JP2020512338A - 腎臓疾患の治療方法 - Google Patents
腎臓疾患の治療方法 Download PDFInfo
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Abstract
Description
本明細書において使用される活性化合物は、ケモカインタンパク質であるストロマ細胞由来因子1(SDF−1)である。本化合物は、C−X−Cモチーフケモカイン12(CXCL12)としても公知であり、ヒトにおいては、これは、CXCL12遺伝子によってコードされる。SDF−1は、例えば、M.D’Apuzzoら、The chemokine SDF−1,stromal cell−derived factor 1,attracts early stage B cell precursors via the chemokine receptor CXCR4、Eur.J.Immunol.、27巻、1788〜1793頁(1997年);Y.Tabata、米国特許第8,435,953号、ならびにPennら、米国特許第8,513,213号および米国特許第8,513,007号;ならびにS.Itescu、米国特許第7,662,392号において、公知かつ記載されており、これらの開示は、引用することでそれらの全体が本明細書の記載の一部をなすものとする。J.K.Williams、国際公開第2015/171417号も参照のこと。
上記に記載の活性化合物は、公知技術に従って、投与のために、医薬担体中で製剤化されてもよい。例えば、Remington、The Science And Practice of Pharmacy(第9版、1995年)を参照のこと。本発明による医薬製剤の製造において、活性化合物(その生理学的に許容される塩を含む)は、典型的には、とりわけ、許容される担体と混合される。当然ながら、担体は、製剤中の任意の他の成分と適合するという意味で許容されていなければならず、かつ患者に有害であってはならない。担体は、固体もしくは液体、または両方であってもよく、好ましくは、単位用量製剤、例えば、錠剤として、化合物と製剤化され、これは、0.01重量%または0.5重量%から95重量%または99重量%の活性化合物を含有していてもよい。1つまたは複数の活性化合物が、本発明の製剤中に組み込まれていてもよく、これは、1つまたは複数の補助成分を含んでいてもよい、構成要素と混合することを含む、調剤学の周知技術のいずれかによって調製され得る。
上述のように、本発明は、活性化合物(その薬学的に許容される塩を含む)を非経口投与のための薬学的に許容される担体中に含む、医薬製剤を提供する。
いくつかの実施形態において、SDF−1は、血管新生増殖因子(例えば、血管内皮増殖因子(VEGF))と組み合わせて投与される。例えば、Schreinerらに対する米国特許第6,352,975号;Chadeら、Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney:a novel potential therapeutic approach、Am J Physiol Renal Physiol、2012年5月15日、302巻(10号)、F1342〜50頁;Chadeらに対する米国特許出願公開第2016/077618号を参照のこと。
慢性腎臓疾患(CKD)は、推定ですべてのネコの1%から3%に影響を及ぼす。ネコ科動物のCKDの有病率は、年齢とともに増加し、15歳以上のネコの30%から50%程度がCKDを有しており、CKDの有病率は、増加していると思われる。
CXCL12を、実験的に生じさせた慢性腎臓疾患を有するネコの腎臓に直接投与する。
SDF−1(4)、担体(4)、Txなし(4)、対照(1)の4群を試験した。CKDモデルを、上記に記載のようにして、ネコにおいて外科的に作成した(n=12)。200ngの合計投与量の後腹膜注射を、超音波誘導の下、左腎皮質へのそれぞれ66.7ngの3回の注射で、左腎臓(n=6)に行った。
腎臓の容積、ならびに血液および尿の尺度に対するCXCL12の有益な効果があった。しかしながら、コラーゲンを含有する担体の注射(国際公開第2015/171417号を参照のこと)は、いくらかの腎臓の病理を引き起こす場合があり、および/またはこれらの尺度のいくらかの有害な変化を引き起こす場合がある。図1Aから図1Dに示す組織学的分析は、損傷が、腎臓の皮質−髄質、線維症および細胞損傷をもたらし、SDF−1(CXCL12)が、より正常な皮質−髄質構造を回復することを証拠付ける。結果は有望であるが、少数の動物の試験であるため、今のところ統計学的有意性はない。
Claims (25)
- 腎臓疾患を患っているかまたは発症するリスクがある対象を治療する方法であって、前記対象の腎臓に治療有効量でストロマ細胞由来因子1(SDF−1)を投与することを含む、方法。
- 前記腎臓疾患が、急性腎不全、慢性腎臓疾患、末期の腎疾患または貧血である、請求項1に記載の方法。
- 前記対象が、ヒト対象である、請求項1または請求項2に記載の方法。
- 前記対象が、非ヒト哺乳動物の対象である、請求項1または請求項2に記載の方法。
- 前記対象が、ネコ、イヌまたはウマである、請求項1または請求項2に記載の方法。
- 前記対象が、飼いネコである、請求項1または請求項2に記載の方法。
- 前記腎臓疾患が、慢性間質性腎炎である、請求項1から6のいずれか1項に記載の方法。
- 前記SDF−1が薬学的に許容される担体中に提供される、請求項1から7のいずれか1項に記載の方法。
- 前記薬学的に許容される担体が、無菌である(例えば、エンドトキシンフリーもしくはパイロジェンフリーの水、またはエンドトキシンフリーもしくはパイロジェンフリーの水の生理食塩水)、請求項8に記載の方法。
- 前記投与するステップが、前記腎臓へのSDF−1の直接投与によって行われる、請求項1から9のいずれか1項に記載の方法。
- 前記直接投与が、前記腎臓組織上また中への注射によって行われる、請求項10に記載の方法。
- 前記直接投与が、前記腎臓組織中への注入によって行われる、請求項10に記載の方法。
- 前記直接投与が、前記腎臓上および/または中の複数の部位で行われる、請求項11または請求項12に記載の方法。
- 前記直接投与が、中腎皮質中へである、請求項11から13のいずれか1項に記載の方法。
- 前記投与が、前記腎臓の細胞破壊の減少および/または線維症の減少をもたらす、請求項1から14のいずれか1項に記載の方法。
- 前記SDF−1が、哺乳動物のSDF−1である、請求項1から15のいずれか1項に記載の方法。
- 前記SDF−1が、ヒトSDF−1αまたはヒトSDF−1βである、請求項16に記載の方法。
- 前記SDF−1が、ネコSDF−1またはイヌSDF−1である、請求項16に記載の方法。
- 前記投与するステップが、SDF−1をコードする核酸ベクターを前記腎臓に注射することによって行われ、このベクターが前記コードされたSDF−1を発現する、請求項1から18のいずれか1項に記載の方法。
- 前記ベクターが、プラスミドベクターまたはウイルスベクターである、請求項19に記載の方法。
- 前記SDF−1と組み合わせて血管新生増殖因子(例えば、血管内皮増殖因子(VEGF))を前記対象に投与することをさらに含む、請求項1から20のいずれか1項に記載の方法。
- SDF−1および水性担体を含む、腎臓疾患の治療のための無菌注射用組成物。
- コラーゲンまたはゼラチンを含む、請求項22に記載の無菌注射用組成物。
- VEGFをさらに含む、請求項22または請求項23に記載の無菌注射用組成物。
- 腎臓疾患を患っているかもしくは発症するリスクがある対象を治療する方法の実施における使用のための、または腎臓疾患を患っているかもしくは発症するリスクがある対象を治療する方法の実施のための医薬の調製における使用のための、本明細書に記載のSDF−1またはSDF−1をコードするベクター。
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DE69915310T2 (de) | 1998-09-09 | 2005-03-10 | Scios Inc., Fremont | Methoden zur behandlung der salzabhängigen hypertonie |
CA2412436C (en) | 2000-06-05 | 2013-05-21 | The Trustees Of Columbia University In The City Of New York | Identification and use of human bone marrow-derived endothelial progenitor cells to improve myocardial function after ischemic injury |
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