JP2022516607A - 皮膚および毛髪障害を治療するための方法および組成物 - Google Patents
皮膚および毛髪障害を治療するための方法および組成物 Download PDFInfo
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Abstract
Description
本明細書および添付の特許請求の範囲で使用される場合、単数形「a」、「an」、および「the」は、文脈が別段明示しない限り、複数の指示対象を含む。したがって、例えば、「薬学的担体」への言及には、2つ以上のかかる担体の混合物などが含まれる。
開示される組成物を調製するために使用される構成要素、ならびに本明細書に開示される方法の中で使用される組成物自体が開示される。これらおよび他の材料が本明細書に開示されており、これらの材料の組み合わせ、サブセット、相互作用、群などが開示される場合、これらの化合物の各々の様々な個別的および集合的な組み合わせおよび並び替えの具体的な参照が明示的に開示されていない場合があるが、各々が本明細書に具体的に企図され、説明されていることが理解される。例えば、特定の治療組成物(例えば、増殖因子、エクソソーム、またはMSCに由来するタンパク質を含む組成物など)が開示され、議論され、治療組成物(例えば、増殖因子、エクソソーム、またはMSCに由来するタンパク質を含む組成物など)を含むいくつかの分子に対して行われ得るいくつかの変更が議論される場合、具体的には、治療組成物(例えば、増殖因子、エクソソーム、またはMSCに由来するタンパク質を含む組成物など)の各々および全ての組み合わせおよび並び替え、ならびに特に明記しない限り、可能な変更が企図される。したがって、分子のクラスA、B、およびC、ならびに分子のクラスD、E、およびFが開示され、組み合わせ分子の例としてA-Dが開示される場合、各々が個別に列挙されていなくても、各々は個別的および集合的に企図され、すなわち、組み合わせであるA-E、A-F、B-D、B-E、B-F、C-D、C-E、およびC-Fが開示されているとみなされる。同様に、これらの任意のサブセットまたは組み合わせもまた開示される。したがって、例えば、A-E、B-F、およびC-Eのサブグループは、開示されているとみなされるであろう。この概念は、本出願のすべての態様に適用され、開示される組成物の作製方法および使用方法におけるステップを含むが、これらに限定されない。したがって、実施することができる様々な追加のステップがある場合、これらの追加のステップの各々は、開示される方法の任意の特定の実施形態または実施形態の組み合わせにより実施できることが理解される。
現在、特定の皮膚色や民族に特異的な皮膚製品はほとんど存在しない。したがって、従来の皮膚製品は、各皮膚色または特定の人種の真皮に見られる生物学的な違いに適切に対処しない。
毛母における幹細胞因子(SCF)発現は、毛幹構造細胞の直前の前駆細胞を特定し、転写因子KROX20は、毛幹前駆細胞へと分化する上皮細胞の亜系統を特徴付ける。幹細胞因子(SCF、KITリガンドまたは造血幹細胞因子としても知られる)は、造血幹細胞、肥満細胞、およびメラノサイトの維持を含む、複数の生理学的恒常性事象を調節する増殖因子である。毛髪の色素沈着に対するSCFおよびその受容体KITの重要な役割は、いくつかのSCFおよびKIT欠損動物における毛髪色素の不在によって支持されている。メラノサイトが、この種類の色素沈着低下において関連する標的細胞であることが明らかである。なぜなら、それらがメラニン産生細胞であり、ならびに毛包(HF)の主なKIT発現細胞であるからである。HFにおけるメラノサイトの活性を支持するSCFの供給源は、皮膚の線維芽細胞であるように見える。
毛髪は、ケラチンと呼ばれるタンパク質から作られる。毛髪は、毛包に座し、毛包の基部には、新しい毛髪の生成が刺激された毛包上皮幹細胞と呼ばれる幹細胞がある。平均的な頭部には、100,000個以上の毛包があり、各毛包は、毛髪を生成してから休止する周期を繰り返す。毛髪の生成と休止の周期は正常であり、常に頭部全体に毛髪を有することになる。
本明細書に記載の方法およびパラメータを使用して生成されたエクソソーム懸濁液のプロテオミクス評価を行って、記載の発明の臨床的に意義のある有効性に寄与する分子組成を特徴付けた。プロテオミック評価は、市販のRayBio Tech(Norcross,GA,USA)製の抗体アレイを利用した。(細胞外微小環境内の)細胞膜の外面で、分泌、輸送、または存在のいずれかをすることが知られている230個の異なるタンパク質の濃度の測定を行った。重複した試験試料中に生理学的に適切な濃度で存在し、***不全の治療に潜在的に有効であると科学文献で支持されたタンパク質を、表2に列挙する。生理学的に適切な濃度は、平均濃度が1pg/mL以上であると見なされた。平均濃度が50ug/mLを超えるタンパク質の文献調査を実施して、臨床効果を支持する最も可能性の高い候補分子を特定した。
全体を通して指摘されるように、本明細書に開示される治療組成物は、間葉系幹細胞(MSC)に由来するエクソソームおよび/または増殖因子を利用することができる。骨髄濃縮物または脂肪由来間質血管細胞群(SVF)、または臍帯、胎盤、または羊膜由来の様々な生後産物内に含まれる既存の自己および同種のMSCであるが、増殖させたMSC培養物は、創傷、整形外科病理、および脊椎病理を治療するために現在使用されている。既存の治療は、大量のMSCセクレトーム(増殖因子、サイトカイン、ケモカイン、エクソソーム、細胞外小胞、および/または抽出物を含むが、これらに限定されない)を含有しない。さらに、当該技術分野では、幹細胞を含む治療(注射可能な治療を含む)が、老化を防止し、瘢痕、不均一な色素沈着を治療するのに役立つことができるという証拠があるにもかかわらず、既存の皮膚製品(クリーム、ローション、血清、化粧など)など、皮膚を治療し強化するのに潜在的に役立つ成分を含む一方で、他の局所用製品は、表皮に浸透せず、より重要なことに、ヒトMSC、またはMSC由来の増殖因子およびタンパク質を含んでいない。実際、本開示以前に、これらの用途に使用することができる活性のMSC増殖因子製品は開発されていない。したがって、一態様では、創傷、整形外科障害、整形外科損傷、眼科、脊髄損傷、または脊髄障害の治療に使用するためのMSCセクレトーム組成物(MSC増殖因子、MSCエクソソーム、MSC抽出物、および/または組成物を含む細胞外小胞を含むが、これらに限定されない)が、本明細書に開示され、当該治療組成物は、(i)間葉系幹細胞(MSC)由来調製物を含む増殖因子の粉末添加剤、および(ii)薬学的に許容される担体を含む。
上に記載のように、組成物は、薬学的に許容される担体中で、インビボで投与され得る。「薬学的に許容される」とは、生物学的にまたは他の望ましくないものではない材料、すなわち、任意の望ましくない生物学的作用を引き起こすことなく、またはそれが含まれる医薬組成物の他の成分のいずれかと有害な様式で相互作用することなく、核酸もしくはベクターと共に、対象に投与され得る材料、を意味する。担体は、当業者に周知であろうが、活性成分の任意の分解を最小限に抑え、対象における任意の有害な副作用を最小限に抑えるために当然選択されるであろう。
抗体を含む組成物は、薬学的に許容される担体と組み合わせて、治療に使用することができる。
組成物を投与するための有効投与量およびスケジュールは、経験的に決定され、そのような決定を行うことは当該技術分野の技能の範囲内である。組成物の投与のための投与量範囲は、障害の症状に作用する所望の効果をもたらすのに十分な大きなものである。投与量は、望ましくない交差反応、アナフィラキシー反応などの副作用を引き起こすほど大きくてはならない。一般に、投与量は、患者の年齢、状態、性別、および疾患の程度、投与経路、または他の薬物がレジメンに含まれるかどうかに応じて異なり、当業者によって決定され得る。投与量は、任意の禁避症の発生時に、個々の医師によって調整され得る。投与量は異なってもよく、1日に1回以上の用量の投与で投与され得る。ガイダンスは、所与のクラスの医薬品の適切な投与量について文献中に見出され得る。例えば、抗体の適切な用量を選択するためのガイダンスは、抗体の治療用途に関する文献、例えば、Handbook of Monoclonal Antibodies,Ferrone et al.,eds.,Noges Publications,Park Ridge,N.J.,(1985)ch.22 and pp.303-357、Smith et al.,Antibodies in Human Diagnosis and Therapy,Haber et al.,eds.,Raven Press,New York(1977)pp.365-389に見出される。単独で使用される抗体の典型的な1日の投与量は、上記の要因に応じて、約1μg/kg体重から最大100mg/kg体重の範囲、またはそれ以上であってもよい。
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Claims (19)
- 毛髪障害もしくは皮膚障害を治療、阻害、軽減、予防、もしくは回復するための治療組成物、または***不全を治療するための治療組成物を作製するための方法であって、
エンドユーザーの毛髪、皮膚色、皮膚タイプ、人種、民族を特定することと、
前記エンドユーザーと同じ毛髪タイプ、色、および/もしくは民族を有するか、または***不全に感受性ではない標的ドナーであるが、前記ドナーが決して毛髪障害、皮膚障害、または***不全を経験することがなく、性別、人種、および民族に特異的であり得ることを示す一塩基多型(SNP)プロファイルを有する標的ドナーから、間葉系皮膚細胞(MSC)を得ることと、
前記得られたMSCから、MSC、ケラチノサイト、およびメラノサイトの増殖因子の粉末調製物を調製することであって、前記MSC調製物が、正常な過酸素培養条件下で培養された細胞または細胞条件培地、および過酷な創傷治癒条件下で培養された細胞からなる群から選択される少なくとも1つのメンバーを含む、調製することと、
前記粉末調製物を、基剤に添加することと、を含み、
前記治療組成物が、局所用組成物および注射用組成物からなる群から選択されるメンバーを含む、方法。 - 前記毛髪障害または皮膚障害が、白髪、脱毛症、または皮膚変色を含む、請求項1に記載の方法。
- 前記皮膚変色が、白斑、肝斑、イチゴ状母斑、または酒さに起因する、請求項2に記載の方法。
- 前記治療組成物が、皮膚変色を修正する、請求項3に記載の方法。
- 前記脱毛症が、男性型脱毛症、アンドロゲン性脱毛症、円形脱毛症、瘢痕性脱毛症、休止期脱毛症、または女性型脱毛症を含む、請求項2に記載の方法。
- 前記治療組成物が、毛包の活性化を刺激して、発毛を促進する、請求項5に記載の方法。
- 前記治療組成物が、毛髪の色素沈着の産生を刺激する、請求項2に記載の方法。
- 前記SNPが、インターロイキン18(IL-18)、血小板由来増殖因子(PDGF)受容体(PDGFR)B(PDGFR-B)、組織メタロプロテアーゼ阻害物質(TIMP)1(TIMP-1)、TIMP-2、IL-23、アクチビンA、細胞内接着分子(ICAM-2)、プラスミノーゲン活性化因子インヒビター1(PAI-1)、オステオポンチン(OPN)、インスリン、インスリン増殖因子結合タンパク質4(IGF-BP4)、腫瘍壊死因子(TNF)受容体(TNF-R)、ニューレグリン-1 B1(NRG1-B1)、ウロキナーゼ型プラスミノーゲン活性化因子受容体(uPAR)、エクトジスプラシンA2受容体(XEDAR)、フォリスタチン、および/または活性化白血球細胞接着分子(ALCAM)をコードする1つ以上の遺伝子に存在する1つ以上のSNPを含む、請求項1に記載の方法。
- 前記SNPが、前記IL-18のSNP rs1946518(-607C>A)および/またはrs187238(-137G>C)を含む、請求項1に記載の方法。
- 毛髪障害または皮膚障害を治療、阻害、軽減、予防、または回復するための治療組成物であって、
組成物基剤と、
エンドユーザーと同じ毛髪タイプ、毛髪色、毛髪タイプ、および/または毛髪色を有するドナーであるが、前記ドナーが決して毛髪障害および/または皮膚障害を有さず、性別、人種、および民族に特異的であり得ることを示す一塩基多型(SNP)プロファイルを有するドナーに由来する間葉系幹細胞(MSC)、ケラチノサイト、および/またはメラノサイトの増殖因子の粉末調製物であって、前記MSC調製物が、正常な過酸素培養条件下で培養された細胞または細胞条件培地、および過酷な創傷治癒条件下で培養された細胞からなる群から選択される少なくとも1つのメンバーを含む、粉末調製物と、を含む、治療調製物。 - 前記SNPが、インターロイキン18(IL-18)、血小板由来増殖因子(PDGF)受容体(PDGFR)B(PDGFR-B)、組織メタロプロテアーゼ阻害物質(TIMP)1(TIMP-1)、TIMP-2、IL-23、アクチビンA、細胞内接着分子(ICAM-2)、プラスミノーゲン活性化因子インヒビター1(PAI-1)、オステオポンチン(OPN)、インスリン、インスリン増殖因子結合タンパク質4(IGF-BP4)、腫瘍壊死因子(TNF)受容体(TNF-R)、ニューレグリン-1 B1(NRG1-B1)、ウロキナーゼ型プラスミノーゲン活性化因子受容体(uPAR)、エクトジスプラシンA2受容体(XEDAR)、フォリスタチン、および/または活性化白血球細胞接着分子(ALCAM)をコードする1つ以上の遺伝子に存在する1つ以上のSNPを含む、請求項10に記載の治療組成物。
- 前記SNPが、前記IL-18のSNP rs1946518(-607C>A)および/またはrs187238(-137G>C)を含む、請求項10に記載の治療組成物。
- 前記毛髪障害が、脱毛症または白髪を含む、請求項10に記載の治療組成物。
- 前記脱毛症が、男性型脱毛症、アンドロゲン性脱毛症、円形脱毛症、瘢痕性脱毛症、休止期脱毛症、または女性型脱毛症を含む、請求項10に記載の治療組成物。
- 請求項10~14のいずれか一項に記載の治療組成物のうちのいずれかを、対象に投与することを含む、毛髪障害を治療する方法。
- 前記皮膚障害が、白斑、肝斑、イチゴ状母斑、または酒さに起因する皮膚変色を含む、請求項10に記載の治療組成物。
- 請求項10~12または16のいずれか一項に記載の治療組成物のうちのいずれかを、対象に投与することを含む、皮膚障害を治療する方法。
- 特定の皮膚色、人種、タイプ、または民族のための皮膚治療組成物を作製するための方法であって、
エンドユーザーの皮膚色、タイプ、人種、および民族を特定することと、
前記ドナーの適切な一塩基多型パネルに基づいて、前記エンドユーザーと同じ皮膚色、タイプ、人種、および民族を有する標的ドナーから、間葉系皮膚細胞(MSC)を得ることと、
前記得られたMSCから、MSC、ケラチノサイト、およびメラノサイトの増殖因子の粉末調製物を調製することであって、前記MSC調製物が、正常な過酸素培養条件下で培養された細胞または細胞条件培地、および過酷な創傷治癒条件下で培養された細胞からなる群から選択される少なくとも1つのメンバーを含む、調製することと、
前記粉末調製物を、化粧料基剤に添加することと、を含む、方法。 - 特定の皮膚色、人種、タイプ、または民族のための皮膚治療組成物であって、
組成物基剤と、
エンドユーザーと同じ皮膚色、タイプ、人種、および民族を有するドナーに由来する間葉系幹細胞(MSC)、ケラチノサイト、および/またはメラノサイトの増殖因子の粉末調製物であって、前記MSC調製物が、正常な過酸素培養条件下で培養された細胞または細胞条件培地、および過酷な創傷治癒条件下で培養された細胞からなる群から選択される少なくとも1つのメンバーを含む、粉末調製物と、を含む、皮膚治療組成物。
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