JP7044768B2 - プラダー・ウィリー症候群を治療する方法 - Google Patents
プラダー・ウィリー症候群を治療する方法 Download PDFInfo
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- JP7044768B2 JP7044768B2 JP2019515783A JP2019515783A JP7044768B2 JP 7044768 B2 JP7044768 B2 JP 7044768B2 JP 2019515783 A JP2019515783 A JP 2019515783A JP 2019515783 A JP2019515783 A JP 2019515783A JP 7044768 B2 JP7044768 B2 JP 7044768B2
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Description
本出願は、2016年6月3日に出願された米国仮特許出願第62/345,133号;2016年8月16日に出願された米国仮出願第62/375,662号の優先権を主張し、そのそれぞれはその全体を参照することにより本明細書に援用される。
本発明は、National Institute of Health(NIH)からの補助金SK052431の下で政府の助成を受けてなされた。
「薬学的に許容される担体」という用語は、本明細書において使用される時、化学薬剤の保有または輸送に関与する、薬学的に許容される材料、組成物またはベヒクル(液体充填物質もしくは固体充填物質、希釈物質、賦形剤、溶媒またはカプセル化材料等)を意味する。希釈物質または担体の成分は、活性化合物の治療有効性を減じるようであるべきでない。
(1)状態、障害または病態に罹患するかまたはその素因があり得るが、状態、障害または病態の臨床症状をまだ経験しないかまたは提示しない人において発症する状態、障害または病態の臨床症状の出現を予防または遅延させること;または
(2)状態、障害もしくは病態を阻害すること、すなわち、疾患の発症もしくはその再発(維持治療の場合に)または少なくとも1つのその臨床症状、徴候、もしくは検定を阻止する、低減するまたは遅延させること;または
(3)疾患を軽減すること、すなわち、状態、障害もしくは病態またはその臨床上のもしくは準臨床的な症状もしくは徴候の少なくとも1つの退行を引き起こすこと、
を含む。
iPSC由来視床下部ニューロンおよびβ細胞中のPC1の発現および活性の操作
ホルスコリンによるシクラーゼ活性化および/またはホスホジエステラーゼの阻害(テオフィリン、IBMX)によるcAMP異化作用の阻害は、PWSのインビトロモデルにおいてPC1レベルを増加させ、プロホルモンプロセシングを結果的に増加させるだろう。PWSのインビボおよびインビトロのモデルにおけるPCSK1の明らかな複数組織での欠損の同定は、PWSの主な神経内分泌症状を緩和し得る合理的な治療標的化を可能にする(図1)。
Snord116p-/m+マウス、Pc1-/-マウスおよびPc1+/-マウスにおけるPC1代謝の分子生理学の確認。
アデニル酸シクラーゼ(AC)活性化および同時のPDE阻害によってcAMPレベルを増加させることは、PWSのエクスビボおよびインビボのモデルにおいてPC1レベルを増加させ、結果としてPWSのSnord116p-/m+マウスモデルにおけるプロホルモンプロセシングを増加させ得る。Snord116の父性由来の欠失のあるマウス(PWSのマウスモデル)はPC1の転写物およびタンパク質の低減と関連するプロインスリンからインスリンへのプロセシングが損なわれるので、野生型(WT)マウスおよびSnord116p-/m+マウスから膵島を単離し、ホルスコリン、テオフィリン、およびホルスコリン+テオフィリンへのこれらの細胞の応答が分析されるだろう。同じ操作および測定がiPSC由来β細胞について実行されるだろう。単離された膵島でSnord116p-/m+マウスからのプロインスリンプロセシングが、WT同腹仔に比較して救済され得るならば、次いで、ホルスコリン、テオフィリン、およびホルスコリン+テオフィリンで処理されたSnord116p-/m+マウスでのプロインスリンプロセシング救済の調査が、インビボで遂行されるだろう。
ホルスコリンを様々な細胞モデルへ適用し、結果は、ホルスコリンがPCSK1転写レベルおよびPC1タンパク質レベルをしっかりと確実に増加させ、かつプロホルモンプロセシングを機能的に増加させることを例証する。PCSK1/Pcsk1転写レベルは、10μMのホルスコリンへ曝露されたiPSC由来ニューロンおよび初代マウスニューロンにおいて2~3倍の間に増加した(図5A、C、D)。
PDE阻害物質もiPSC由来ニューロンにおいて試験され、ホスホジエステラーゼの阻害もまたPCSK1の転写を増加させ得ることが見出された。しかしながら、PCSK1転写レベルに対するPDE阻害の効果量は、ホルスコリンによるACアゴニズムによって誘導されたものよりも低い。テオフィリン(10mM)およびロフルミラスト(1mM)の両方は、単一薬剤としてPCSK1転写を増加させ、一方でMK0952はこれまでに、インビトロでホルスコリンと組み合わせたときだけPCSK1転写を増加させることが見出されている(図6A~C、F)。ホルスコリンおよびロフルミラストによる組み合わせ処理は、これらの薬剤が、いずれかの薬剤が単独で与えられる場合よりも低い濃度で(1μMのホルスコリン、100nMのロフルミラスト)、PCSK1転写を誘導しおよび増加させる相加的な(おそらく相乗的な)様式で、一緒に作動し得ることを実証する(図6D)。この場合もまた、ホルスコリンおよびロフルミラストによる組み合わせ処理に起因するPCSK1転写の増加が、POMCからACTHへのプロホルモンのプロセシングも増加させる(図6E)。具体的には、単離されたマウス膵島における段階的な濃度のホルスコリンによる試験は、25μMおよび50μMの濃度で、PC1タンパク質の3倍のアップレギュレーションを示した。PC2タンパク質レベルにおける変化は、ホルスコリン適用に応答して観察されなかった。本発明者は、E19.5マウスから単離された初代マウスニューロンへ適用された10μMのホルスコリンは、Pcsk1転写レベルを約2倍増加させることも見出した。
PWS患者を最も限定する表現型は過食症であり、それは、中枢神経系、特に視床下部において起こるプロセスによって媒介される可能性が最も高い。したがって、過食症を寛解することを目的とする薬剤は、血液脳関門を透過できなければならない。MK0952は、限定的な全血液活性(IC50=555nM)を備えた、内因的に強力な(IC50=0.6nM)脳透過PDE4阻害物質である(M.Gallant et al.2010)。本明細書において記載されるように、MK0952は、現在のところPDE阻害リード候補である。
プラダー・ウィリー症候群(PWS)に罹患した患者における化合物の臨床試験
PWSに罹患した個体について提案された臨床試験の予備的なデザインは、プロ転換酵素1(PC1)の発現が、PWSに罹患した個体のニューロンにおいて減少するという仮説に基づく(Burnett et al.2017)。アデニル酸シクラーゼアゴニストおよびPDE4阻害物質への実験的なインビトロおよびインビボでの曝露は、ヒト幹細胞由来ニューロンおよび齧歯類前脳ニューロンならびにヒト線維芽細胞において、PC1の発現および活性のアップレギュレーションを引き起こす。これらの薬物の投与は、活性なホルモンへの関与するプロホルモンの変換を増加するであろうことが予想される。
1.PWSの行動表現型および内分泌表現型に対する候補治療剤の効果を例証する。
2.かかる薬剤の臨床上の安全性プロファイルをモニタリングする。
臨床試験はクロスオーバー試験デザインを利用するだろう(Cleophas et al.2006、Wellek and Blettner 2012、およびLouis et al.1984)。このデザインは、小さなコホート中の被験体間の変動を考慮して治療効果を評価する検出力を提供する(図8A)。2つの治療選択肢の間のウォッシュアウト期間はキャリーオーバー効果を軽減し;研究の短い継続期間は「時間効果」(経時的な疾患プロセスにおける変化に対する効果)を最小限にするだろう。
1.遺伝的に証明されたPWの診断
2.年齢が>18歳
*組み換え成長ホルモン療法は差し支えない。
1.重症の精神障害
2.医薬物の服用に非協力的
3.全身疾患、例えば炎症性腸疾患のような重篤な胃腸病、心臓疾患、特に律動障害、糖尿病の診断、肝疾患もしくは肝不全、または腎疾患もしくは腎不全。
4.ヘモグロビン<10gm/dLとして定義される貧血
5.標的薬物との相互作用の可能性がある薬物(例えばPDE4阻害物質は、抗痙攣医薬物、シメチジン、オメプラゾール、抗生物質などと相互作用する)を用いる患者。これらの薬物の多くは肝酵素活性を変更し、PDE4阻害物質の代謝を妨害し得る。除外薬物の完全なリストは、同定された治療剤の薬物動態学的特性および薬物動力学的特性に基づくだろう。
1.標準的な食事に応答するホルモンプロファイル:プロホルモンの変換(インスリンへのプロインスリンなど等)に対するPC1の効果に基づいて、薬物の投与は、プロホルモン:ホルモン(例えばプロインスリン:インスリン)の比の増加を引き起こすだろうことが予想される(Burnett et al.2017)。これは標準的なMMTTへのホルモン応答性によって試験されるだろう。MMTTは、流動食(6cc/kgのブーストまたは等価物から最大360ccへ)を投与し、続いてインスリン、プロインスリン、POMCプロホルモン、ACTH、AgRP、プログルカゴン、グルカゴン、GLP1、オキシトシン(およびプロペプチド)、グレリン、プログレリン、遊離脂肪酸、およびグルコースを周期的に測定することによって遂行される。MMTTはPWSに罹患した被験体の臨床試験において検証されている(P.Gumus Balikcioglu et al.2015)。
1.PWSに罹患した小児における以前の試験および高い効果量を達成する必要性に基づいて、標準的な混合食を試験のために選択した。
2.試験は、Irving Institute for Clinical and Translational Researchの外来患者施設において遂行されるだろう。
3.試験についてのIRBプロトコールは、適切なPDE阻害物質および/またはシクラーゼ活性化物質に関して準備されるだろう。
4.メタボロミクスプロファイリングは、もしこの予備的研究で得られるのであれば、Hormone and Metabolite Core of the Diabetes and Endocrinology Research Centerにおいて遂行されるだろう。
プラダー・ウィリー症候群を治療する方法(内在性および外来性のMC4Rアゴニズムの組み合わせ療法)。
PWSに罹患した個体は、細胞性cAMP産生のレベルを上昇させることおよび/またはその分解を遮断することを介してPC1産生を増加することによりプロセシングされたホルモンの内在性レベルを増加する薬剤を使用して、治療されるだろう。
PC1をコードする遺伝子(PCSK1)はPWSの細胞ベースのモデルおよび動物モデルにおいてダウンレギュレートされるが、遺伝子自体はインタクトであり、したがって薬理学的操作を受け得る。本データは、PCSK1/PC1の細胞性レベルを薬理学的に操作するための進行中の前臨床試験の結果を提供する。インビトロ実験は、アデニリルシクラーゼアゴニストであるホルスコリンの適用がヒト幹細胞由来ニューロン、マウス初代神経細胞においてPCSK1発現をしっかりと確実にアップレギュレートし、かつマウス単離膵島においてPC1タンパク質レベルを増加させることを実証する。さらに、ホルスコリン治療は、幹細胞由来視床下部のニューロンにおけるPOMCプロホルモンプロセシングも増加させる。幹細胞ニューロンへのPDE阻害物質のテオフィリンおよびロフルミラストの適用は、単一薬剤として、およびホルスコリンと組み合わせて、いずれもPCSK1転写レベルを増加させる。ロフルミラストおよびホルスコリンの組み合わせ治療は、幹細胞視床下部のニューロンにおいてPOMCプロホルモンプロセシング(食欲不振誘発性のペプチドへの)も相加的に増加させる。ホルスコリンおよびMK0952(クラス4 PDE阻害物質)の両方による幹細胞由来ニューロンの処理は、PCSK1 mRNAを増加させる。最後に、10mg/kgのMK0952の単一経口用量は、野生型マウスにおいて視床下部のPcsk1転写レベルを25%増加させる。インビボでのMK0952のより長い適用は、野生型マウスおよび父性由来のSnord116についてのハイポモルフマウスの両方において、次に試験されるだろう。加えて、本発明者は、Andrea Haqqおよび共同研究者と共同研究して、PWSに罹患した個体および一致する対照において血中循環プロホルモンおよびプロセシングされたホルモンレベル(例えばプロインスリン、POMC、プロオキシトシン、プロBDNF)を測定するだろう。
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Claims (2)
- ホスホジエステラーゼ4阻害物質(PDE4i)を含む医薬組成物であって、それを必要とする被験体でプラダー・ウィリー症候群(PWS)を治療すること、それによりPWSの1つまたは複数の症状を緩和する、消失する、または予防することにおける使用のための、前記PDE4iがMK0952またはロフルミラストである、医薬組成物。
- ホスホジエステラーゼ4阻害物質(PDE4i)を含む医薬組成物であって、それを必要とする被験体でプラダー・ウィリー症候群(PWS)を治療すること、それによりPWSの1つまたは複数の症状を緩和する、消失する、または予防することにおける使用のための、前記PDE4iがテオフィリンである、医薬組成物。
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EP3831376A1 (en) * | 2016-06-03 | 2021-06-09 | The Trustees of Columbia University in the City of New York | Pde4 inhibitors for treating obesity, schaaf-yang syndrome or autism spectrum disorder |
EP3600318A4 (en) * | 2017-03-31 | 2021-06-09 | Epizyme, Inc. | METHODS FOR USING EHMT2 INHIBITORS |
WO2018195450A1 (en) | 2017-04-21 | 2018-10-25 | Epizyme, Inc. | Combination therapies with ehmt2 inhibitors |
US10736894B2 (en) | 2018-02-15 | 2020-08-11 | Ovid Therapeutics Inc. | Methods of treating developmental syndromes with PDE10A inhibitors |
TW202031283A (zh) | 2018-09-20 | 2020-09-01 | 馬克 C 曼寧 | 穩定卡貝縮宮素鼻內製劑 |
CN111264851A (zh) * | 2020-03-03 | 2020-06-12 | 河南省儿童医院郑州儿童医院 | Pws综合征靶向替代保健食品及其制备方法 |
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EP3831376A1 (en) | 2016-06-03 | 2021-06-09 | The Trustees of Columbia University in the City of New York | Pde4 inhibitors for treating obesity, schaaf-yang syndrome or autism spectrum disorder |
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