JP6175431B2 - ムコ多糖症およびその他のリソソーム障害に対する抗tnf療法 - Google Patents
ムコ多糖症およびその他のリソソーム障害に対する抗tnf療法 Download PDFInfo
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Description
本発明は、ムコ多糖症およびその他のリソソーム障害に対する抗TNFα療法に関する。
リソソーム蓄積障害とは、40種超の異なる遺伝性疾患の群を表し、リソソームに存在する酵素の異常を原因とする。リソソーム蓄積障害に罹患した者は、特有の障害および関係する特定の遺伝子型に応じて、広範な臨床症状を呈する。リソソーム蓄積障害と関連する臨床症状は、罹患者とその家族に甚大な影響を及ぼし得る。例えば、細網内皮疾患、中枢神経系機能障害、行動異常、および深刻な精神遅滞は、多くのリソソーム蓄積障害の特徴である。ムコ多糖症(MPS)という特有のリソソーム蓄積障害群では、その他の臨床症状として、骨格異常、臓器肥大症、角膜混濁、および身体的形態異常を挙げ得る。
[本発明1001]
以下を含む、リソソーム蓄積障害を有する対象を治療する方法:
リソソーム蓄積障害を有する対象を選択すること、ならびに
前記選択した対象において前記リソソーム蓄積障害を治療するのに有効な条件の下で、前記選択した対象に、酵素補充療法薬および抗TNFα治療薬を投与すること。
[本発明1002]
前記酵素補充療法薬が、アルグルセラーゼ、イミグルセラーゼ、ベラグルセラーゼアルファ、ラロニダーゼ、アガルシダーゼベータ、ガルスルファーゼ、アルグルコシダーゼアルファ、N−アセチルガラクトサミン−6スルファターゼ、およびイデュルスルファーゼからなる群から選択される、本発明1001の方法。
[本発明1003]
前記抗TNFα療法薬が、インフリキシマブ、アダリムマブ、エタネルセプト、ゴリムマブ、およびナタリズマブからなる群から選択される、本発明1001の方法。
[本発明1004]
前記抗TNFα療法薬がポリ硫酸ペントサン(PPS)である、本発明1001の方法。
[本発明1005]
追加の療法を実施すること
をさらに含む、本発明1001の方法。
[本発明1006]
前記追加の療法が、骨髄移植、シャペロン療法、および遺伝子療法からなる群から選択される、本発明1005の方法。
[本発明1007]
前記リソソーム蓄積障害が、スフィンゴリピドーシス、ムコ多糖蓄積症(ムコ多糖症)、糖タンパク症(glycoproteinoses)、ムコリピドーシス、糖原病II型、セロイドリポフスチン沈着症、およびその他のリソソームタンパク質機能異常からなる群から選択される、本発明1001の方法。
[本発明1008]
前記リソソーム蓄積障害がスフィンゴリピドーシスであり、前記スフィンゴリピドーシスがニーマンピック病である、本発明1001の方法。
[本発明1009]
前記リソソーム蓄積障害がムコ多糖症であり、前記ムコ多糖症がMPS I型(ハーラー/シャイエ症候群)、MPS II型(ハンター症候群)、MPS VI型(マロトー・ラミー症候群)、MPS III型(サンフィリッポ症候群)、MPS IV型(モルキオ症候群)、またはMPS VII型(スライ病)である、本発明1001の方法。
[本発明1010]
前記投与することを、経口的に、吸入により、鼻腔内滴下により、局所的に、経皮的に、非経口的に、皮下に、静脈内注射により、動脈内注射により、筋内注射により、胸膜内に(intraplurally)、腹腔内に、または粘膜への塗布により行う、本発明1001の方法。
[本発明1011]
前記投与することを繰り返すこと
をさらに含む、本発明1001の方法。
[本発明1012]
前記対象が乳児または年少者である、本発明1001の方法。
[本発明1013]
前記対象が成人である、本発明1001の方法。
[本発明1014]
前記対象が、リソソーム蓄積障害と関連する骨格病変を有する、本発明1001の方法。
[本発明1015]
以下を含む、酵素補充療法によって治療しているリソソーム蓄積障害を有する対象において炎症性サイトカインを低減させる方法:
前記対象において前記炎症性サイトカインを低減させるのに有効な条件の下で、前記対象に抗TNFα治療薬を投与すること。
[本発明1016]
前記投与を受ける、リソソーム蓄積障害と関連する骨格病変を有する対象を選択すること
をさらに含む、本発明1015の方法。
[本発明1017]
前記酵素補充療法のための薬剤が、アルグルセラーゼ、イミグルセラーゼ、ベラグルセラーゼアルファ、ラロニダーゼ、アガルシダーゼベータ、ガルスルファーゼ、アルグルコシダーゼアルファ、N−アセチルガラクトサミン−6スルファターゼ、およびイデュルスルファーゼからなる群から選択される、本発明1015の方法。
[本発明1018]
前記抗TNFα療法薬が、インフリキシマブ、アダリムマブ、エタネルセプト、ゴリムマブ、およびナタリズマブからなる群から選択される、本発明1015の方法。
[本発明1019]
前記抗TNFα療法薬がポリ硫酸ペントサン(PPS)である、本発明1015の方法。
[本発明1020]
追加の療法を実施すること
をさらに含む、本発明1015の方法。
[本発明1021]
前記追加の療法が、骨髄移植、シャペロン療法、および遺伝子療法からなる群から選択される、本発明1020の方法。
[本発明1022]
前記リソソーム蓄積障害が、スフィンゴリピドーシス、ムコ多糖蓄積症(ムコ多糖症)、糖タンパク症、ムコリピドーシス、糖原病II型、セロイドリポフスチン沈着症、およびその他のリソソームタンパク質機能異常からなる群から選択される、本発明1015の方法。
[本発明1023]
前記リソソーム蓄積障害がスフィンゴリピドーシスであり、前記スフィンゴリピドーシスがニーマンピック病である、本発明1015の方法。
[本発明1024]
前記リソソーム蓄積障害がムコ多糖症であり、前記ムコ多糖症がMPS I型(ハーラー/シャイエ症候群)、MPS II型(ハンター症候群)、MPS VI型(マロトー・ラミー症候群)、MPS III型(サンフィリッポ症候群)、MPS IV型(モルキオ症候群)、またはMPS VII型(スライ症候群)である、本発明1015の方法。
[本発明1025]
前記投与することを、経口的に、吸入により、鼻腔内滴下により、局所的に、経皮的に、非経口的に、皮下に、静脈内注射により、動脈内注射により、筋内注射により、胸膜内に、腹腔内に、または粘膜への塗布により行う、本発明1015の方法。
[本発明1026]
前記投与することを繰り返すこと
をさらに含む、本発明1015の方法。
[本発明1027]
前記対象が乳児または年少者である、本発明1015の方法。
[本発明1028]
前記対象が成人である、本発明1015の方法。
[本発明1029]
以下を含む、リソソーム蓄積障害を有する対象を治療する方法:
リソソーム蓄積障害を有する対象を選択すること、および
前記選択した対象において前記リソソーム蓄積障害を治療するのに有効な条件の下で、前記選択した対象にポリ硫酸ペントサン(PPS)を投与すること。
[本発明1030]
追加の療法を実施すること
をさらに含む、本発明1029の方法。
[本発明1031]
前記追加の療法が、骨髄移植、シャペロン療法、および遺伝子療法からなる群から選択される、本発明1030の方法。
[本発明1032]
前記リソソーム蓄積障害が、スフィンゴリピドーシス、ムコ多糖蓄積症(ムコ多糖症)、糖タンパク症、ムコリピドーシス、糖原病II型、セロイドリポフスチン沈着症、およびその他のリソソームタンパク質機能異常からなる群から選択される、本発明1029の方法。
[本発明1033]
前記リソソーム蓄積障害がスフィンゴリピドーシスであり、前記スフィンゴリピドーシスがニーマンピック病である、本発明1029の方法。
[本発明1034]
前記リソソーム蓄積障害がムコ多糖症であり、前記ムコ多糖症がMPS I型(ハーラー/シャイエ症候群)、MPS II型(ハンター症候群)、MPS VI型(マロトー・ラミー症候群)、MPS III型(サンフィリッポ症候群)、MPS IV型(モルキオ症候群)、またはMPS VII型(スライ病)である、本発明1029の方法。
[本発明1035]
前記投与することを、経口的に、吸入により、鼻腔内滴下により、局所的に、経皮的に、非経口的に、皮下に、静脈内注射により、動脈内注射により、筋内注射により、胸膜内に、腹腔内に、または粘膜への塗布により行う、本発明1029の方法。
[本発明1036]
前記投与することを繰り返すこと
をさらに含む、本発明1029の方法。
[本発明1037]
前記対象が乳児または年少者である、本発明1029の方法。
[本発明1038]
前記対象が成人である、本発明1029の方法。
[本発明1039]
前記対象が、リソソーム蓄積障害と関連する骨格病変を有する、本発明1029の方法。
[本発明1040]
以下を含む、リソソーム蓄積障害と関連する骨格病変を有する対象を治療する方法:
リソソーム蓄積障害と関連する骨格病変を有する対象を選択すること、ならびに
前記対象においてリソソーム蓄積障害と関連する前記骨格病変を治療するのに有効な条件の下で、前記選択した対象に、基質抑制療法薬および抗TNFα治療薬を投与すること。
[本発明1041]
前記基質抑制療法薬が、ミグルスタットおよびエリグルスタットからなる群から選択される、本発明1040の方法。
[本発明1042]
前記抗TNFα療法薬が、インフリキシマブ、アダリムマブ、エタネルセプト、ゴリムマブ、およびナタリズマブからなる群から選択される、本発明1040の方法。
[本発明1043]
前記抗TNFα療法薬がポリ硫酸ペントサン(PPS)である、本発明1040の方法。
[本発明1044]
追加の療法を実施すること
をさらに含む、本発明1040の方法。
[本発明1045]
前記追加の療法が、酵素補充療法、骨髄移植、シャペロン療法、および遺伝子療法からなる群から選択される、本発明1044の方法。
[本発明1046]
前記リソソーム蓄積障害が、スフィンゴリピドーシス、ムコ多糖蓄積症(ムコ多糖症)、糖タンパク症、ムコリピドーシス、糖原病II型、セロイドリポフスチン沈着症、およびその他のリソソームタンパク質機能異常からなる群から選択される、本発明1040の方法。
[本発明1047]
前記リソソーム蓄積障害がスフィンゴリピドーシスであり、前記スフィンゴリピドーシスがニーマンピック病である、本発明1040の方法。
[本発明1048]
前記リソソーム蓄積障害がムコ多糖症であり、前記ムコ多糖症がMPS I型(ハーラー/シャイエ症候群)、MPS II型(ハンター症候群)、MPS VI型(マロトー・ラミー症候群)、MPS III型(サンフィリッポ症候群)、MPS IV型(モルキオ症候群)、またはMPS VII型(スライ症候群)である、本発明1040の方法。
[本発明1049]
前記投与することを、経口的に、吸入により、鼻腔内滴下により、局所的に、経皮的に、非経口的に、皮下に、静脈内注射により、動脈内注射により、筋内注射により、胸膜内に、腹腔内に、または粘膜への塗布により行う、本発明1040の方法。
[本発明1050]
前記投与することを繰り返すこと
をさらに含む、本発明1040の方法。
[本発明1051]
前記対象が乳児または年少者である、本発明1040の方法。
[本発明1052]
前記対象が成人である、本発明1040の方法。
本発明の第一の態様は、リソソーム蓄積障害を有する対象を治療する方法に関する。この方法は、リソソーム蓄積障害を有する対象を選択すること、および選択した対象においてリソソーム蓄積障害を治療するのに有効な条件の下で、選択した対象に、酵素補充療法薬と抗TNFα治療薬を投与することを含む。
動物−MPS VI型ラットについては過去に記述されており、本発明の研究者および他の研究者に広く使われている(Yoshida et al.,"Arylsulfatase B−Deficient Mucopolysaccharidosis in Rats,"J.Clin.Invest.91:1099−1104(1993)、Kunieda et al.,"Mucopolysaccharidosis Type VI in Rats:Isolation of CDNAs Encoding Arylsulfatase B,Chromosomal Localization of the Gene,and Identification of the Mutation,"Genomics 29:582−587(1995)(いずれの文献も、参照によりその全体が本明細書に組み込まれる))。繁殖コロニーは、ヘテロ接合体の交配対から確立し、確立された方法を用いて、尾部クリップDNAで遺伝子型の決定を行った(Kunieda et al.,"Mucopolysaccharidosis Type VI in Rats:Isolation of CDNAs Encoding Arylsulfatase B,Chromosomal Localization of the Gene,and Identification of the Mutation,"Genomics 29:582−587(1995)(参照によりその全体が本明細書に組み込まれる))。ラットの安楽死は、二酸化炭素の吸入によって行った。いずれの動物プロトコールも、Mount Sinai Institutional Animal Care and Use Committeeによって認可されたものであり(許可番号08−0108)、NIHのガイドラインに従って行った。
21日齢のMPS VI型ラットをERT(1mg/kg、週に1度)、またはERTと抗TNFα療法(3mg/kg、週に2回)との併用プロトコールのいずれかによって処置した。いずれも、静脈(尾静脈)内に投与した。ラットは、合わせて8カ月間処置した(すなわち32回のERT投与および64回の抗TNFα投与)。対照として、正常な同腹ラットと未処置のMPS VI型同腹ラットを用いた(n=8匹/群)。抗TNFα療法は、TNFαに対するラット特異的モノクローナル抗体CNTO1081(Centocorから提供)を用いて行った。Naglazyme(登録商標)(BioMarinから提供)は、ヒト型の遺伝子組み換えN−アセチルガラクトサミン−4−スルファターゼ(MPS VI型における欠損酵素)であり、ERTで用いた。最後の処置から2週間後(すなわち37週齢時)に、ラットを殺処分した。
上記の処置の運動活性および歩行に対する作用も評価した。加速ロータロッド装置において(図2A)、最低速度(10RPM)では、ERT処置ラットも併用処置ラットも、未処置のMPS VI型ラット(平均70秒)とは対照的に、回転するバーの上に最大期間(180秒間)留まった。より速い速度(20および30RPM)では、併用処置群の方がERT群よりも有意に改善したことが観察された。図2Bは、これらのラットの歩行パターンの代表的な図を示している。全体的に、ERT処置ラットの方が未処置のMPS VI型ラットよりも長く、揃った足取りで速く歩行しており、これは、併用療法によって改善された。例えば、後足の動作の角度は、60°(未処置のMPS VI型)から45°(ERT)、30°(併用)に縮小し、前足の距離は2.8cm(未処置)から4.2cm(ERT)、5.1cm(併用)に改善した。
セラミドは、炎症、アポトーシス、および感染の誘発に関与するシグナル伝達スフィンゴリピドであり、MPS関節軟骨細胞に蓄積することが示されている(Simonaro et al.,"Involvement of the Toll−Like Receptor 4 Pathway and Use of TNF−Alpha Antagonists for Treatment of the Mucopolysaccharidoses,"Proc.Natl.Acad.Sci.107:222−7(2010)(参照によりその全体が本明細書に組み込まれる))。セラミドは、呼吸合併症を伴ういくつかの疾患から得られる気管にも蓄積し、軟骨のホメオスタシスにおいて重要な役割を果たすので(Becker et al.,"Accumulation of Ceramide in the Trachea and Intestine of Cystic Fibrosis Mice Causes Inflammation and Cell Death,"Biochem.Biophys.Res.Commun.17:368−74(2010)(参照によりその全体が本明細書に組み込まれる))、MPS VI型ラットの気管のセラミドについて調べるに至った。図4Bに示されているように、未処置およびERT処置済みのMPS VI型ラットの気管の上皮細胞において、強いセラミド染色が観察され、併用処置を行ったラットの気管では、正常な状態まで低下した。
上記の療法の効果をさらに調べるために、骨の成長板の組織学的分析を行った。MPS VI型ラットの成長板は、空胞のある大きい細胞により、野生型同腹ラットの成長板よりも厚い。加えて、MPSラットでは、成長板の正常な柱構成が崩壊しており、これが異常な骨の形成の一因となっている(Simonaro et al.,"Involvement of the Toll−Like Receptor 4 Pathway and Use of TNF−Alpha Antagonists for Treatment of the Mucopolysaccharidoses,"Proc.Natl.Acad.Sci.107:222−7(2010)、Metcalf et al.,"Mechanism of Shortened Bones in Mucopolysaccharidosis VII,"Mol.Genet.Metab.97:202−211(2009)(いずれの文献も、参照によりその全体が本明細書に組み込まれる))。いずれの処置プロトコールでも、MPS VI型の成長板の組織学的分析結果に対する顕著な作用は見られなかった。
最後に、処置済みおよび未処置のMPS VI型ラットから関節軟骨細胞を採取して、コラーゲンの発現とアポトーシスマーカーの変化を評価した。コラーゲンIIA1型およびX型のレベルは、MPS VI型ラットでは正常よりも低く、それぞれ、処置済みのラットでは未処置のMPS VI型ラットよりも高かった(図5A)。このウエスタンブロットで明らかに認められたように、併用処置によって、コラーゲンIIA1型の発現が増大し、この所見は、軟骨切片の免疫組織学的染色によって確認された(図5B)。これは、抗TNFα療法により、MPS VI型ラットの関節軟骨細胞におけるTUNEL染色が低減されたことを示した過去の研究と合致している(Simonaro et al.,"Involvement of the Toll−Like Receptor 4 Pathway and Use of TNF−Alpha Antagonists for Treatment of the Mucopolysaccharidoses,"Proc.Natl.Acad.Sci.107:222−7(2010)(参照によりその全体が本明細書に組み込まれる))。ERT処置および併用処置のいずれによっても、マトリックス分解酵素のアグリカナーゼであるADAMTS5の発現が低下したが、一方で、MPS VI型ラットから採取した軟骨細胞で増大しているアポトーシスマーカーPARP(Simonaro et al.,"Articular Chondrocytes From Animals With a Dermatan Sulfate Storage Disease Undergo a High Rate of Apoptosis and Release Nitric Oxide and Inflammatory Cytokines:A Possible Mechanism Underlying Degenerative Joint Disease in the Mucopolysaccharidoses,"Lab Investi.81:1319−1328(2001)(参照によりその全体が本明細書に組み込まれる))は、併用処置プロトコールによってのみ低下した。
ERTは、関節の可動性、運動性、および呼吸の改善を含め、明らかな臨床上の利点をMPS患者にもたらすが(Decker et al.,"Enzyme Replacement Therapy for Mucopolysaccharidosis VI: Growth and Pubertal Development in Patients Treated With Recombinant Human N−Acetylgalactosamine 4−Sulfatase,"J.Pediatr.Rehabil.Med.3:89−100(2010)、Miebach,E,"Enzyme Replacement Therapy in Mucopolysaccharidosis Type I.Treatment of Mucopolysaccharidosis Type II(Hunter syndrome)with Indursulfase:The Relevance of Clinical Trial End Points,"Acta Paediatr.Suppl.94:58−60(2005)(いずれの文献も、参照によりその全体が本明細書に組み込まれる))、ERTの軟骨および骨に対する効果は非常に限られている。これは、注入した遺伝子組み換え酵素の体内分布(注入した遺伝子組み換え酵素は、その血管への供給不足により、上記の組織に到達しにくい)、および、薬物の送達を遅らせるマトリックス内に標的細胞(例えば軟骨細胞)が埋め込まれている事実に起因し得る。したがって、ERT後のMPS患者における関節の可動性の改善は、軟骨および骨に対する直接的な作用よりも、軟組織(例えば腱)の変化に関係していると考えられる。加えて、遺伝子組み換え酵素を極めて低年齢のMPS動物の関節空間に直接注射したときでも、骨および軟骨への作用は非常に限られていた(Auclair et al.,"Long−Term Intra−Articular Administration of Recombinant Human N−Acetylgalactosamine 4−Sulfatase in Feline Mucopolysaccharidosis VI,"Mol.Gen.Metab.91:352(2007)(参照によりその全体が本明細書に組み込まれる))。したがって、上記の組織におけるERTの転帰を改善するという重要なニーズが依然として存在する。
本願出願人による過去の研究によって、MPS動物モデルでの軟骨および骨の病因におけるTLR4炎症経路の重要性が示された(Simonaro et al.,"Involvement of the Toll−Like Receptor 4 Pathway and Use of TNF−Alpha Antagonists for Treatment of the Mucopolysaccharidoses,"Proc.Natl.Acad.Sci.107:222−7(2010)(参照によりその全体が本明細書に組み込まれる))。直接的なTLR4阻害剤は臨床用としては認可されていないので、MPS VI型のラットモデルにおけるTLR4経路の下流産物によって抗TNFα療法の効果を評価した。ヒトにおいては、関節リウマチ、乾癬性関節炎、クローン病を含むいくつかの一般的な炎症性疾患の治療に、抗TNFα抗体(例えばRemicade(登録商標)(インフリキシマブ))が用いられている(Klaasen et al.,"Body Mass Index and Clinical Response to Infliximab in Rheumatoid Arthritis,"Arthritis Rheum.63:359−64(2011)、Rodgers et al.,"Etanercept,Infliximab and Adalimumab for the Treatment of Psoriatic Arthritis:A Systematic Review and Economic Evaluation,"Health Technol.Assess.15:1−329(2011)、Rutella et al.,"Infliximab Therapy Inhibits Inflammation−Induced Angiogenesis in the Mucosa of Patients With Crohn's Disease,"Am.J.Gastroenterol(2011)(いずれの文献も、参照によりその全体が本明細書に組み込まれる))。この抗TNFα療法によるMPS VI型ラットの処置により、炎症および関節軟骨のアポトーシスは低減したが、骨の成長または可動性では有意な改善が見られなかったことが見出された(Simonaro et al.,"Involvement of the Toll−Like Receptor 4 Pathway and Use of TNF−Alpha Antagonists for Treatment of the Mucopolysaccharidoses,"Proc.Natl.Acad.Sci.107:222−7(2010)(参照によりその全体が本明細書に組み込まれる))。
この実験では、ERTと抗TNFα療法との併用効果を評価して、ERT単独の場合よりも何らかの臨床的/病理学的利点があるかを判断した。TNFαに対してはラット特異的モノクローナル抗体を用い(CNTO1081)、ERTではヒト遺伝子組み換えN−アセチル−ガラクトサミン−4−スルファターゼ (Naglazyme(登録商標))を用いた。このヒト酵素に対する免疫応答は、静脈内注射後、MPS VI型ラットおよびネコで生じることが知られているが、これらの反応は通常、重篤ではない。免疫抑制を用いて、この応答を最小限にできるが(Connor,V,"Anti−TNF Therapies:A Comprehensive Analysis of Adverse Effects Associated With Immunosuppression,"Rheumatol.Int.31:327−37(2011)(参照によりその全体が本明細書に組み込まれる))、この実験では、すでに抗TNFα療法を実施済みであるので、本発明の実験設計には、既知の免疫抑制剤、追加の複合処置は加えなかった。いくつかのERT療法では、注入した酵素に対する免疫応答により、その効果が著しく限定される場合があり、抗TNFα療法とERTを併用する潜在的利点の1つは、この応答を最小限にして、追加の免疫抑制の必要性をなくす点であり得る。しかしながら、この潜在的利点は、感染の増大という潜在的リスクとのバランスを慎重に得なければならないので、比較臨床試験において慎重に評価しなければならない。
「原理を証明する」データを得るために、6カ月齢のMPS VI型ラット6匹をPPSで3カ月間処置した。6カ月齢のMPS VI型ラットは、骨疾患、軟骨疾患、および炎症性疾患を起こしており、したがって、この初期実験における具体的な目的は、PPSが、進行疾患を有するMPS動物において臨床的または病理学的所見のいずれかを遅延または逆転できたかを評価することであった。図6A〜6Dで見てとれるように、処置済みの9カ月齢のMPS VI型ラットの顔貌は、未処置のMPS VI型対照ラットと大きく異なっていた。図7A〜7Fによって示されているように、正常ラット(図7A、7D)、PPS処置を行ったMPS VI型ラット(図7C、7F)、およびPPS処置を行っていないMPS VI型ラット(図7B、7E)の頭蓋のX線写真およびマイクロCT画像を撮影した。処置済みのラット(図7C、7F)の方が、頭蓋が長く、眼(MPS VI型では通常、眼窩の異常により隆起している)は、正常のように凹所に置かれており、眼のポルフィリン分泌は著しく少なかった。示されている画像は、上記の動物における一般的な観察結果の代表的なものである。頭蓋X線写真により、これらの観察結果が確認され、処置群(すなわちPPS処置群)において、処置開始時の年齢が高かったにもかかわらず、有意に頭蓋および鼻がより長かったことが明らかになった(図7A〜7F)。
Claims (18)
- ポリ硫酸ペントサン(PPS)を含む、リソソーム蓄積障害を有する対象の治療において用いるための、薬学的組成物。
- 抗TNFα治療薬を含む、リソソーム蓄積障害を有する対象の治療において用いるための薬学的組成物であって、該抗TNFα治療薬がポリ硫酸ペントサン(PPS)であり、該治療が炎症性サイトカインを低減させ、かつ、リソソーム蓄積障害を有する対象が酵素補充療法によって治療されている、薬学的組成物。
- 酵素補充療法薬および抗TNFα治療薬を含む、リソソーム蓄積障害を有する対象の治療において用いるための薬学的組成物であって、該抗TNFα治療薬がポリ硫酸ペントサン(PPS)である、薬学的組成物。
- 基質抑制療法薬および抗TNFα治療薬を含む、リソソーム蓄積障害と関連する骨格病変を有する対象の治療において用いるための薬学的組成物であって、該抗TNFα治療薬がポリ硫酸ペントサン(PPS)である、薬学的組成物。
- 前記酵素補充療法のための薬剤が、アルグルセラーゼ、イミグルセラーゼ、ベラグルセラーゼアルファ、ラロニダーゼ、アガルシダーゼベータ、ガルスルファーゼ、アルグルコシダーゼアルファ、N−アセチルガラクトサミン−6スルファターゼ、およびイデュルスルファーゼからなる群から選択される、請求項2または3に記載の薬学的組成物。
- 前記対象が、骨髄移植、シャペロン療法、および遺伝子療法からなる群から任意で選択される追加の療法を実施される、請求項1〜3のいずれか一項に記載の薬学的組成物。
- 前記対象が、酵素補充療法、骨髄移植、シャペロン療法、および遺伝子療法からなる群から任意で選択される追加の療法を実施される、請求項4に記載の薬学的組成物。
- 前記リソソーム蓄積障害が、スフィンゴリピドーシス、ムコ多糖蓄積症(ムコ多糖症)、糖タンパク症(glycoproteinoses)、ムコリピドーシス、糖原病II型、セロイドリポフスチン沈着症、およびその他のリソソームタンパク質機能異常からなる群から選択される、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 経口的に、吸入により、鼻腔内滴下により、局所的に、経皮的に、非経口的に、皮下に、静脈内注射により、動脈内注射により、筋内注射により、胸膜内に(intraplurally)、腹腔内に、または粘膜への塗布により投与されるように用いられる、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 1回より多く投与されるように用いられる、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 前記対象が乳児、年少者または成人である、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 前記対象が、リソソーム蓄積障害と関連する骨格病変を有する、請求項1〜3のいずれか一項に記載の薬学的組成物。
- 前記基質抑制療法薬が、ミグルスタットおよびエリグルスタットからなる群から選択される、請求項4に記載の薬学的組成物。
- 前記リソソーム蓄積障害が、ファブリー病、ゴーシェ病、およびポンペ病からなる群から選択される、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 前記リソソーム蓄積障害がムコ多糖蓄積症(ムコ多糖症)である、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 前記ムコ多糖症が、MPS I型(ハーラー/シャイエ症候群)、MPS II型(ハンター症候群)、MPS VI型(マロトー・ラミー症候群)、MPS III型(サンフィリッポ症候群)、MPS IV型(モルキオ症候群)、またはMPS VII型(スライ病)である、請求項15に記載の薬学的組成物。
- 前記リソソーム蓄積障害がスフィンゴリピドーシスである、請求項1〜4のいずれか一項に記載の薬学的組成物。
- 前記スフィンゴリピドーシスがニーマンピック病である、請求項17に記載の薬学的組成物。
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