑吞沒之巨噬細胞和小膠質細胞,致使過度計算視網膜神經節細胞。在距離視神經乳頭中心1或3mm處計算視網膜的視網膜神經節細胞,以分別提供中心和中外圍視網膜神經節細胞的密度。在各視網膜中心區域(約佔視網膜中心區域40%)和中外圍區域(約佔視網膜中外圍區域30%)隨機選擇5個62,500μm2區域,藉由ImageMaster-pro10(Amersham Biosciences)進行計數(每組n=6)。
(6)閃光視覺誘發電位
實驗流程如先前研究所述[16-19]。簡言之,梗塞形成兩週後記錄視覺誘發電位。以視覺電子診斷系統(Espion,Diagnosys LLC,Littleton,MA,USA)測量FVEP。根據前一份報告中對第一個正向小波(P1)的定義,在FVEP測量中識別並記錄P1波。比較各組(各組n=6隻)P1波的潛伏期和P1-N2振幅來評估視覺功能。
(7)視神經之製備
實驗流程如先前研究所述[16-19]。簡言之,在第四週老鼠犧牲時,收集視交叉和眼球之間約5至7mm長的一段視神經。神經立即冷凍於-70℃以用於組織學和IHC研究。
(8)視網膜片段之製備
實驗流程如先前研究所述[16-19]。簡言之,將含有鞏膜和視網膜的眼杯,在室溫下4%三聚甲醛中固定兩小時。各視網膜杯靠近視神經盤處被
切成兩部分。將組織在30%蔗糖中脫水過夜並保存於-20℃直到進一步處理。將視網膜杯的一部份固定在4%三聚甲醛中進行切片。
(9)原位TUNEL檢測用於測量細胞凋亡
實驗流程如先前研究所述[16-19]。簡言之,將視網膜冷凍切片經TUNEL檢測試劑組(DeadEnd Fluorometric TUNEL System;Promega Corporation,Madison,WI,USA)染色。以10高倍視野(HPF,×400倍放大)計算各樣本的神經節細胞層(GCL)中TUNEL陽性細胞。
(10)ED1/IBA之IHC的發炎反應測量。
實驗流程如先前研究所述[16-19]。ED1抗體可對抗外部巨噬細胞和內部小膠質細胞。IBA1抗體對內部小膠質細胞有專一性反應。視神經冷凍切片經ED1/IBA1之IHC處理。為了比較,在視神經病變部位的六個HPF(×400倍放大)中計數ED1/IBA1陽性細胞。
實施例1iPEG-GCSF治療之安全測試
玻璃體內注射PEG-GCSF的安全性藉由正常Wistar大鼠測試。在本實施例中,經玻璃體內注射PEG-GCSF兩週後,測量FVEP的改變以評估視覺功能。
結果示於圖1A,顯示以PEG-GCSF處理的大鼠的視覺功能與以磷酸鹽緩衝生理食鹽水(PBS)處理的對照組相同。圖1B顯示圖1A中P1-N2振幅的定量數據,且發現兩組間並沒有顯著差異。各組振幅值以平均值±標準差(SD)(各組n=6隻大鼠)表示。
此外,使用23號針頭,藉由心臟穿刺,將血液抽取至肝抗凝血素塗層管。所有操作皆在動物全身麻醉的狀態下執行。也藉由計算視神經
擠壓大鼠經玻璃體內注射PEG-GCSF七天後的白血球(WBCs)數量判定白血球增多症的發生。由Cellometer K2自動細胞記數器(Nexcelom Bioscience LLC;Lawrence,MA,USA)計數WBCs。結果顯示於圖2,發現有或無投藥PEG-GCSF的組別間之白血球數無顯著差異。
由以上的結果可知,經玻璃體內注射PEG-GCSF不但不會影響視覺功能,也不會造成白血球增多症,因此對於視神經病變之治療具有安全性。
實施例2:PEG-GCSF對於ONC大鼠的視覺功能之影響
在本實施例中,在用PEG-GCSF經玻璃體內注射處理ONC大鼠後,透過FVEP評估視覺功能。ONC大鼠在ONC後第0天經玻璃體內注射PEG-GCSF,且在ONC後兩週測量FVEP。
結果示於圖3A和3B,顯示玻璃體內注射PEG-GCSF保留了ONC模型的視覺功能。
實施例3:PEG-GCSF對於ONC大鼠的視網膜神經節細胞密度之影響
在本實施例中,在ONC大鼠經玻璃體內注射PEG-GCSF後計算視網膜神經節細胞的密度。ONC大鼠在ONC後第0天經玻璃體內注射PEG-GCSF,且在ONC後兩週計算視網膜神經節細胞密度。
結果示於圖4,顯示經玻璃體內注射PEG-GCSF保留ONC模型的視網膜神經節細胞密度。
實施例4:PEG-GCSF對於ONC大鼠的免疫反應之影響
在本實施例中,透過評估以PEG-GCSF處理後ONC大鼠中的發炎性浸潤和小膠質細胞活化來評估PEG-GCSF對發炎反應的影響。ONC大鼠在ONC後第0天經玻璃體內注射PEG-GCSF,且在ONC後兩週進行ED1和IBA1的免疫組織化學實驗。
如圖5A至5C圖,顯示藉由PEG-GCSF治療,ED1陽性細胞減少,但IBA1陽性細胞在視神經損傷處卻增多。因此可將PEG-GCSF的治療視為抑制了ONC大鼠巨噬細胞浸潤和誘發ONC大鼠小膠質細胞的活化。
實施例5:PEG-GCSF對於ONC大鼠的視網膜神經節細胞細胞凋亡之影響
在本實施例中,藉由TUNEL檢測來評估ONC大鼠經玻璃體內注射PEG-GCSF後視網膜神經節細胞細胞層的視網膜神經節細胞死亡。ONC大鼠在ONC後第0天經玻璃體內注射PEG-GCSF,且在ONC後兩週進行TUNEL檢測。
結果示於圖6,顯示ONC大鼠有無接受PEG-GCSF治療,並沒有顯著差異。因此可將此視為接受PEG-GCSF治療的ONC動物之視網膜神經節細胞細胞凋亡受到抑制。
實施例6:臨床試驗
本實施例中的臨床試驗為第一期的準實驗試驗,其在花蓮慈濟醫院執行。從本計畫的第二年至計畫的第三年,這個研究招募了8位病人,在花蓮慈濟醫院進行完全面眼科檢查和全身檢查。
間接創傷性視神經病變(ITON)病患定義為最佳矯正視力(best corrected visual acuity,BCVA)、視野、色覺下降,以及相對性瞳孔傳入障礙
(relatively afferent pupillary defect,RAPD)陽性,而眼底和視神經檢查結果正常,且在螺旋式眼眶與視神經管電腦斷層(CT)掃描中沒有觀察到直接視神經創傷的證據。因此,所有病人皆在注射PEG-GCSF(Neulasta,Amgen,Inc.)前一天,由BCVA、視野、色覺、RAPD、FVEP檢查與CT定義為間接創傷性視神經病變病患。病患也在治療前做了腎功能檢查、肝功能檢查、血液凝固檢驗及全血細胞記數檢查。符合招募標準(納入和排除標準可參見以下)的病患會被充分告知治療內容,且會獲得病患的知情同意書。
創傷性視神經病變之納入標準:
a. 20至70歲;
b. 在創傷後1至4週罹患間接創傷性視神經病變;
c. 具有正常視盤的外型和視網膜黃斑的外觀;
d. BCVA降低(Snellen視力檢查表;小於20/200)或C-24中央視野缺失多於10dB(MD<-10dB);
e. 色彩視覺缺陷和RAPD陽性;
f. 於視神經螺旋式眼眶和視神經管電腦斷層掃描下沒有直接創傷的證據;
g. 正常的IOP(10至21mm Hg);
h. 正常的凝血功能[凝血酶原時間(prothrombin time,PT):8至12秒;部份凝血酶原時間(partial thromboplastin time,PTT):23.9至35.5秒;國際標準化比值(international normalized ratio,INR):0.85至1.15)];
k. 合格的腎功能指數[血清中血液尿素氮(BUN):6至22mg/dL;血清肌酸酐:0.7至1.5mg/dL(男性),0.5至1.2mg/dL(女性)]。
排除標準:
a. 有其他會影響視覺功能的損傷;
b. 直接視神經病變;
c. 失去光感;
d. 懷孕和哺乳中的女性;
e. 罹患癌症;
f. 罹患鐮型紅血球疾病;
g. G-CSF過敏反應;
h. 急性傳染病;
i. 良性顱內高壓症狀(1.兩隻眼睛皆有視神經乳頭水腫且沒有自發的靜脈脈動;2.由光學同調斷層掃描(optical coherence tomography,OCT)影像發現視神經乳頭纖維層增厚;
j. 相關的顱內出血或嚴重的顱骨骨折;
k. 依據試驗主持人的觀點,任何其他臨床狀況的病史或證據可能會對病人的安全造成風險或是與研究流程的評估或完成衝突:糖尿病視網膜病變;黃斑部病變;控制不良的高血壓;具有中風和心血管疾病病史;青光眼。
在招募病人進入試驗後,於病人受傷眼睛的玻璃體內注射0.15mL的Neulasta(pegfilgrastim)。首先,在受傷的眼睛中點碘液來抗發炎,接著投予Alcaine眼藥水作為局部麻醉。於1mL的注射筒中注滿0.15mL的Neulasta並搭配30-規的斜面針頭用於玻璃體內注射。在注射Neulasta時,同時執行眼前房減壓術來平衡IOP。收集來自眼前房的水樣液做為後續微陣列分析。投予病人Neulasta之後,每天在原注射的眼睛點Tobradex眼藥水(Alcon)四次。病人住院觀察一天來監測BCVA、IOP、眼底狀況、全血細胞數及任何不良反應。
在為期三個月的接續試驗中,每位病患固定於治療後第一天、第七天、第七天、第三十天、第九十天檢測其BCVA、RPAD、色覺、視野、FVEP中P-100波的潛伏期、視網膜神經纖維層(retinal nerve fiber layer,RNFL)的厚度、IOP及全血細胞數。
如圖7A至7B所示,病患的logMAR BCVA在Neulasta治療後30天有顯著改善。此外,在研究人群中觀察到63%病患經Neulasta治療呈現改善的結果。如圖8所示,病患logMAR BCVA在Neulasta治療後30天有顯著改善,且在Neulasta治療後90天有更顯著改善。如圖12所示,創傷性視神經病變個體初始BCVA為0.1,在BCVA治療後90天BCVA已改善至0.4。
綜上所述,結果揭示給予長效白血球集落刺激因子治療視神經病變的功效,且沒有副作用。例如,單次玻璃體內注射PEG-GCSF於創傷性視神經病變中展現良好的神經保護效果。
雖本揭露中一些實施列已詳述於上文,但所屬領域具通常知識者可能對所示之實施例作各種不同的修飾或更動,且基本上不悖離本揭露之教示與優點。該修飾與更動涵蓋於本揭露範圍內,並於附加的申請專利範圍中闡明。
本說明書中引用和討論的所有參考文獻均以引用其整體併入本文,其程度如同各參考文獻單獨以引用方式併入。
[先前技術文獻]
[1] Sarkies N. “Traumatic optic neuropathy.” Eye (London, England) 2004; 18: 1122-1125.
[2] Steinsapir K.D., et al. “Traumatic optic neuropathy.” Survey of Ophthalmology 1994; 38: 487-518.
[3] Anderson R.L., et al. “Optic nerve blindness following blunt forehead trauma.” Ophthalmology 1982; 89: 445-455.
[4] Gross C.E., et al. “Evidence for orbital deformation that may contribute to monocular blindness following minor frontal head trauma.” Journal of neurosurgery. 1981; 55: 963-966.
[5] Levkovitch-Verbin H. “Animal models of optic nerve diseases.” Eye (London, England) 2004; 18: 1066-1074.
[6] Osborne N.N., et al. “Optic nerve and neuroprotection strategies.” Eye (London, England) 2004; 18: 1075-1084.
[7] Lee V., et al. “Surveillance of traumatic optic neuropathy in the UK.” Eye (London, England) 2010; 24: 240-250.
[8] Levin L.A., et al. “The treatment of traumatic optic neuropathy: the International Optic Nerve Trauma Study.” Ophthalmology 1999; 106: 1268-1277.
[9] Mahapatra A.K., et al. “Traumatic optic neuropathy in children: a prospective study.” Pediatric Neurosurgery 1993; 19: 34-39.
[10] Edwards P., et al. “Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.” Lancet (London, England) 2005; 365: 1957-1959.
[11] Singman E.L., et al. “Indirect traumatic optic neuropathy.” Military Medical Research 2016; 3: 2.
[12] Cook M.W., et al. “Traumatic optic neuropathy. A meta-analysis.” Archives of Otolaryngology-Head & Neck Surgery 1996; 122: 389-392.
[13] Entezari M., et al. “High-dose intravenous methylprednisolone in recent traumatic optic neuropathy; a randomized double-masked placebo-controlled clinical trial.” Graefe’s Archive for Clinical and Experimental Ophthalmology 2007; 245: 1267-1271.
[14] Yu-Wai-Man P., et al. “Surgery for traumatic optic neuropathy.” The Cochrane Database of Systematic Reviews 2005; CD005024.
[15] Steinsapir K.D., et al. “Methylprednisolone exacerbates axonal loss following optic nerve trauma in rats.” Restorative Neurology and Neuroscience 2000; 17: 157-163.
[16] Tsai R.K., et al. “Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in neurodegeneration after optic nerve crush in rats.” Experimental Eye Research 2008; 87: 242-250.
[17] Huang T.L., et al. “Efficacy of intravitreal injections of triamcinolone acetonide in a rodent model of nonarteritic anterior ischemic optic neuropathy.” Investigative Ophthalmology & Visual Science 2016; 57: 1878-1884.
Claims (18)
- 一種治療有其需要之個體之視神經病變之方法,包括向該個體給藥醫藥組成物,其包含有效量的長效顆粒性白血球集落刺激因子及其藥學上可接受的賦形劑。
- 如請求項1所述之方法,其中,該長效白血球集落刺激因子選自由重組白血球集落刺激因子、複合白血球集落刺激因子、白血球集落刺激因子融合蛋白及其任意組合所組成群組的至少一者。
- 如請求項2所述之方法,其中,該複合白血球集落刺激因子為連接至白血球集落刺激因子的非免疫原性親水聚合物。
- 如請求項3所述之方法,其中,該非免疫原性親水聚合物係共價連接至該白血球集落刺激因子。
- 如請求項3所述之方法,其中,該非免疫原性親水聚合物選自由聚乙二醇、聚氧丙烯、聚氧乙烯-聚氧丙烯嵌段共聚物、聚乙烯吡咯烷酮、聚丙烯醯嗎啉、多醣、胺羰聚乙二醇及其任意組合所組成群組之至少一者。
- 如請求項5所述之方法,其中,該長效白血球集落刺激因子為聚乙基化白血球集落刺激因子(PEG-GCSF)。
- 如請求項2所述之方法,其中,該白血球集落刺激因子融合蛋白包括融合至選自由白蛋白及IgG免疫球蛋白片段所組成群組之蛋白質的白血球集落刺激因子。
- 如請求項7所述之方法,其中,該免疫球蛋白片段為該IgG之Fc片段。
- 如請求項1所述之方法,其中,該長效白血球集落刺激因子之有效量為10ng至100ng。
- 如請求項1所述之方法,其中,該長效白血球集落刺激因子之有效量為1μg至2μg。
- 如請求項1所述之方法,其中,該視神經病變係選自由缺血性視神經病變、視神經炎、壓迫性視神經病變、浸潤性視神經病變、創傷性視神經病變、粒線體視神經病變、營養性視神經病變、青光眼視神經病變、中毒性視神經病變、放射性視神經病變、遺傳性視神經病變及其任意組合所組成群組之至少一者。
- 如請求項1所述之方法,其中,該醫藥組成物以口服、玻璃體內注射、腹膜內注射、靜脈注射、皮內注射、肌肉注射、皮下注射或經皮給藥至該個體。
- 如請求項12所述之方法,其中,該醫藥組成物經玻璃體內注射給藥至該個體。
- 如請求項1所述之方法,其中,該醫藥組成物於治療期間給藥至該個體1至4次。
- 如請求項1所述之方法,其中,該醫藥組成物於治療期間以單次注射給藥至該個體。
- 如請求項1所述之方法,其中,該醫藥組成物於視神經病變發生後一個月內給藥至該個體。
- 如請求項1所述之方法,其中,該個體為哺乳動物。
- 如請求項17所述之方法,其中,該哺乳動物選自由齧齒動物、鼠、猴、天竺鼠、犬、貓、牛、羊、豬、馬、兔及人類所組成之群組。
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