JP6755264B2 - クッシング症候群についての処置を診断および評価するための方法 - Google Patents
クッシング症候群についての処置を診断および評価するための方法 Download PDFInfo
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Description
本願は、2015年5月18日に出願された米国仮出願第62/163,130号の優先権を主張し、その内容は、全体においてすべての目的のために参照によって組み込まれる。
本明細書において使用される略語は、化学および生物学的技術分野内でのそれらの従来の意味を有する。本明細書および添付の特許請求の範囲において使用される場合、単数形の「a」、「an」および「the」は、文脈上、明確に指示がない限り、複数形を含む。
発明の詳細な説明
I.諸言
a.グルココルチコイド受容体アンタゴニスト(GRA)による疾患の処置
b.クッシング症候群
II.方法
a.GRAに対する、または高コルチゾール血症の処置のための内科的もしくは外科的治療に対する、臨床または生化学的応答の評価
i.試料の抽出、調製および分析
ii.FKBP5の量、活性または発現の比較
iii.閾値、対照値および差分閾値
iv.GRAの投与
b.クッシング症候群の診断
10人の健康な対象を、19日前にプレドニゾンで処置する。12日前に、対象を、プレドニゾン(25mg)およびミフェプリストン(600mg)で処置する。1日目に、対象を、プレドニゾン(25mg)およびCORT125134(500mg)で処置する。血液試料を、各投与の前、および各投与後の種々の時点で採取する。試験の模式図を図1に表す。FKBP5遺伝子の発現レベルを、各日の投与前に得られた投与前の試料において、および各日の投与後の種々の時点で得られた投与後試料において測定する。試料中の発現レベルの生データを、各試料のグリセルアルデヒドリン酸脱水素酵素(GAPDH)遺伝子の発現レベルに対して正規化する。図2に図示するように、GRアゴニストであるプレドニゾンの投与後の全血試料中の正規化されたFKBP5遺伝子の発現レベルは、投与前レベルを約10〜50倍上回る。GRAであるミフェプリストンまたはCORT125134の投与は、FKBP5発現の倍数変化の顕著な低下を引き起こす。
参考文献
・Barik S. Immunophilins: for the love of proteins. Cellular and molecular life sciences: CMLS, 2006, 63:2889−2900.
・Baughman G, Wiederrecht G.J, Campbell N F, Martin M M, Bourgeois S. FKBP51, a novel T−cell−specific immunophilin capable of calcineurin inhibition. Molec. Cell. Biol., 1995, 15: 4395−4402.
・Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T, Muller N, Pfister H, Lieb R, Mueller JC, Lohmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller−Myhsok B. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature genetics 2004, 36:1319−1325.
・Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Hein CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA, 2008, 299:1291−1305.
・Binder EB. The role of FKBP5, a co−chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, 2009, 34(Supp. 1): S186−S195.
・Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O’Leary JC 3rd, Fontaine SN, Breydo L, Zhang B, Li P, Wang L, Colman C, Paulson HL, Muschol M, Uversky VN, Klengel, T, Binder EB, Kayed R, Golde TE, Berchtold N, Dickey CA. Accelerated neurodegeneration through chaperone−mediated oligomerization of tau. J. Clin. Invest. 2013, 123:4158−5169.
・Caldwell JM, Blanchard C, Collins MH, Putman PE, Kaul A, Aceves SS, Bouska CA, Rothenberg ME. Glucocorticoid−regulated genes in eosinophilic esophagitis: a role for FKBP51. J. Allergy Clin. Immunol., 2010, 125:879−888.
・Ewald RE, Wand GS, Seifuddin F, Yang X, Tamashiro KL, Potash JB, Zandi P, Lee RS. Alterations in DNA methylation of Fkbp5 as a determinant of blood−brain correlation of glucocorticoid exposure. Psychoneuroendocrinol. 2014, 44:112−122.
・Kimura M, Nagai T, Matsushita R, Hashimoto A, Hirohata S. Role of FK506 binding protein 5 (FKBP5) in osteoblast differentiation. Mod. Rheumatol., 2013, 23:1133−1139.
・Lee RS, Tamashiro KL, Yang X, Purcell RH, Harvey A, Willour VL, Huo Y, Rongione M, Wand GS, Potash JB. Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinol. 2010, 151:4332−4343.
・O’Leary JC III, Zhang, B, Koren J III, Blair L, Dickey CA. The role of FKBP5 in mood disorders: Action of FKBP5 on steroid hormone receptors leads to questions about its evolutionary importance. CNS Neurol. Disord. Drug Targets, 2013, 12:1157−1162.
・Pereira MJ, Palming J, Svensson MK, Rizell M, Dalenback J, Hammare M, Fall T, Sidibeh CO, Svensson P−A, Eriksson JW. FKBP5 gene expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance, Metabolism, 2014, doi: 10.1016/j.metabol.2014.05.015.
・Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506−binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. Gen. Comp. Endocrinol., 2001, 124:152−165.
・Vermeer H, Hendriks−Stegeman BI, van der Burg B, van Buul−Offers SC, Jansen M. Glucocorticoid−induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential biomarker for glucocorticoid sensitivity, potency, and bioavailability. J. Endocrinol. Metab. 2003, 88:277−284.
・Willour VL, Chen H, Toolan J, Belmonte P, Cutler DJ, Goes FS, Zandi PP, Lee RS, MacKinnon DF, Mondimore FM, Schweizer B, Bipolar disorder phenome group, NIMH genetics initiative bipolar disorder consortium, DePaulo JR Jr., Gershon ES, McMahon FJ, Potash JB. Family−based association of FKBP5 in bipolar disorder. Mol. Psychiatry, 2009, 14:261−268.
・Yang L, Isoda F, Yen K, Kleopoulos SP, Janssen W, Fan X, Mastaitis J, Dunn−Meynell A, Levis B, McCrimmon R, Sherwin R, Musatov, S, Mobbs, CV. Hypothalamic Fkbp51 induced by fasting, and elevated hypothalamic expression promotes obese phenotypes.
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
ヒト対象におけるグルココルチコイド受容体アンタゴニスト(GRA)に対する生化学的応答を評価するための方法であって、
a)前記対象からの第1の試料中の、51kDaのFK506結合タンパク質(FKBP5タンパク質)の第1の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の第1の発現レベルを測定するステップであって、
i)前記第1の試料は、初代細胞を含み、
ii)前記第1の試料は、前記GRAを前記対象に投与する前に得られる、ステップ;
b)前記対象からの第2の試料中の、FKBP5タンパク質の第2の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の第2の発現レベルを測定するステップであって、
i)前記第2の試料は、初代細胞を含み、
ii)前記第2の試料は、前記GRAを前記対象に投与した後に得られる、ステップ;ならびに
d)前記第1および第2の量、活性または発現レベルを比較するステップ
を含み、前記第2の試料中の、FKBP5タンパク質の前記量もしくは活性の減少、またはFKBP5タンパク質をコードする前記遺伝子の前記発現レベルの減少が、前記GRAに対する前記生化学的応答を示す、方法。
(項目2)
前記第1の試料が、複数用量のGRAを前記対象に投与する前に得られ、前記第2の試料が、前記複数用量のGRAを前記対象に投与した後に得られる、項目1に記載の方法。
(項目3)
前記a)および/またはb)の測定するステップが、前記試料中のFKBP5タンパク質をコードするmRNAの量を定量するステップを含む、項目1に記載の方法。
(項目4)
前記a)および/またはb)の測定するステップが、前記試料中のFKBP5タンパク質の前記量を定量するステップを含む、項目1に記載の方法。
(項目5)
前記測定するステップが、前記試料中のFKBP5タンパク質の活性の量を定量するステップを含む、項目1に記載の方法。
(項目6)
前記試料中のFKBP5タンパク質の活性の量を定量するステップが、前記試料中のFKBP5タンパク質のペプチジル−プロリル−シス−トランスイソメラーゼ活性を測定するステップを含む、項目5に記載の方法。
(項目7)
前記試料中のFKBP5タンパク質の活性の量を定量するステップが、前記試料中のグルココルチコイド受容体(GR)と結合しているFKBP5タンパク質の量を測定するステップを含む、項目5に記載の方法。
(項目8)
前記対象に投与される前記GRAが、ミフェプリストンを含む、項目1に記載の方法。
(項目9)
前記対象に投与される前記GRAが、ミフェプリストンではない、項目1に記載の方法。
(項目10)
前記対象に投与される前記GRAが、ヘテロアリール−ケトンGRAを含む、項目9に記載の方法。
(項目11)
前記第1または第2の試料が、全血またはその画分を含む、項目1に記載の方法。
(項目12)
前記第1または第2の試料が、鼻粘膜上皮の擦過試料を含む、項目1に記載の方法。
(項目13)
前記患者が、前記グルココルチコイド受容体アンタゴニスト(GRA)の投与を必要とする、項目1に記載の方法。
(項目14)
前記患者が、上昇したレベルのコルチゾールを有する、項目13に記載の方法。
(項目15)
前記患者ががんを有し、前記第1および第2の試料が腫瘍細胞を含む、項目1に記載の方法。
(項目16)
前記第1および第2の試料が、全血またはその画分を含む、項目1に記載の方法。
(項目17)
増加させた量のGRAを、前記第2の試料中の、FKBP5タンパク質の前記量もしくは活性の減少が検出されない、またはFKBP5タンパク質をコードする前記遺伝子の前記発現レベルの減少が検出されない前記対象に投与するステップを含む、項目1に記載の方法。
(項目18)
ヒト対象におけるクッシング症候群を診断するための方法であって、
a)前記対象から得られた試料中の、51kDaのFK506結合タンパク質(FKBP5タンパク質)の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の発現レベルを測定するステップであって、前記試料は初代細胞を含む、ステップ;および
b)前記量、活性または発現レベルが対照に対して高い場合に、対象がクッシング症候群に罹患している可能性が高いと同定するステップ
を含む方法。
(項目19)
前記測定するステップが、前記試料の前記初代細胞中のFKBP5タンパク質をコードするmRNAの量を定量するステップを含む、項目18に記載の方法。
(項目20)
前記測定するステップが、前記試料の前記初代細胞中のFKBP5タンパク質の量を定量するステップを含む、項目18に記載の方法。
(項目21)
前記測定するステップが、前記試料の前記初代細胞中のFKBP5タンパク質の活性を定量するステップを含む、項目18に記載の方法。
(項目22)
前記試料の前記初代細胞中のFKBP5タンパク質の活性を定量するステップが、前記試料の前記初代細胞中の、FKBP5タンパク質のペプチジル−プロリル−シス−トランスイソメラーゼ活性を定量するステップを含む、項目21に記載の方法。
(項目23)
前記試料の前記初代細胞中のFKBP5タンパク質の活性を定量するステップが、前記試料の前記初代細胞中のGRと結合しているFKBP5タンパク質の量を定量するステップを含む、項目21に記載の方法。
(項目24)
前記対象から得られる前記試料が、全血またはその画分を含む、項目18に記載の方法。
(項目25)
前記対象が、前記試料を前記対象から得る前に、経蝶形骨洞手術を受けている、項目18に記載の方法。
(項目26)
FKBP5タンパク質の量もしくは活性、または前記FKBP5タンパク質をコードする遺伝子の発現レベルが対照に対して高い場合に、クッシング症候群のための処置を投与するステップを含む、項目18に記載の方法。
(項目27)
前記クッシング症候群のための処置を投与するステップが、前記対象にグルココルチコイド受容体アンタゴニスト(GRA)を投与することを含む、項目26に記載の方法。
(項目28)
ヒト対象における、前記対象に高コルチゾール血症の処置のための内科的または外科的治療を投与すること対する生化学的応答を評価するための方法であって、
a)前記対象からの第1の試料中の、51kDaのFK506結合タンパク質(FKBP5タンパク質)の第1の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の第1の発現レベルを測定するステップであって、
i)前記第1の試料は、初代細胞を含み、
ii)前記第1の試料は、高コルチゾール血症の処置のための前記内科的または外科的治療を前記対象に投与する前に得られる、ステップ;
b)前記対象からの第2の試料中の、FKBP5タンパク質の第2の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の第2の発現レベルを測定するステップであって、
i)前記第2の試料は、初代細胞を含み、
ii)前記第2の試料が、高コルチゾール血症の処置のための前記内科的または外科的治療を前記対象に投与した後に得られる、ステップ;ならびに
d)前記第1および第2の量、活性または発現レベルを比較するステップ
を含み、前記第2の試料中の、FKBP5タンパク質の量もしくは活性の減少、または前記FKBP5タンパク質をコードする遺伝子の発現レベルの減少が、高コルチゾール血症の処置のための前記内科的または外科的治療に対する生化学的応答を示す、方法。
(項目29)
高コルチゾール血症の処置のための前記内科的または外科的治療が、ステロイド産生の阻害、ACTHモジュレーターの投与、GRAの投与、経蝶形骨洞手術、反復経蝶形骨洞手術、片側副腎摘除術、両側副腎摘除術、放射線治療、非下垂体性ACTH分泌腫瘍の切除、ペプチド受容体放射性核種治療による処置およびこれらの組合せからなる群から選択される、項目28に記載の方法。
(項目30)
前記ステロイド産生の阻害が、ケトコナゾール、レボケトコナゾール、メチラポン、LCI699、ミトタン、アミノグルテチミド、エトミデートまたはこれらの組合せの投与を含む、項目29に記載の方法。
(項目31)
前記ACTHモジュレーターの投与が、ドーパミンアゴニスト、ソマトスタチン、ソマトスタチンアナログ、レチノイン酸、R−ロスコビチンまたはこれらの組合せの投与を含む、項目29に記載の方法。
(項目32)
前記ドーパミンアゴニストが、ブロモクリプチンおよびカベルゴリンからなる群から選択される、項目31に記載の方法。
(項目33)
前記第2の試料中、前記FKBP5タンパク質の量もしくは活性の減少が検出されない、または前記FKBP5タンパク質をコードする遺伝子の前記発現レベルの減少が検出されない高コルチゾール血症の処置のための、さらなる内科的または外科的治療を投与するステップを含む、項目28に記載の方法。
Claims (16)
- 51kDaのFK506結合タンパク質(FKBP5タンパク質)の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の発現レベルを、ヒト対象におけるグルココルチコイド受容体アンタゴニスト(GRA)に対する生化学的応答を評価するための指標とする方法であって、
a)前記対象からの第1の試料中の、FKBP5タンパク質の第1の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の第1の発現レベルが測定され、
i)前記第1の試料は、初代細胞を含み、
ii)前記第1の試料は、前記GRAが前記対象に投与される前に得られ;
b)前記対象からの第2の試料中の、FKBP5タンパク質の第2の量もしくは活性、またはFKBP5タンパク質をコードする遺伝子の第2の発現レベルが測定され、
i)前記第2の試料は、初代細胞を含み、
ii)前記第2の試料は、前記GRAが前記対象に投与された後に得られ;
c)前記第1および第2の量、活性または発現レベルが比較され、
前記第2の試料中の、FKBP5タンパク質の前記量もしくは活性の減少、またはFKBP5タンパク質をコードする前記遺伝子の前記発現レベルの減少が、前記GRAに対する前記生化学的応答を示し、
前記第2の試料中の、FKBP5タンパク質の前記量もしくは活性の減少が検出されない、またはFKBP5タンパク質をコードする前記遺伝子の前記発現レベルの減少が検出されないことは、増加させた量のGRAが前記対象に投与されることを示す、方法。 - 前記第1の試料が、前記対象へのGRAの複数回投与の前に得られ、前記第2の試料が、前記対象へのGRAの複数回投与の後に得られる、請求項1に記載の方法。
- 前記a)および/またはb)の測定が、前記試料中のFKBP5タンパク質をコードするmRNAの量を定量するステップを含む、請求項1に記載の方法。
- 前記a)および/またはb)の測定が、前記試料中のFKBP5タンパク質の前記量を定量するステップを含む、請求項1に記載の方法。
- 前記a)および/またはb)の測定が、前記試料中のFKBP5タンパク質の活性の量を定量するステップを含む、請求項1に記載の方法。
- 前記試料中のFKBP5タンパク質の活性の量を定量するステップが、前記試料中のFKBP5タンパク質のペプチジル−プロリル−シス−トランスイソメラーゼ活性を測定するステップを含む、請求項5に記載の方法。
- 前記試料中のFKBP5タンパク質の活性の量を定量するステップが、前記試料中のグルココルチコイド受容体(GR)と結合しているFKBP5タンパク質の量を測定するステップを含む、請求項5に記載の方法。
- 前記対象に投与される前記GRAが、ミフェプリストンを含む、請求項1に記載の方法。
- 前記対象に投与される前記GRAが、ミフェプリストンではない、請求項1に記載の方法。
- 前記対象に投与される前記GRAが、ヘテロアリール−ケトンGRAを含む、請求項9に記載の方法。
- 前記第1または第2の試料が、全血またはその画分を含む、請求項1に記載の方法。
- 前記第1または第2の試料が、鼻粘膜上皮の擦過試料を含む、請求項1に記載の方法。
- 前記対象が、がん、乳がん、トリプルネガティブ乳がん、前立腺がん、転移性前立腺がん、卵巣がん、クッシング症候群またはクッシング病を有するかまたは有する疑いがある、請求項1に記載の方法。
- 前記対象が、上昇したレベルのコルチゾールを有する、請求項13に記載の方法。
- 前記対象ががんを有し、前記第1および第2の試料が腫瘍細胞を含む、請求項1に記載の方法。
- 前記第1および第2の試料が、全血またはその画分を含む、請求項1に記載の方法。
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