JP2023015402A - 治療用酸性セラミダーゼ組成物ならびにそれを作製および使用する方法 - Google Patents
治療用酸性セラミダーゼ組成物ならびにそれを作製および使用する方法 Download PDFInfo
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Abstract
Description
本発明は、治療用酸性セラミダーゼ組成物ならびにそれを作製および使用する方法に関する。
酸性セラミダーゼ(「AC」;N-アシルスフィンゴシンデアシラーゼ、I.U.B.M.B. Enzyme No. EC 3.5.1.23)は、ヒト遺伝障害のファーバー脂肪肉芽腫症(「FD」)におけるその関与のために、セラミダーゼ酵素ファミリーの最も広く研究されたメンバーである。該タンパク質は、複数の供給源から精製されており、ヒトおよびマウスのcDNAおよび遺伝子が得られている(Bernardo et al., "Purification, Characterization, and Biosynthesis of Human Acid Ceramidase," J. Biol. Chem. 270:11098-102 (1995)(非特許文献1); Koch et al., "Molecular Cloning and Characterization of a Full-length Complementary DNA Encoding Human Acid Ceramidase. Identification of the First Molecular Lesion Causing Farber Disease," J. Biol. Chem. 2711:33110-5 (1996)(非特許文献2); Li et al., "Cloning and Characterization of the Full-length cDNA and Genomic Sequences Encoding Murine Acid Ceramidase," Genomics 50:267-74 (1998)(非特許文献3); Li et al., "The Human Acid Ceramidase Gene (ASAH): Chromosomal Location, Mutation Analysis, and Expression," Genomics 62:223-31 (1999)(非特許文献4))。このセラミダーゼおよび他のセラミダーゼのバイオロジーにおける関心の高まりは、これらの酵素がセラミド代謝において中心的な役割を果たすという事実から生じる。
[本発明1001]
不活性酸性セラミダーゼ前駆体を含有する培地を提供する段階;
不活性酸性セラミダーゼ前駆体の一部を活性酸性セラミダーゼに変換するのに有効な条件下で該培地をインキュベートする段階;および
インキュベートした培地を、不活性酸性セラミダーゼ前駆体および活性酸性セラミダーゼを含むセラミダーゼ混合物として回収する段階
を含む、治療用組成物を生成する方法。
[本発明1002]
インキュベートする段階が、該インキュベートする段階を24時間、pH4および温度4℃または37℃において、その他は一致した条件下で行うときに達成される、不活性酸性セラミダーゼ前駆体の活性酸性セラミダーゼへの変換率と比較して、該変換率を低減させるのに有効な条件下で行われる、本発明1001の方法。
[本発明1003]
インキュベートする段階中のセラミダーゼ混合物のpHが、4.0超かつ6.5以下である、本発明1002の方法。
[本発明1004]
インキュベートする段階中のセラミダーゼ混合物の温度が、少なくとも-30℃かつ37℃未満である、本発明1002の方法。
[本発明1005]
インキュベートする段階が、酸性スフィンゴミエリナーゼ活性を取り除くのに有効な条件下で培地を加熱することを含む、本発明1001の方法。
[本発明1006]
培地を提供する段階が、
酸性セラミダーゼをコードするDNAで形質転換した細胞を提供すること、および
不活性酸性セラミダーゼ前駆体を含有する培地を生成するのに有効な条件下で該形質転換した細胞を培養すること
を含む、本発明1001の方法。
[本発明1007]
インキュベートする段階が、該インキュベートする段階を24時間、pH4および温度4℃または37℃において、その他は一致した条件下で行うときに達成される、不活性酸性セラミダーゼ前駆体の活性酸性セラミダーゼへの変換率と比較して、該変換率を高めるのに有効な条件下で行われる、本発明1001の方法。
[本発明1008]
不活性酸性セラミダーゼ前駆体、および
活性酸性セラミダーゼ
を含むセラミダーゼ混合物と;
薬学的に許容される担体と
を含む治療用組成物。
[本発明1009]
セラミダーゼ混合物において、不活性酸性セラミダーゼ前駆体の量が活性酸性セラミダーゼの量より多い、本発明1008の治療用組成物。
[本発明1010]
セラミダーゼ混合物において、不活性酸性セラミダーゼ前駆体の量が活性酸性セラミダーゼの量より少ない、本発明1008の治療用組成物。
[本発明1011]
セラミダーゼ混合物が、5~95重量%の不活性酸性セラミダーゼ前駆体および95~5重量%の活性酸性セラミダーゼを含む、本発明1008の治療用組成物。
[本発明1012]
セラミダーゼ混合物が、20~80重量%の不活性酸性セラミダーゼ前駆体および80~20重量%の活性酸性セラミダーゼを含む、本発明1011の治療用組成物。
[本発明1013]
セラミダーゼ混合物が、30~70重量%の不活性酸性セラミダーゼ前駆体および70~30重量%の活性酸性セラミダーゼを含む、本発明1011の治療用組成物。
[本発明1014]
セラミダーゼ混合物が、40~60重量%の不活性酸性セラミダーゼ前駆体および60~40重量%の活性酸性セラミダーゼを含む、本発明1011の治療用組成物。
[本発明1015]
セラミダーゼ混合物が、55~95重量%の不活性酸性セラミダーゼ前駆体および45~5重量%の活性酸性セラミダーゼを含む、本発明1011の治療用組成物。
[本発明1016]
セラミダーゼ混合物が、70~95重量%の不活性酸性セラミダーゼ前駆体および30~5重量%の活性酸性セラミダーゼを含む、本発明1011の治療用組成物。
[本発明1017]
セラミダーゼ混合物が、80~90重量%の不活性酸性セラミダーゼ前駆体および20~10重量%の活性酸性セラミダーゼを含む、本発明1011の治療用組成物。
[本発明1018]
アジュバントをさらに含む、本発明1008の治療用組成物。
[本発明1019]
アジュバントが、フラゲリン、フロイント完全または不完全アジュバント、水酸化アルミニウム、リゾレシチン、pluronicポリオール、ポリアニオン、ペプチド、油乳剤、ジニトロフェノール、iscomatrix、およびリポソームポリカチオンDNA粒子からなる群より選択される、本発明1018の治療用組成物。
[本発明1020]
酸性セラミダーゼ処置の方法において、該処置で使用される酸性セラミダーゼを、不活性酸性セラミダーゼ前駆体および活性酸性セラミダーゼを含むセラミダーゼ混合物として製剤化する段階を含む、改善。
[本発明1021]
前記セラミダーゼ混合物により軟骨細胞を生成する段階を含む、本発明1020の方法。
[本発明1022]
軟骨細胞に分化する可能性を有する細胞の集団を選択する段階、および
選択した細胞の細胞集団を前記セラミダーゼ混合物で処置し、選択した集団中の1つまたは複数の細胞を軟骨細胞へと変換する段階
をさらに含む、本発明1021の方法。
[本発明1023]
選択した集団中の細胞が哺乳類の細胞である、本発明1022の方法。
[本発明1024]
選択した細胞集団が、骨髄細胞、間葉系幹細胞および/または線維芽細胞の集団を含む、本発明1023の方法。
[本発明1025]
前記セラミダーゼ混合物で軟骨形成を促進する段階を含む、本発明1020の方法。
[本発明1026]
軟骨細胞への分化の必要がある幹細胞の集団を選択する段階;
該幹細胞の集団を前記セラミダーゼ混合物で処置し、該幹細胞集団内の間葉系幹細胞を濃縮する段階;および
濃縮した間葉系幹細胞の集団を該セラミダーゼ混合物で処置し、間葉系幹細胞の軟骨細胞への分化を促進する段階
を含む、本発明1025の方法。
[本発明1027]
間葉系幹細胞が哺乳類のものである、本発明1026の方法。
[本発明1028]
前記セラミダーゼ混合物を対象に投与し、関節の疾患または障害について対象を処置する段階を含む、本発明1020の方法。
[本発明1029]
関節の疾患または障害が、変形性関節症、関節リウマチ、ムコ多糖症、変性関節疾患、関節損傷、およびファーバー脂肪肉芽腫症からなる群より選択される、本発明1028の方法。
[本発明1030]
前記セラミダーゼ混合物を対象に投与し、神経変性疾患または神経変性障害について対象を処置する段階を含む、本発明1020の方法。
[本発明1031]
神経変性疾患または神経変性障害が、アルツハイマー病、前頭側頭型認知症、レビー小体型認知症、プリオン病、パーキンソン病、ハンチントン病、進行性核上性麻痺、大脳皮質基底核変性症、多系統萎縮症、筋萎縮性側索硬化症、封入体筋炎、変性ミオパチー、脊髄小脳萎縮症、代謝性ニューロパチー、糖尿病性ニューロパチー、内分泌性ニューロパチー、起立性低血圧症、脳損傷、脊髄損傷、脳卒中、および脊髄性筋萎縮症などの運動ニューロン疾患からなる群より選択される、本発明1030の方法。
[本発明1032]
前記セラミダーゼ混合物を対象に投与し、心疾患または心障害について対象を処置する段階を含む、本発明1020の方法。
[本発明1033]
心疾患または心障害が、心臓疾患、心外傷、アテローム性動脈硬化症、血栓症、および心筋細胞アポトーシスからなる群より選択される、本発明1032の方法。
[本発明1034]
前記セラミダーゼ混合物を対象に投与し、糖尿病について対象を処置する段階を含む、本発明1020の方法。
[本発明1035]
前記セラミダーゼ混合物を対象に投与し、嚢胞性線維症、COPDおよび/または開放創を有する対象における病原体感染について対象を処置する段階を含む、本発明1020の方法。
[本発明1036]
病原体感染が、ウイルス感染、真菌感染、プリオン感染、または細菌感染である、本発明1035の方法。
[本発明1037]
前記セラミダーゼ混合物を対象に投与し、セラミド蓄積感染について対象を処置する段階を含む、本発明1020の方法。
[本発明1038]
前記セラミダーゼ混合物を対象に投与し、ファーバー病について対象を処置する段階を含む、本発明1020の方法。
[本発明1039]
前記処置が、前記セラミダーゼ混合物を、経口で、吸入により、鼻腔内滴下により、局所に、経皮で、非経口で、皮下に、静脈内注射、動脈内注射、筋肉内注射、胸膜内に、腹腔内に、髄腔内に、または粘膜への適用により対象に投与することを含む、本発明1020の方法。
[本発明1040]
前記投与を繰り返す段階をさらに含む、本発明1039の方法。
[本発明1041]
前記処置がインビボで行われる、本発明1020の方法。
[本発明1042]
前記処置がインビトロで行われる、本発明1020の方法。
[本発明1043]
セラミドレベルを低減させる1つまたは複数のさらなる作用物質を投与する段階をさらに含む、本発明1020の方法。
本発明の第1の局面は、セラミダーゼ混合物および薬学的に許容される担体を含む治療用組成物に関する。セラミダーゼ混合物には、不活性AC前駆体および活性ACが含まれる。
ACαサブユニットは、位置22のアミノ酸から始まり、位置142まで続き(SEQ ID NO: 1に太字で示す)、一方、ACのβサブユニットは、位置143のアミノ酸から始まり、位置395まで続く(SEQ ID NO: 1に斜体で示す)。
rACの調製(ロット6およびロット7)-ヒトAsah1遺伝子を過剰発現するチャイニーズハムスター卵巣細胞を作製し、rACを培地から精製した(その全体が参照により本明細書に組み入れられる、He et al., "Purification and Characterization of Recombinant, Human Acid Ceramidase. Catalytic Reactions and Interactions With Sphingomyelinase," J. Biol. Chem. 278:32978-32986 (2003))。ロット6の精製後、インビトロ操作を何も行わなかった(不活性AC前駆体の量がより多い)。ロット7の酵素の精製後、rACをpH 4のクエン酸リン酸緩衝液中で37℃で3時間インキュベートした。
活性セラミダーゼがより少ないrAC調製物は、活性セラミダーゼがより多いものより優れている(図1A~1C)。図1Aに示すように、ウエスタンブロット解析によって、2種類の異なるバイオリアクター泳動物(ロット6およびロット7)における不活性前駆体rACに対する活性(α/β)rACの相対量が示された。ロット7はロット6より活性rACを多く有していた。インビトロ実施例(IVFおよび軟骨細胞)は、比がおよそ90:10(不活性:活性)(ロット6)とおよそ80:20(不活性:活性)(ロット7)であった2種類のrAC調製物を比較した(図1A)。標準的な形態学的方法(例えば、膜の完全性など) (その全体が参照により本明細書に組み入れられる、Eliyahu et al., "Acid Ceramidase Improves the Quality of Oocytes and Embryos and the Outcome of In Vitro Fertilization," FASEB J. 24:1229-1238 (2010))を用いて、アポトーシスを24時間の時点で測定した。
混入酸性スフィンゴミエリナーゼ活性(ASM)をrAC調製物から取り除く方法を開発した。これには、60℃で10~20分間の最終rAC調製物のインキュベーションが必要とされる。このインキュベーションは、rAC(活性、または不活性対活性の比)には影響を与えないが、ASM活性を全て取り除き、これは製造に不可欠である(図2)。
組換えヒト酸性セラミダーゼ(rhAC)を過剰発現しかつ分泌するチャイニーズハムスター卵巣細胞から、馴化培地(DMEM、pH 6.8、10%ウシ胎仔血清を含有)を収集した(He et al., "Purification and Characterization of Recombinant, Human Acid Ceramidase. Catalytic Reactions and Interactions With Acid Sphingomyelinase," J. Biol. Chem. 278:32978-32986 (2003)、その全体が参照により本明細書に組み入れられる)。細胞をT-75 mmフラスコ中で約100%培養密度まで増殖させ、次いで、さらに4日間の増殖の後に、培地を収集した。収集した培地を0.22 mm膜を通してろ過してデブリを取り除き、37℃インキュベータ内に様々な長さの時間で置いた。インキュベーション時間の終わりに、培地を-20℃でアッセイ前に凍結した。AC活性(図3)を以前に記載された(He et al., Anal Biochem, 274:264 (1999)、その全体が参照により本明細書に組み入れられる)ように決定した:反応混合物を37℃で1時間インキュベートした。ACウエスタンブロット(図4):6.5 μl/レーンをαサブユニットに対するマウス抗ヒトACモノクローナル抗体(1:300, #SC136275, Santa Cruz)を用いて展開した。このデータは、rhACを含有する培地の37℃で3~17日間のインビトロインキュベーションが不活性前駆体の活性酵素への変換をもたらすことを示す(αサブユニットおよび酵素活性の増加により表される)。
以前に記載されたように(He et al., "Purification and Characterization of Recombinant, Human Acid Ceramidase. Catalytic Reactions and Interactions With Acid Sphingomyelinase," J. Biol. Chem. 278:32978-32986 (2003)、その全体が参照により本明細書に組み入れられる)、精製した組換えヒトAC(rhAC; EMEM中に4 ug/ul、pH 6.8)を過剰発現したチャイニーズハムスター卵巣細胞の培地から単離した。ACウエスタンブロット(図5):6.5 μl/レーンをαサブユニットに対するマウス抗ヒトACモノクローナル抗体(1:300, #SC136275, Santa Cruz)を用いて展開した。このデータは、37℃で24時間の精製したrhACのインビトロインキュベーション(図5A)が、前駆体の活性型への完全な変換をもたらしたことを示す。1~8時間のインキュベーション(図5B)は、線形の変換の進行を示した。
SEQUENCE LISTING
<110> Icahn School of Medicine at Mount Sinai
<120> THERAPEUTIC ACID CERAMIDASE COMPOSITIONS AND METHODS OF MAKING
AND USING THEM
<150> US 61/784,594
<151> 2013-03-14
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 395
<212> PRT
<213> Homo sapiens
<400> 1
Met Pro Gly Arg Ser Cys Val Ala Leu Val Leu Leu Ala Ala Ala Val
1 5 10 15
Ser Cys Ala Val Ala Gln His Ala Pro Pro Trp Thr Glu Asp Cys Arg
20 25 30
Lys Ser Thr Tyr Pro Pro Ser Gly Pro Thr Tyr Arg Gly Ala Val Pro
35 40 45
Trp Tyr Thr Ile Asn Leu Asp Leu Pro Pro Tyr Lys Arg Trp His Glu
50 55 60
Leu Met Leu Asp Lys Ala Pro Met Leu Lys Val Ile Val Asn Ser Leu
65 70 75 80
Lys Asn Met Ile Asn Thr Phe Val Pro Ser Gly Lys Val Met Gln Val
85 90 95
Val Asp Glu Lys Leu Pro Gly Leu Leu Gly Asn Phe Pro Gly Pro Phe
100 105 110
Glu Glu Glu Met Lys Gly Ile Ala Ala Val Thr Asp Ile Pro Leu Gly
115 120 125
Glu Ile Ile Ser Phe Asn Ile Phe Tyr Glu Leu Phe Thr Ile Cys Thr
130 135 140
Ser Ile Val Ala Glu Asp Lys Lys Gly His Leu Ile His Gly Arg Asn
145 150 155 160
Met Asp Phe Gly Val Phe Leu Gly Trp Asn Ile Asn Asn Asp Thr Trp
165 170 175
Val Ile Thr Glu Gln Leu Lys Pro Leu Thr Val Asn Leu Asp Phe Gln
180 185 190
Arg Asn Asn Lys Thr Val Phe Lys Ala Ser Ser Phe Ala Gly Tyr Val
195 200 205
Gly Met Leu Thr Gly Phe Lys Pro Gly Leu Phe Ser Leu Thr Leu Asn
210 215 220
Glu Arg Phe Ser Ile Asn Gly Gly Tyr Leu Gly Ile Leu Glu Trp Ile
225 230 235 240
Leu Gly Lys Lys Asp Ala Met Trp Ile Gly Phe Leu Thr Arg Thr Val
245 250 255
Leu Glu Asn Ser Thr Ser Tyr Glu Glu Ala Lys Asn Leu Leu Thr Lys
260 265 270
Thr Lys Ile Leu Ala Pro Ala Tyr Phe Ile Leu Gly Gly Asn Gln Ser
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Gly Glu Gly Cys Val Ile Thr Arg Asp Arg Lys Glu Ser Leu Asp Val
290 295 300
Tyr Glu Leu Asp Ala Lys Gln Gly Arg Trp Tyr Val Val Gln Thr Asn
305 310 315 320
Tyr Asp Arg Trp Lys His Pro Phe Phe Leu Asp Asp Arg Arg Thr Pro
325 330 335
Ala Lys Met Cys Leu Asn Arg Thr Ser Gln Glu Asn Ile Ser Phe Glu
340 345 350
Thr Met Tyr Asp Val Leu Ser Thr Lys Pro Val Leu Asn Lys Leu Thr
355 360 365
Val Tyr Thr Thr Leu Ile Asp Val Thr Lys Gly Gln Phe Glu Thr Tyr
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Leu Arg Asp Cys Pro Asp Pro Cys Ile Gly Trp
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Claims (43)
- 不活性酸性セラミダーゼ前駆体を含有する培地を提供する段階;
不活性酸性セラミダーゼ前駆体の一部を活性酸性セラミダーゼに変換するのに有効な条件下で該培地をインキュベートする段階;および
インキュベートした培地を、不活性酸性セラミダーゼ前駆体および活性酸性セラミダーゼを含むセラミダーゼ混合物として回収する段階
を含む、治療用組成物を生成する方法。 - インキュベートする段階が、該インキュベートする段階を24時間、pH4および温度4℃または37℃において、その他は一致した条件下で行うときに達成される、不活性酸性セラミダーゼ前駆体の活性酸性セラミダーゼへの変換率と比較して、該変換率を低減させるのに有効な条件下で行われる、請求項1に記載の方法。
- インキュベートする段階中のセラミダーゼ混合物のpHが、4.0超かつ6.5以下である、請求項2に記載の方法。
- インキュベートする段階中のセラミダーゼ混合物の温度が、少なくとも-30℃かつ37℃未満である、請求項2に記載の方法。
- インキュベートする段階が、酸性スフィンゴミエリナーゼ活性を取り除くのに有効な条件下で培地を加熱することを含む、請求項1に記載の方法。
- 培地を提供する段階が、
酸性セラミダーゼをコードするDNAで形質転換した細胞を提供すること、および
不活性酸性セラミダーゼ前駆体を含有する培地を生成するのに有効な条件下で該形質転換した細胞を培養すること
を含む、請求項1に記載の方法。 - インキュベートする段階が、該インキュベートする段階を24時間、pH4および温度4℃または37℃において、その他は一致した条件下で行うときに達成される、不活性酸性セラミダーゼ前駆体の活性酸性セラミダーゼへの変換率と比較して、該変換率を高めるのに有効な条件下で行われる、請求項1に記載の方法。
- 不活性酸性セラミダーゼ前駆体、および
活性酸性セラミダーゼ
を含むセラミダーゼ混合物と;
薬学的に許容される担体と
を含む治療用組成物。 - セラミダーゼ混合物において、不活性酸性セラミダーゼ前駆体の量が活性酸性セラミダーゼの量より多い、請求項8に記載の治療用組成物。
- セラミダーゼ混合物において、不活性酸性セラミダーゼ前駆体の量が活性酸性セラミダーゼの量より少ない、請求項8に記載の治療用組成物。
- セラミダーゼ混合物が、5~95重量%の不活性酸性セラミダーゼ前駆体および95~5重量%の活性酸性セラミダーゼを含む、請求項8に記載の治療用組成物。
- セラミダーゼ混合物が、20~80重量%の不活性酸性セラミダーゼ前駆体および80~20重量%の活性酸性セラミダーゼを含む、請求項11に記載の治療用組成物。
- セラミダーゼ混合物が、30~70重量%の不活性酸性セラミダーゼ前駆体および70~30重量%の活性酸性セラミダーゼを含む、請求項11に記載の治療用組成物。
- セラミダーゼ混合物が、40~60重量%の不活性酸性セラミダーゼ前駆体および60~40重量%の活性酸性セラミダーゼを含む、請求項11に記載の治療用組成物。
- セラミダーゼ混合物が、55~95重量%の不活性酸性セラミダーゼ前駆体および45~5重量%の活性酸性セラミダーゼを含む、請求項11に記載の治療用組成物。
- セラミダーゼ混合物が、70~95重量%の不活性酸性セラミダーゼ前駆体および30~5重量%の活性酸性セラミダーゼを含む、請求項11に記載の治療用組成物。
- セラミダーゼ混合物が、80~90重量%の不活性酸性セラミダーゼ前駆体および20~10重量%の活性酸性セラミダーゼを含む、請求項11に記載の治療用組成物。
- アジュバントをさらに含む、請求項8に記載の治療用組成物。
- アジュバントが、フラゲリン、フロイント完全または不完全アジュバント、水酸化アルミニウム、リゾレシチン、pluronicポリオール、ポリアニオン、ペプチド、油乳剤、ジニトロフェノール、iscomatrix、およびリポソームポリカチオンDNA粒子からなる群より選択される、請求項18に記載の治療用組成物。
- 酸性セラミダーゼ処置の方法において、該処置で使用される酸性セラミダーゼを、不活性酸性セラミダーゼ前駆体および活性酸性セラミダーゼを含むセラミダーゼ混合物として製剤化する段階を含む、改善。
- 前記セラミダーゼ混合物により軟骨細胞を生成する段階を含む、請求項20に記載の方法。
- 軟骨細胞に分化する可能性を有する細胞の集団を選択する段階、および
選択した細胞の細胞集団を前記セラミダーゼ混合物で処置し、選択した集団中の1つまたは複数の細胞を軟骨細胞へと変換する段階
をさらに含む、請求項21に記載の方法。 - 選択した集団中の細胞が哺乳類の細胞である、請求項22に記載の方法。
- 選択した細胞集団が、骨髄細胞、間葉系幹細胞および/または線維芽細胞の集団を含む、請求項23に記載の方法。
- 前記セラミダーゼ混合物で軟骨形成を促進する段階を含む、請求項20に記載の方法。
- 軟骨細胞への分化の必要がある幹細胞の集団を選択する段階;
該幹細胞の集団を前記セラミダーゼ混合物で処置し、該幹細胞集団内の間葉系幹細胞を濃縮する段階;および
濃縮した間葉系幹細胞の集団を該セラミダーゼ混合物で処置し、間葉系幹細胞の軟骨細胞への分化を促進する段階
を含む、請求項25に記載の方法。 - 間葉系幹細胞が哺乳類のものである、請求項26に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、関節の疾患または障害について対象を処置する段階を含む、請求項20に記載の方法。
- 関節の疾患または障害が、変形性関節症、関節リウマチ、ムコ多糖症、変性関節疾患、関節損傷、およびファーバー脂肪肉芽腫症からなる群より選択される、請求項28に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、神経変性疾患または神経変性障害について対象を処置する段階を含む、請求項20に記載の方法。
- 神経変性疾患または神経変性障害が、アルツハイマー病、前頭側頭型認知症、レビー小体型認知症、プリオン病、パーキンソン病、ハンチントン病、進行性核上性麻痺、大脳皮質基底核変性症、多系統萎縮症、筋萎縮性側索硬化症、封入体筋炎、変性ミオパチー、脊髄小脳萎縮症、代謝性ニューロパチー、糖尿病性ニューロパチー、内分泌性ニューロパチー、起立性低血圧症、脳損傷、脊髄損傷、脳卒中、および脊髄性筋萎縮症などの運動ニューロン疾患からなる群より選択される、請求項30に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、心疾患または心障害について対象を処置する段階を含む、請求項20に記載の方法。
- 心疾患または心障害が、心臓疾患、心外傷、アテローム性動脈硬化症、血栓症、および心筋細胞アポトーシスからなる群より選択される、請求項32に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、糖尿病について対象を処置する段階を含む、請求項20に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、嚢胞性線維症、COPDおよび/または開放創を有する対象における病原体感染について対象を処置する段階を含む、請求項20に記載の方法。
- 病原体感染が、ウイルス感染、真菌感染、プリオン感染、または細菌感染である、請求項35に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、セラミド蓄積感染について対象を処置する段階を含む、請求項20に記載の方法。
- 前記セラミダーゼ混合物を対象に投与し、ファーバー病について対象を処置する段階を含む、請求項20に記載の方法。
- 前記処置が、前記セラミダーゼ混合物を、経口で、吸入により、鼻腔内滴下により、局所に、経皮で、非経口で、皮下に、静脈内注射、動脈内注射、筋肉内注射、胸膜内に、腹腔内に、髄腔内に、または粘膜への適用により対象に投与することを含む、請求項20に記載の方法。
- 前記投与を繰り返す段階をさらに含む、請求項39に記載の方法。
- 前記処置がインビボで行われる、請求項20に記載の方法。
- 前記処置がインビトロで行われる、請求項20に記載の方法。
- セラミドレベルを低減させる1つまたは複数のさらなる作用物質を投与する段階をさらに含む、請求項20に記載の方法。
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DK2968479T3 (da) | 2019-08-12 |
JP6832158B2 (ja) | 2021-02-24 |
IL241390B (en) | 2020-03-31 |
US10918702B2 (en) | 2021-02-16 |
IL272214A (en) | 2020-03-31 |
EP3659619A1 (en) | 2020-06-03 |
JP2021042227A (ja) | 2021-03-18 |
US20190231857A1 (en) | 2019-08-01 |
EP2968479A4 (en) | 2016-07-27 |
CA2905449A1 (en) | 2014-10-02 |
IL304629A (en) | 2023-09-01 |
MX2022003486A (es) | 2022-04-25 |
US20160038574A1 (en) | 2016-02-11 |
ES2739811T3 (es) | 2020-02-04 |
IL241390A0 (en) | 2015-11-30 |
EP2968479A1 (en) | 2016-01-20 |
IL272214B (en) | 2022-01-01 |
HK1220399A1 (zh) | 2017-05-05 |
JP6832386B2 (ja) | 2021-02-24 |
PL2968479T3 (pl) | 2019-10-31 |
BR112015024538A2 (pt) | 2018-05-08 |
US9937246B2 (en) | 2018-04-10 |
HUE046113T2 (hu) | 2020-02-28 |
JP2019150042A (ja) | 2019-09-12 |
EP2968479B1 (en) | 2019-07-17 |
US20180193436A1 (en) | 2018-07-12 |
US10238721B2 (en) | 2019-03-26 |
MX2015012471A (es) | 2016-08-03 |
IL288427A (en) | 2022-01-01 |
WO2014160390A1 (en) | 2014-10-02 |
JP2016520519A (ja) | 2016-07-14 |
HRP20191361T1 (hr) | 2019-11-01 |
PT2968479T (pt) | 2019-08-07 |
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