TWI614031B - 防止皮膚老化相關症狀的醫藥組合物及其使用方法 - Google Patents
防止皮膚老化相關症狀的醫藥組合物及其使用方法 Download PDFInfo
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- TWI614031B TWI614031B TW101140641A TW101140641A TWI614031B TW I614031 B TWI614031 B TW I614031B TW 101140641 A TW101140641 A TW 101140641A TW 101140641 A TW101140641 A TW 101140641A TW I614031 B TWI614031 B TW I614031B
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本發明提供一種醫藥組合物，其透過表現Cisd2基因來防止皮膚老化相關症狀；並提供一種防止皮膚老化相關症狀的方法，其包含投予一攜帶Cisd2基因之載體；此外，本發明進一步提供另外一種防止皮膚老化相關症狀的醫藥組合物，其包含一CISD2蛋白。
Description
本發明係關於一種防止皮膚老化相關症狀的醫藥組合物及其使用方法。
造成皮膚的老化原因可區分為外在的與內在的因素，內在的因素包含先天基因隨時間排程的老化，影響到陽光曝曬及非曝曬的皮膚，特徵為皮膚變的乾燥、鬆弛、出現皺紋及萎縮。基因上的老化因人而異，所以皮膚隨老化而失去的緊實感及彈性會因個人而有所不同，而且同一個人身上的皮膚也會因不同的部位而有不同程度的老化。
外在的因素主要是由於環境中界所接觸的有害因子，如抽煙、污染物質及陽光。慢性反覆性的曝露於陽光(紫外線A及B)是造成皮膚老化最顯著的外在因子，這種老化又稱之為日光性老化。日光性老化影響部位為曝曬於陽光的皮膚，臨床特徵為皮膚出現細小及粗大皺紋、表面粗糙、乾燥、鬆弛、細小微血管擴張、紫斑以及出現不規則的色素沉澱，如黑斑(老年斑或肝斑)及去色素斑，同時罹患良性及惡性皮膚癌的機率也會增加。
皮膚抗老化一直是生物科技研究重要的課題與目標，在目前皮膚抗老化的避免上面，並無任何有效機制或藥物可以減緩或停止先天性基因的自然老化，因此，目前在臨床上僅能消極的透過預防接觸外在因素的有害分子以減緩皮膚老化過程。
目前於市場上或研究上，有許多研發藥物或機器已被用來改善人體防止接觸外在因素的有害分子以減緩皮膚老化，包括外用抗氧化物如維他命C及E、大豆異黃胴素、茶葉多酚等，使用保溼劑，維他命A酸，果酸等；使用皮膚美白產品如左旋維他命C及麴酸等，注射肉毒桿菌素，玻尿酸或膠原蛋白，也可使用雷射或脈衝光換膚甚至電波拉皮等。
發明人先前的研究中發現，Cisd2基因所表現的蛋白，在細胞內主要位在粒線體的外膜上面。粒線體則是一個含雙層膜(外膜和內膜)的胞器，是細胞製造能量的工廠，當缺少Cisd2蛋白時，在神經退化、肌肉萎縮之前，約在小鼠2週左右(約人類5至8歲)，粒線體的外膜首先出現破損，繼而內膜破損及整個粒線體破壞；粒線體的功能，例如進行有氧呼吸的電子傳遞鏈反應，也相繼受到影響；這些結果顯示Cisd2蛋白是維持粒線體結構完整的關鍵。由於粒線體是細胞製造能量的工廠，對肌肉和神經細胞尤其重要，一旦缺少Cisd2蛋白時，細胞能量的主要供應分子-三磷酸腺苷(ATP)即出現供應不足之失調情形，神經和肌肉首先受到影響，老鼠的老化徵狀因此接踵而來。
Cisd2基因屬於含有CDGSH硫鐵區域(CDGSH iron sulfur domain)家族，此家族基因之CDGSH為一保守區域(conserved domain)，此家族成員包含Cisd1基因、Cisd2基因及Cisd3基因。其中Cisd1會產生CISD1蛋白，此蛋白係為一穿膜蛋白；Cisd3對於第二型糖尿病有關。
Cids2基因位於染色體4q上，會產生CISD2蛋白，並參與在細胞死亡過程。過去研究顯示，缺乏Cisd2基
因的小鼠，其會有早熟、粒線體退化及失能的現象。
有鑑於此，發明人投入相當之心力，探就透過Cisd2基因的調控確認Cisd2基因在皮膚老化症狀是否扮演重要的角色，並研究如何透過調控Cisd2基因及CISD2蛋白的表現來防止皮膚老化症狀，本發明之技術將可成功提供一解決皮膚老化內在因素的方法，對於透過先天基因的調控來解決皮膚抗老化的研究領域提供一個重要的里程碑。
有鑑於此，本發明主要目的之一為在由基因層面提供一種透過增加Cisd2基因表現防止皮膚老化症狀的醫藥組合物及其使用方法，甚而提供一種檢測皮膚老化症狀的方法。
為達上述目的，本發明提供一種醫藥組合物，其係透過表現Cisd2基因來防止皮膚老化症狀。前述防止皮膚老化相關症狀的醫藥組合物，其包含一攜帶Cisd2基因之載體及一藥物上可接受之佐劑。
本發明又提供一種防止皮膚老化相關症狀的方法，其包含投予一攜帶Cisd2基因之載體。
較佳地，其中前述Cisd2基因係為一人類Cisd2基因或一鼠類Cisd2基因。
本發明再提供另外一種防止皮膚老化相關症狀的醫藥組合物，其包含一CISD2蛋白及一藥物上可接受之佐劑。
較佳地，佐劑係為無機佐劑、有機佐劑、合成佐劑或油劑。
較佳地，前述CISD2蛋白係為一人類CISD2蛋白或一鼠類CISD2蛋白。
較佳地，前述載體係為一傳染媒介載體(vector)、一脂質體(liposome)、一聚合物(polymer)、一醫藥可接受之組合物或一可便於攜帶之裝置。
較佳地，前述載體係為一腺病毒載體(adenovirus vector)、反轉錄病毒載體(retrovirus vector)、腺伴隨病毒載體(adeno-associated virus vector)、單純泡疹病毒載體(herpes simplex virus vector)、SV40載體、多瘤病毒載體(polyma virus vector)、乳突病毒載體(papilloma virus vector)、微小核糖核酸病毒載體(Picornavirus vector)、疫苗病毒載體(vaccinia virus vector)、慢病毒載體(lentiviral vector)、α-病毒載體、輔助病毒依賴型腺病毒載體(helper-dependent adenovirus vector)或一質體。
較佳地，前述皮膚老化相關症狀係為細胞損傷、組織損傷、器官失能、皮膚老化相關壽命減少或致癌作用(carcinogenesis)。
較佳地，前述組織包含皮膚組織或脂肪組織，其中皮膚組織包括表皮層、真皮層、脂肪層、毛囊、毛髮以及皮脂腺，而脂肪組織則包括脂肪層。
較佳地，前述皮膚老化相關症狀係為毛囊的減少、皮脂腺減少、皮脂腺細胞核減少、抗水性變弱、皮下脂肪層變薄、毛髮較無光澤、毛髮減少或或灰白毛髮較多。
較佳地，前述投予係透過塗抹於皮膚或頭皮上、體內注射、口服(oral administration)或上述方式之結合。其中上述體內注射又包含下列各種方法：靜脈內注射
(intravenous administration)、皮下注射(subcutaneous administration)、動脈內注射(intra-arterial administration)、肌肉內注射(intra-muscular administration)。
綜上所述，本發明提供二種醫藥組合物及其使用方法，可從Cisd2基因層面調控或利用其蛋白質，進而防止皮膚老化之相關症狀產生。進一步，可應用本發明技術進行皮膚老化症狀的檢測。
本發明所開發之醫藥組合物及其使用方法係透過表現Cisd2基因來防止皮膚老化症狀。前述防止皮膚老化相關症狀的醫藥組合物，其包含一攜帶Cisd2基因之載體。
本發明所述之Cisd2基因係為任何動物之Cisd2基因，於較佳實施例中，其為一人類Cisd2基因或一鼠類Cisd2基因。於較佳實施例中，其Cisd2基因序列係為：SEQ ID NO：1。
本發明所述之CISD2蛋白任何動物之CISD2蛋白，於較佳實施例中，其為一人類CISD2蛋白或一鼠類CISD2蛋白。於較佳實施例中，其CISD2蛋白之胺基酸序列係為：SEQ ID NO：2。
本發明所述「佐劑」係為無機佐劑、有機佐劑、合成佐劑或油劑。包含，但不限於：氫氧化鋁、明礬、微生物、雙股多核苷酸鏈、異丙肌苷、礦物油或花生油等。
本發明所述之「載體」係指任何可便於傳輸之物品，包含，但不限於：為一傳染媒介載體(vector)、一
脂質體(liposome)、一聚合物(polymer)、一醫藥可接受之組合物或一可便於攜帶之裝置。在較佳實施例中，前述載體係為一腺病毒載體(adenovirus vector)、反轉錄病毒載體(retrovirus vector)、腺伴隨病毒載體(adeno-associated virus vector)、單純泡疹病毒載體(herpes simplex virus vector)、SV40載體、多瘤病毒載體(polyma virus vector)、乳突病毒載體(papilloma virus vector)、微小核糖核酸病毒載體(Picornavirus vector)、疫苗病毒載體(vaccinia virus vector)、慢病毒載體(lentiviral vector)、α-病毒載體、輔助病毒依賴型腺病毒載體(helper-dependent adenovirus vector)或一質體。
本發明所述之「皮膚老化相關症狀」係指習知之皮膚老化症狀，包括，但不限於：毛囊的減少、皮脂腺減少、皮脂腺細胞核減少、抗水性變弱、皮下脂肪層變薄、毛髮較無光澤、毛髮減少或灰白毛髮較多。
本發明所「適用之組織」包含各種動物組織，包含，但不限於：皮膚組織或脂肪組織。
本發明所述之「投予方式」可為各種將醫藥組合物傳輸至身體的方式，包含，但不限於：塗抹於皮膚或頭皮上、體內注射、口服(oral administration)或上述方式之結合。其中上述體內注射又包含下列各種方法：靜脈內注射(intravenous administration)、皮下注射(subcutaneous administration)、動脈內注射(intra-arterial administration)、肌肉內注射(intra-muscular administration)。
以下實施例僅為本發明之示例性實施，目的在於闡述本發明詳細實施方式，不在於限制本發明範疇，並且針對本發明實施例使用的實驗操作方式作詳細說明。
收集各種小鼠組織，用含磷酸之10%福爾馬林緩衝液固定，再用石蠟包埋。組織切片(3-4微米)進行蘇木精-伊紅(Hematoxylin-Eosin,H&E)和Masson三色(tirchome)染色(參照：Young and Health,2003)。
將石蠟包埋的骨骼肌(3微米)進行圍脂滴蛋白perilipin的免疫組織染色。先將骨骼肌切片浸泡在含有10mM檸檬酸鈉的抗原修復緩衝液(pH值6.0)中，在微波爐(尚朋堂SM-1220，650W)中加熱10分鐘共2次。然後將切片與原發性抗圍脂滴蛋白(perilipin)抗體(1：100，Cell signaling D418的兔來源多株抗體)培養在25-40℃環境下18~24小時，並以次級抗體(Invitrogen Flour，共軛山羊抗兔抗體)偵測之。再將切片用螢光顯微鏡(OLYPUS BX51)拍攝圖片(搭配軟體：DP Controller Ver.3.1.1.267)。其中細胞核以DAPI(4'-6-二脒基-2-苯基吲哚，Sigma公司)染色並計量。
將各種小鼠組織以含有戊二醛(1.5%)和多聚甲醛(1.5%)的磷酸鹽緩衝混合液(pH7.3)固定。再以1% OsO4及1.5%的hexanoferrate鉀(potassium hexanoferrate)溶液進行後固定，然後以二甲砷酸(cacodylate)和0.2 M5的馬來酸鈉緩衝液(pH值6.0)潤洗，再以1%乙酸雙氧鈾進行塊狀染色。接著進行脫水，各種組織被EPON
包覆並切片，再如前述以TEM觀察之(參考Kao et al,1995)。
將結果以平均值±SD表示，並使用Student’s t test檢驗比較兩個組的數據。當分析不同組的統計數據時，P<0.05被判定是有顯著差異的。
本說明書所載CISD2轉基因質體的構成如下：具體來說，鼠的CISD2蛋白生成基因是由RNA-5-聚合酶II之大次單元啟動子來驅動(Pol II；NCBI Accession M14101 bases 1-712)。pIRES-EGFP質體(CLONTECH #6064-1)衍生出0.33 kb的合成內含子和0.28 kb的牛生長激素polyA信號(PA)。兩個重複的“HS4雞肉的絕緣體(NCBI Accession U78775 bases 10-1199)被插於polyA信號之下游以阻止位置效應(positional effects)。將C57BL/6受精卵以原核顯微注射，以產生10隻CISD2基因轉殖鼠。以PCR測定前述鼠尾部DNA的表現型。小鼠被飼養在無特定病原體的環境下。這項動物實驗流程係由陽明大學的「實驗動物照護和使用委員會」所製定。
為了確認Cisd2基因對皮膚(毛髮)老化症狀的影響，以15個月大之未經基因轉殖鼠(15-mo WT)及34個月大之經基因轉殖鼠(34-mo TG)進行外觀比較，其
結果如第一圖所示。由外觀看來，經Cisd2基因轉殖鼠其有延緩色素沉澱(delayed de-pigmentation)的現象，且相較於較為年幼之未經基因轉殖鼠，其毛髮較不灰白。
接著，以3個月大之未經基因轉殖鼠(野生型)及24個月大之經基因轉殖鼠(基因轉殖型)之毛囊進行梅生三色染色(Masson’s trichome staining)再進行比較，其結果如第二圖所示。
其中，HF代表毛囊(hair follicles)，SG代表皮脂腺(sebaceous gland)。
將上述結果量化，其結果如第三圖所示，其中，第三A圖代表每個毛囊中皮脂腺之細胞核數目，第三B圖代表每個毛囊之皮脂腺數目。
皮脂腺係毛囊中分泌皮脂的組織。比較3個月大之未經基因轉殖鼠(野生型)及24個月大之經基因轉殖鼠(基因轉殖型)，由上述實驗結果可知，當轉殖了Cisd2基因後，鼠毛囊之皮膚老化相關的萎縮症狀就減少了，且含有二個皮脂腺的毛囊也顯著地增加了。
皮脂腺會分泌皮脂以包覆於毛囊外，在有毛的哺乳類動物中，這些皮脂對於動物抗水性及溫度調節扮演重要的角色。此外，不同年齡的動物之皮脂腺分泌能力不同，對水的抗性也不同。
為了觀察Cids2基因轉殖後，對鼠之抗水性及溫度
調節能力的影響，取3個月大之未經基因轉殖鼠(野生型)及24個月大之經基因轉殖鼠(基因轉殖型)進行抗水試驗(water repulsion)的比較。每一組有4隻小鼠。
將試驗對象鼠浸入37℃的水中3分鐘，再將之取出，置於紙毛巾上以吸去多餘水分，測量5~60分鐘之體重和體溫，其結果如第四圖所示。
結果顯示，鼠被浸入水中再取出5分鐘後，無論有無經過基因轉殖，3個月大的鼠皆已幾乎全乾。相較於此，24個月大之未經基因轉殖鼠(野生型)，其對水的抗性較差。再看24個月大之基因轉殖鼠(基因轉殖型)，其對水的抗性則與3個月大的鼠相近。由此可知，經過Cisd2基因轉殖後，會使鼠的抗水性能力提升。
皮膚的皮膚老化與皮膚厚度減少有關，主要因為皮下脂肪及肌肉的減少。因此接著以組織染色觀察試驗鼠之皮膚厚度，包含真皮層、脂肪層和肌肉層的厚度，其結果如第五圖所示。接著，量化前述結果，如第六圖所示，第六A圖為皮膚(包括真皮層、脂肪層、肌肉層)厚度，第六B圖為真皮層厚度，第六C圖為脂肪層厚度。
在第五圖及第六圖中可見，24個月大之試驗鼠皮膚組織中，經Cisd2基因轉殖(基因轉殖型)的小鼠其皮膚(包括真皮層、脂肪層、肌肉層)厚度較未經基因轉殖(野生型)的小鼠要厚。
取12個月大的小鼠，分為二個族群，一為經基因轉殖(基因轉殖型)及一為未經基因轉殖(野生型)，觀察其毛髮再生現象，其結果如第七圖所示。
由圖可知，經過Cisd2基因轉殖的小鼠其毛髮再生
現象要比未經基因轉殖(野生型)的小鼠要來得顯著。
綜上所述，皮膚老化症狀包括：皮脂腺與毛囊的萎縮、掉髮、皮膚(包括真皮層、脂肪層、肌肉層)厚度變薄(因為皮下脂肪與肌肉的萎縮所導致)。本發明Cisd2基因轉殖可延緩因皮膚老化引起的皮脂腺與毛囊萎縮，由於皮脂腺未萎縮，因此可分泌適量油脂於皮膚表面(表皮層)，達到抗水的功效，使老鼠從浸溼到乾的時間也較短，更可增加「有結合2個皮脂腺的毛囊」之比例，使毛髮較具有光澤，也較少白頭髮，並增加頭髮再生的速率，顯著的防止皮膚老化症狀。
第一圖係為Cisd2基因轉殖前後之小鼠外觀比較圖。
第二圖係為Cisd2基因轉殖前後之小鼠的毛囊組織染色圖。
第三圖係為Cisd2基因轉殖前後之小鼠的毛囊組織中皮脂腺細胞核及皮脂腺數量的統計。
第四圖係為Cisd2基因轉殖前後之小鼠抗水性試驗結果。
第五圖係為Cisd2基因轉殖前後之小鼠之皮膚組織(真皮層、脂肪層、肌肉層)染色圖。
第六圖係為Cisd2基因轉殖前後之小鼠皮膚組織(真皮層、脂肪層、肌肉層)厚度的量化結果。
第七圖係為Cisd2基因轉殖前後之小鼠的毛髮再生現象圖。
<110> 國立陽明大學
<120> 防止皮膚老化相關症狀的醫藥組合物及其使用方法
<130> 2011RDPA013
<150> US61/555,182
<151> 2011-11-03
<160> 2
<170> PatentIn version 3.3
<210> 1
<211> 2885
<212> DNA
<213> Mus musculus
<400>1
<210> 2
<211> 135
<212> PRT
<213> Mus musculus
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Claims (12)
- 一種用於製備防止皮膚老化相關症狀之醫藥組合物的用途，其中該組合物包含一攜帶Cisd2基因之載體以及一藥物上可接受之佐劑。
- 如申請專利範圍第1項所述之用途，其中前述Cisd2基因係為一人類Cisd2基因或一鼠類Cisd2基因。
- 如申請專利範圍第1項所述之用途，其中前述載體係為一傳染媒介載體(vector)、一脂質體(liposome)、一聚合物(polymer)、一醫藥可接受之組合物或一可便於攜帶之裝置。
- 如申請專利範圍第3項所述之用途，其中前述傳染媒介載體係為一腺病毒載體(adenovirus vector)、反轉錄病毒載體(retrovirus vector)、腺伴隨病毒載體(adeno-associated virus vector)、單純泡疹病毒載體(herpes simplex virus vector)、SV40載體、多瘤病毒載體(polyma virus vector)、乳突病毒載體(papilloma virus vector)、微小核糖核酸病毒載體(Picornavirus vector)、疫苗病毒載體(vaccinia virus vector)、慢病毒載體(lentiviral vector)、α-病毒載體、輔助病毒依賴型腺病毒載體(helper-dependent adenovirus vector)或一質體。
- 如申請專利範圍第1項所述之用途，其中前述皮膚老化相關症狀係為細胞損傷、組織損傷、器官失能、皮膚老化相關壽命減少或致癌作用(carcinogenesis)。
- 如申請專利範圍第5項所述之用途，其中前述組織係為一皮膚組織或一脂肪組織。
- 如申請專利範圍第6項所述之用途，其中該皮膚組織包括表皮層、真皮層、脂肪層、毛囊、毛髮及皮脂腺，該脂肪組織則包括脂肪層。
- 如申請專利範圍第1項所述之用途，其中前述皮膚老化相關症狀係為毛囊的 減少、皮脂腺減少、皮脂腺細胞核減少、抗水性變弱、皮下脂肪層變薄、毛髮較無光澤、毛髮減少或灰白毛髮較多。
- 如申請專利範圍第1項所述之用途，其中前述投予係透過注射於皮膚或頭皮上。
- 一種用於製備防止皮膚老化相關症狀之醫藥組合物的用途，其中該組合物包含一CISD2蛋白以及一藥物上可接受之佐劑。
- 如申請專利範圍第10項所述之用途，其中前述CISD2蛋白係為一人類CISD2蛋白或一鼠類CISD2蛋白。
- 如申請專利範圍第10項所述之用途，其中前述投予係透過注射於皮膚或頭皮上、體內注射、口服(oral administration)或上述方式之結合。
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| US201161555182P | 2011-11-03 | 2011-11-03 | |
| US61/555,182 | 2011-11-03 |
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| KR101886342B1 (ko) * | 2010-11-30 | 2018-08-10 | (주)아모레퍼시픽 | 피부 노화와 관련된 유전자 및 피부 노화를 방지하는 물질을 스크리닝하는 방법 |
| JP2019519221A (ja) * | 2016-05-20 | 2019-07-11 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 加齢関連疾患及び症状の遺伝子治療法 |
| EP4142758A2 (en) * | 2020-04-28 | 2023-03-08 | President and Fellows of Harvard College | High efficiency gene delivery system |
| TWI831339B (zh) * | 2021-08-24 | 2024-02-01 | 國立陽明交通大學 | 化合物用於製備Ｃｉｓｄ２不足相關病症的藥物的用途 |
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- 2012-11-02 CN CN2012104331288A patent/CN103203027A/zh active Pending
- 2012-11-02 TW TW101140641A patent/TWI614031B/zh active
- 2012-11-03 US US13/668,268 patent/US20130122082A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
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| Yi-Fan Chen et al., "Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice", GENES & DEVELOPMENT 23:1183–1194. * |
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| US20130122082A1 (en) | 2013-05-16 |
| CN103203027A (zh) | 2013-07-17 |
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