JP7437891B2 - Tmprss6 irna組成物及びその使用方法 - Google Patents
Tmprss6 irna組成物及びその使用方法 Download PDFInfo
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- JP7437891B2 JP7437891B2 JP2019136630A JP2019136630A JP7437891B2 JP 7437891 B2 JP7437891 B2 JP 7437891B2 JP 2019136630 A JP2019136630 A JP 2019136630A JP 2019136630 A JP2019136630 A JP 2019136630A JP 7437891 B2 JP7437891 B2 JP 7437891B2
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Description
本出願は、2013年5月22日に出願された米国仮特許出願第61/826,178号明細書及び2013年12月6日に出願された米国仮特許出願第61/912,988号明細書の優先権の利益を主張するものである。本出願は、2011年11月18日に出願された米国仮特許出願第61/561,710号明細書、及び2012年11月16日に出願されたPCT/US2012/065601号明細書に関する。上記の仮特許出願のそれぞれの全内容が、参照により本明細書に援用される。
本出願は、全体が参照により本明細書に援用される、ASCII形式で電子的に提出されている配列表を含む。2014年5月21日に作成された前記ASCIIのコピーの名称は、121301-00720_SL.txtであり、サイズは449,620バイトである。
センス鎖のヌクレオチドの実質的に全て及びアンチセンス鎖のヌクレオチドの実質的に全てが、修飾ヌクレオチドであり、
センス鎖が、3’末端において結合されたリガンドにコンジュゲートされる二本鎖RNAi剤を提供する。
センス:5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’
アンチセンス:3’np’-Na’-(X’X’X’)k-Nb’-Y’Y’Y’-Nb’-(Z’Z’Z’)l-Na’-nq’5’(III)
(式中:
i、j、k、及びlがそれぞれ、独立して、0又は1であり;
p、p’、q、及びq’がそれぞれ、独立して、0~6であり;
各Na及びNa’が、独立して、修飾又は非修飾のいずれかの0~25のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb及びNb’が、独立して、修飾又は非修飾のいずれかの0~10のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し;
それぞれ存在していても又は存在していなくてもよい各np、np’、nq、及びnq’が、独立して、オーバーハングヌクレオチドを表し;
XXX、YYY、ZZZ、X’X’X’、Y’Y’Y’、及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチド上の3つの同一の修飾の1つのモチーフを表し;
Nb上の修飾が、Y上の修飾と異なり、Nb’上の修飾が、Y’上の修飾と異なり;
センス鎖が、少なくとも1つのリガンドにコンジュゲートされている)
によって表される二本鎖RNAi剤を提供する。
センス:5’np-Na-YYY-Na-nq3’
アンチセンス:3’np’-Na’-Y’Y’Y’-Na’-nq’5’(IIIa)
によって表される。
センス:5’np-Na-YYY-Nb-ZZZ-Na-nq3’
アンチセンス:3’np’-Na’-Y’Y’Y’-Nb’-Z’Z’Z’-Na’-nq’5’(IIIb)
(式中、各Nb及びNb’が、独立して、1~5つの修飾ヌクレオチドを含むオリゴヌクレオチド配列を表す)
によって表される。
センス:5’np-Na-XXX-Nb-YYY-Na-nq3’
アンチセンス:3’np’-Na’-X’X’X’-Nb’-Y’Y’Y’-Na’-nq’5’(IIIc)
(式中、各Nb及びNb’が、独立して、1~5つの修飾ヌクレオチドを含むオリゴヌクレオチド配列を表す)
によって表される。
センス:5’np-Na-XXX-Nb-YYY-Nb-ZZZ-Na-nq3’
アンチセンス:3’np’-Na’-X’X’X’-Nb’-Y’Y’Y’-Nb’-Z’Z’Z’-Na’-nq’5’(IIId)
(式中、各Nb及びNb’が、独立して、1~5つの修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し、各Na及びNa’が、独立して、2~10の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表す)
によって表される。
二本鎖RNAi剤が、二本鎖領域を形成するセンス鎖及びアンチセンス鎖を含み、
センス鎖が、配列番号1、配列番号2、又は配列番号3、配列番号4、又は配列番号5のヌクレオチド配列のいずれか1つと3つ以下のヌクレオチドが異なる少なくとも15連続ヌクレオチドを含み、アンチセンス鎖が、配列番号6、配列番号7、又は配列番号8、配列番号9、又は配列番号10のヌクレオチド配列のいずれか1つと3つ以下のヌクレオチドが異なる少なくとも15連続ヌクレオチドを含み、
センス鎖のヌクレオチドの実質的に全てが、2’-O-メチル修飾及び2’-フルオロ修飾からなる群から選択される修飾を含み、
センス鎖が、5’末端における2つのホスホロチオエートヌクレオチド間結合を含み、
アンチセンス鎖のヌクレオチドの実質的に全てが、2’-O-メチル修飾及び2’-フルオロ修飾からなる群から選択される修飾を含み、
アンチセンス鎖が、5’末端における2つのホスホロチオエートヌクレオチド間結合及び3’末端における2つのホスホロチオエートヌクレオチド間結合を含み、
センス鎖が、3’末端において分枝鎖状の二価又は三価リンカーを介して結合された1つ又は複数のGalNAc誘導体にコンジュゲートされる二本鎖RNAi剤を提供する。
センス:5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’
アンチセンス:3’np’-Na’-(X’X’X’)k-Nb’-Y’Y’Y’-Nb’-(Z’Z’Z’)l-Na’-nq’5’(III)
(式中:
i、j、k、及びlがそれぞれ、独立して、0又は1であり;
p、p’、q、及びq’がそれぞれ、独立して、0~6であり;
各Na及びNa’が、独立して、修飾又は非修飾のいずれかの0~25のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb及びNb’が、独立して、修飾又は非修飾のいずれかの0~10のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し;
それぞれ存在していても又は存在していなくてもよい各np、np’、nq、及びnq’が、独立して、オーバーハングヌクレオチドを表し;
XXX、YYY、ZZZ、X’X’X’、Y’Y’Y’、及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチド上の3つの同一の修飾の1つのモチーフを表し、修飾が、2’-O-メチル又は2’-フルオロ修飾であり;
Nb上の修飾が、Y上の修飾と異なり、Nb’上の修飾が、Y’上の修飾と異なり;
センス鎖が、少なくとも1つのリガンドにコンジュゲートされている)
によって表される二本鎖RNAi剤を提供する。
センス:5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’
アンチセンス:3’np’-Na’-(X’X’X’)k-Nb’-Y’Y’Y’-Nb’-(Z’Z’Z’)l-Na’-nq’5’(III)
(式中:
i、j、k、及びlがそれぞれ、独立して、0又は1であり;
それぞれ存在していても又は存在していなくてもよい各np、nq、及びnq’が、独立して、オーバーハングヌクレオチドを表し;
p、q、及びq’がそれぞれ、独立して、0~6であり;
np’>0であり、少なくとも1つのnp’が、ホスホロチオエート結合を介して隣接するヌクレオチドに結合され;
各Na及びNa’が、独立して、修飾又は非修飾のいずれかの0~25のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb及びNb’が、独立して、修飾又は非修飾のいずれかの0~10のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し;
XXX、YYY、ZZZ、X’X’X’、Y’Y’Y’、及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチド上の3つの同一の修飾の1つのモチーフを表し、修飾が、2’-O-メチル又は2’-フルオロ修飾であり;
Nb上の修飾が、Y上の修飾と異なり、Nb’上の修飾が、Y’上の修飾と異なり;
センス鎖が、少なくとも1つのリガンドにコンジュゲートされている)
によって表される二本鎖RNAi剤を提供する。
センス:5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’
アンチセンス:3’np’-Na’-(X’X’X’)k-Nb’-Y’Y’Y’-Nb’-(Z’Z’Z’)l-Na’-nq’5’(III)
(式中:
i、j、k、及びlがそれぞれ、独立して、0又は1であり;
それぞれ存在していても又は存在していなくてもよい各np、nq、及びnq’が、独立して、オーバーハングヌクレオチドを表し;
p、q、及びq’がそれぞれ、独立して、0~6であり;
np’>0であり、少なくとも1つのnp’が、ホスホロチオエート結合を介して隣接するヌクレオチドに結合され;
各Na及びNa’が、独立して、修飾又は非修飾のいずれかの0~25のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb及びNb’が、独立して、修飾又は非修飾のいずれかの0~10のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し;
XXX、YYY、ZZZ、X’X’X’、Y’Y’Y’、及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチド上の3つの同一の修飾の1つのモチーフを表し、修飾が、2’-O-メチル又は2’-フルオロ修飾であり;
Nb上の修飾が、Y上の修飾と異なり、Nb’上の修飾が、Y’上の修飾と異なり;
センス鎖が、少なくとも1つのリガンドにコンジュゲートされ、リガンドが、二価又は三価の分枝鎖状リンカーを介して結合された1つ又は複数のGalNAc誘導体である)
によって表される二本鎖RNAi剤を提供する。
センス:5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’
アンチセンス:3’np’-Na’-(X’X’X’)k-Nb’-Y’Y’Y’-Nb’-(Z’Z’Z’)l-Na’-nq’5’(III)
(式中:
i、j、k、及びlがそれぞれ、独立して、0又は1であり;
それぞれ存在していても又は存在していなくてもよい各np、nq、及びnq’が、独立して、オーバーハングヌクレオチドを表し;
p、q、及びq’がそれぞれ、独立して、0~6であり;
np’>0であり、少なくとも1つのnp’が、ホスホロチオエート結合を介して隣接するヌクレオチドに結合され;
各Na及びNa’が、独立して、修飾又は非修飾のいずれかの0~25のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb及びNb’が、独立して、修飾又は非修飾のいずれかの0~10のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し;
XXX、YYY、ZZZ、X’X’X’、Y’Y’Y’、及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチド上の3つの同一の修飾の1つのモチーフを表し、修飾が、2’-O-メチル又は2’-フルオロ修飾であり;
Nb上の修飾が、Y上の修飾と異なり、Nb’上の修飾が、Y’上の修飾と異なり;
センス鎖が、少なくとも1つのホスホロチオエート結合を含み;
センス鎖が、少なくとも1つのリガンドにコンジュゲートされ、リガンドが、二価又は三価の分枝鎖状リンカーを介して結合された1つ又は複数のGalNAc誘導体である)
によって表される二本鎖RNAi剤を提供する。
センス:5’np-Na-YYY-Na-nq3’
アンチセンス:3’np’-Na’-Y’Y’Y’-Na’-nq’5’(IIIa)
(式中:
それぞれ存在していても又は存在していなくてもよい各np、nq、及びnq’が、独立して、オーバーハングヌクレオチドを表し;
p、q、及びq’がそれぞれ、独立して、0~6であり;
np’>0であり、少なくとも1つのnp’が、ホスホロチオエート結合を介して隣接するヌクレオチドに結合され;
各Na及びNa’が、独立して、修飾又は非修飾のいずれかの0~25のヌクレオチド又はそれらの組合せを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
YYY及びY’Y’Y’がそれぞれ、独立して、3連続ヌクレオチド上の3つの同一の修飾の1つのモチーフを表し、修飾が、2’-O-メチル又は2’-フルオロ修飾であり;
センス鎖が、少なくとも1つのホスホロチオエート結合を含み;
センス鎖が、少なくとも1つのリガンドにコンジュゲートされ、リガンドが、二価又は三価の分枝鎖状リンカーを介して結合された1つ又は複数のGalNAc誘導体である)
によって表される二本鎖RNAi剤を提供する。
二本鎖RNAi剤が、二本鎖領域を形成するセンス鎖及びアンチセンス鎖を含み、
センス鎖が、配列番号1、配列番号2、又は配列番号3、配列番号4、又は配列番号5のヌクレオチド配列のいずれか1つと3つ以下のヌクレオチドが異なる少なくとも15連続ヌクレオチドを含み、アンチセンス鎖が、配列番号6、配列番号7、又は配列番号8、配列番号9、又は配列番号10のヌクレオチド配列のいずれか1つと3つ以下のヌクレオチドが異なる少なくとも15連続ヌクレオチドを含み、
アンチセンス鎖のヌクレオチドの実質的に全てが、2’-O-メチル修飾及び2’-フルオロ修飾からなる群から選択される修飾を含み、
アンチセンス鎖が、5’末端における2つのホスホロチオエートヌクレオチド間結合及び3’末端における2つのホスホロチオエートヌクレオチド間結合を含み,
センス鎖のヌクレオチドの実質的に全てが、2’-O-メチル修飾及び2’-フルオロ修飾からなる群から選択される修飾を含み、
センス鎖が、5’末端における2つのホスホロチオエートヌクレオチド間結合を含み、
センス鎖が、3’末端において分枝鎖状の二価又は三価リンカーを介して結合された1つ又は複数のGalNAc誘導体にコンジュゲートされる。
本発明がより容易に理解され得るように、いくつかの用語がまず定義される。更に、変数の値又は値の範囲が記載されるときは常に、記載される値の中間の値及び範囲も、本発明の一部であることが意図されることに留意されたい。
対象、例えば、TMPRSS6に関連する疾患、例えば、β-サラセミア(例えば、重症型β-サラセミア及び中間型β-サラセミア)又はヘモクロマトーシスに罹患しているヒトなどの哺乳動物中の細胞などの細胞内でのTMPRSS6遺伝子の発現を阻害する改良された二本鎖RNAi剤、及びこのような二本鎖RNAi剤の使用が本明細書に記載される。
本発明の特定の態様において、本発明の二本鎖RNAi剤としては、例えば、それぞれの全内容が、参照により本明細書に援用される、2011年11月18日に出願された米国仮特許出願第61/561,710号明細書、又は2012年11月16日に出願されたPCT/US2012/065691号明細書に開示される化学的修飾を有する剤が挙げられる。
5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’(I)
(式中:
i及びjがそれぞれ、独立して、0又は1であり;
p及びqがそれぞれ、独立して、0~6であり;
各Naが、独立して、0~25の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nbが、独立して、0~10の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し;
各np及びnqが、独立して、オーバーハングヌクレオチドを表し;
ここで、Nb及びYが、同じ修飾を有さず;
XXX、YYY及びZZZがそれぞれ、独立して、3連続ヌクレオチドにおける3つの同一の修飾の1つのモチーフを表す)
によって表され得る。好ましくは、YYYが、全て2’-F修飾ヌクレオチドである。
5’np-Na-YYY-Nb-ZZZ-Na-nq3’(Ib);
5’np-Na-XXX-Nb-YYY-Na-nq3’(Ic);又は
5’np-Na-XXX-Nb-YYY-Nb-ZZZ-Na-nq3’(Id)。
5’np-Na-YYY-Na-nq3’(Ia)。
5’nq’-Na’-(Z’Z’Z’)k-Nb’-Y’Y’Y’-Nb’-(X’X’X’)l-N’a-np’3’(II)
(式中:
k及びlがそれぞれ、独立して、0又は1であり;
p’及びq’がそれぞれ、独立して、0~6であり;
各Na’が、独立して、0~25の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb’が、独立して、0~10の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し;
各np’及びnq’が、独立して、オーバーハングヌクレオチドを表し;
ここで、Nb’及びY’が、同じ修飾を有さず;
X’X’X’、Y’Y’Y’及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチドにおける3つの同一の修飾の1つのモチーフを表す)
によって表され得る。
5’nq’-Na’-Z’Z’Z’-Nb’-Y’Y’Y’-Na’-np’3’(IIb);
5’nq’-Na’-Y’Y’Y’-Nb’-X’X’X’-np’3’(IIc);又は
5’nq’-Na’-Z’Z’Z’-Nb’-Y’Y’Y’-Nb’-X’X’X’-Na’-np’3’(IId)。
5’np’-Na’-Y’Y’Y’-Na’-nq’3’(Ia)。
センス:5’np-Na-(XXX)i-Nb-YYY-Nb-(ZZZ)j-Na-nq3’
アンチセンス:3’np ’-Na ’-(X’X’X’)k-Nb ’-Y’Y’Y’-Nb ’-(Z’Z’Z’)l-Na ’-nq ’5’
(III)
(式中:
i、j、k、及びlがそれぞれ、独立して、0又は1であり;
p、p’、q、及びq’がそれぞれ、独立して、0~6であり;
各Na及びNa ’が、独立して、0~25の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し、各配列が、少なくとも2つの異なる修飾のヌクレオチドを含み;
各Nb及びNb ’が、独立して、0~10の修飾ヌクレオチドを含むオリゴヌクレオチド配列を表し;
ここで、
それぞれ存在していても又は存在していなくてもよい各np’、np、nq’、及びnqが、独立して、オーバーハングヌクレオチドを表し;
XXX、YYY、ZZZ、X’X’X’、Y’Y’Y’、及びZ’Z’Z’がそれぞれ、独立して、3連続ヌクレオチド上に3つの同一の修飾の1つのモチーフを表す)
によって表される。
5’np-Na-YYY-Na-nq3’
3’np ’-Na ’-Y’Y’Y’-Na ’nq ’5’
(IIIa)
5’np-Na-YYY-Nb-ZZZ-Na-nq3’
3’np ’-Na ’-Y’Y’Y’-Nb ’-Z’Z’Z’-Na ’nq ’5’
(IIIb)
5’np-Na-XXX-Nb-YYY-Na-nq3’
3’np ’-Na ’-X’X’X’-Nb ’-Y’Y’Y’-Na ’-nq ’5’
(IIIc)
5’np-Na-XXX-Nb-YYY-Nb-ZZZ-Na-nq3’
3’np ’-Na ’-X’X’X’-Nb ’-Y’Y’Y’-Nb ’-Z’Z’Z’-Na-nq ’5’
(IIId)
本発明の二本鎖RNA(dsRNA)剤は、任意選択で、1つ又は複数のリガンドにコンジュゲートされ得る。リガンドは、3’末端、5’末端又は両方の末端において、センス鎖、アンチセンス鎖又は両方の鎖に結合され得る。例えば、リガンドは、センス鎖にコンジュゲートされ得る。好ましい実施形態において、リガンドは、センス鎖の3’末端にコンジュゲートされる。好ましい一実施形態において、リガンドは、GalNAcリガンドである。特に好ましい実施形態において、リガンドは、GalNAc3である:
も、標的部分であり得る。ペプチド部分は、細胞膜を介してペプチド、オリゴヌクレオチド、及びタンパク質を含む大型極性分子を運搬することができる「送達」ペプチドであり得る。例えば、HIV Tatタンパク質に由来する配列(GRKKRRQRRRPPQ)(配列番号13)及びショウジョウバエアンテナペディア(Drosophila Antennapedia)タンパク質(RQIKIWFQNRRMKWKK)(配列番号14)は、送達ペプチドとして機能することが可能であることが分かっている。ペプチド又はペプチド模倣体は、ファージディスプレイライブラリー、又は1ビーズ1化合物(one-bead-one-compound)(OBOC)コンビナトリアルライブラリーから特定されたペプチドなどの、DNAのランダム配列によってコードされ得る(Lam et al.,Nature,354:82-84、1991)。好ましくは、組み込まれたモノマー単位を介してiRNA剤に結合されたペプチド又はペプチド模倣体は、アルギニン-グリシン-アスパラギン酸(RGD)-ペプチド、又はRGD模倣体などのペプチドである。ペプチド部分は、約5つのアミノ酸から約40個のアミノ酸の長さの範囲であり得る。ペプチド部分は、安定性又は直接配座特性を高めるためなどの構造修飾を有し得る。後述される構造修飾のいずれも用いられ得る。RGDペプチド部分は、内皮腫瘍細胞又は乳癌腫瘍細胞などの腫瘍細胞を標的とするのに使用され得る(Zitzmann et al.,Cancer Res.,62:5139-43,2002)。RGDペプチドは、肺、腎臓、脾臓、又は肝臓を含む様々な他の組織の腫瘍に対するiRNA剤の標的化を促進することができる(Aoki et al.,Cancer Gene Therapy 8:783-787,2001)。好ましくは、RGDペプチドは、腎臓に対するiRNA剤の標的化を促進する。RGDペプチドは、直鎖状又は環状であり得、特定の組織に対する標的化を促進するために、修飾、例えば、グリコシル化又はメチル化され得る。例えば、グリコシル化RGDペプチドは、iRNA剤を、αVβ3を発現する腫瘍細胞に送達することができる(Haubner et al.,Jour.Nucl.Med.,42:326-336,2001)。増殖細胞に豊富なマーカーを標的とするペプチドが使用され得る。例えば、RGD含有ペプチド及びペプチド模倣体は、癌細胞、特に、インテグリンを示す細胞を標的とすることができる。したがって、RGDペプチド、RGDを含有する環状ペプチド、D-アミノ酸を含むRGDペプチド、ならびに合成RGD模倣体を使用し得る。RGDに加えて、インテグリンリガンドを標的とする他の部分を使用することができる。一般に、このようなリガンドは、増殖細胞及び血管新生を制御するのに使用され得る。このタイプのリガンドの好ましいコンジュゲートは、PECAM-1、VEGF、又は他の癌遺伝子、例えば、本明細書に記載される癌遺伝子を標的とする。
q2A、q2B、q3A、q3B、q4A、q4B、q5A、q5B及びq5Cは、各存在に関して独立して0~20を表し、反復単位は、同一又は異なっていてもよく;
P2A、P2B、P3A、P3B、P4A、P4B、P5A、P5B、P5C、T2A、T2B、T3A、T3B、T4A、T4B、T4A、T5B、T5Cは、各々、各存在に関して独立して不在、CO、NH、O、S、OC(O)、NHC(O)、CH2、CH2NH又はCH2Oであり;
Q2A、Q2B、Q3A、Q3B、Q4A、Q4B、Q5A、Q5B、Q5Cは、各存在に関して独立して不在、アルキレン、置換されたアルキレンであり、ここで、1つ又は複数のメチレンは、O、S、S(O)、SO2、N(RN)、C(R’)=C(R’’)、C≡C又はC(O)のうちの1つ又は複数により中断又は終結されてもよく;
R2A、R2B、R3A、R3B、R4A、R4B、R5A、R5B、R5Cは、各々、各存在に関して独立して不在、NH、O、S、CH2、C(O)O、C(O)NH、NHCH(Ra)C(O)、-C(O)-CH(Ra)-NH-、CO、CH=N-O、
L2A、L2B、L3A、L3B、L4A、L4B、L5A、L5B及びL5Cは、リガンドを表し;即ち、それぞれ、各存在に関して独立して、単糖(GalNAcなど)、二糖、三糖、四糖、オリゴ糖、又は多糖であり;
Raが、H又はアミノ酸側鎖である。
細胞、例えば、ヒト対象(例えば、ヘモクロマトーシスなどのTMPRSS6に関連する障害に罹患している対象などの、iRNA剤を必要とする対象)などの対象中の細胞への本発明のiRNA剤の送達は、いくつかの様々な方法で行うことができる。例えば、送達は、細胞を、本発明のiRNAとインビトロ又はインビボのいずれかで接触させることによって行われ得る。インビボ送達はまた、iRNA、例えば、dsRNAを含む組成物を対象に投与することによって直接行われ得る。あるいは、インビボ送達は、iRNAの発現をコードし、それを導く1つ又は複数のベクターを投与することによって、間接的に行われ得る。これらの代替例は、以下に更に説明される。
TMPRSS6遺伝子を標的とするiRNAは、DNA又はRNAベクターに挿入された転写単位から発現され得る(例えば、Couture,A,et al.,TIG.(1996),12:5-10;Skillern,A.らの国際PCT公開番号国際公開第00/22113号パンフレット、Conradの国際PCT公開番号国際公開第00/22114号パンフレット、及びConradの米国特許第6,054,299号明細書を参照)。発現は、使用される特定の構築物及び標的組織又は細胞型に応じて、一時的(およそ数時間から数週間)であるか又は持続され得る(数週間から数カ月又はそれ以上)。これらの導入遺伝子は、線状構築物、環状プラスミド、又はウイルスベクターとして導入することができ、これらは、組み込み又は非組み込みベクターであり得る。導入遺伝子は、染色体外プラスミドとして継承されるのを可能にするように構築することもできる(Gassmann,et al.,Proc.Natl.Acad.Sci.USA(1995)92:1292)。
本発明は、本発明のiRNAを含む医薬組成物及び製剤も含む。一実施形態において、本明細書に記載されるiRNAと、薬学的に許容され得る担体とを含有する医薬組成物も本明細書に提供される。iRNAを含有する医薬組成物は、TMPRSS6に関連する疾病又は障害、例えば、ヘモクロマトーシスを処置するのに有用である。このような医薬組成物は、送達様式に基づいて製剤化される。一例は、非経口投与を介した、例えば、静脈内(IV)送達による全身投与用に製剤化される組成物である。別の例は、例えば、持続性ポンプ注入などによる脳への注入による、脳実質への直接送達用に製剤化される組成物である。
本発明の組成物及び方法に使用するためのiRNAは、膜分子集合体、例えば、リポソーム又はミセル中の送達用に製剤化され得る。本明細書において使用される際、「リポソーム」という用語は、少なくとも1つの二重層、例えば、1つの二重層又は複数の二重層に配置された両親媒性の脂質から構成される小胞を指す。リポソームは、親油性材料及び水性内部から形成される膜を有する単層及び多層小胞を含む。水性部分は、iRNA組成物を含有する。親油性材料は、水性外部から水性内部を分離し、通常、iRNA組成物を含まないが、場合によっては、含むことがある。リポソームは、作用部位への活性成分の移送及び送達に有用である。リポソーム膜は生体膜と構造が類似しているため、リポソームが組織に付着されると、リポソームの二重層が、細胞膜の二重層と融合する。リポソーム及び細胞の融合が進むにつれて、iRNAを含む内部の水性内容物が、細胞に送達され、ここで、iRNAは、標的RNAに特異的に結合することができ、RNAiを仲介することができる。場合によっては、リポソームはまた、例えば、iRNAを特定の細胞型に指向するように、特異的に標的化される。
本発明のiRNAすなわちdsRNAは、脂質製剤中、例えばLNP中に完全に封入されてもよく、又は他の核酸-脂質粒子を形成してもよい。
DPPC:ジパルミトイルホスファチジルコリン
PEG-DMG:PEG-ジジミリストイル(didimyristoyl)グリセロール(C14-PEG、又はPEG-C14)(2000の平均分子量を有するPEG)
PEG-DSG:PEG-ジスチリルグリセロール(C18-PEG、又はPEG-C18)(2000の平均分子量を有するPEG)
PEG-cDMA:PEG-カルバモイル-1,2-ジミリスチルオキシプロピルアミン(2000の平均分子量を有するPEG)
本発明の核酸-脂質粒子に使用される、例えば、カチオン性脂質などの化合物のいずれも、実施例により詳細に記載される方法を含む公知の有機合成技術によって調製され得る。全ての置換基は、特に示されない限り、以下に定義されるとおりである。
ある実施形態において、本発明の核酸-脂質粒子は、式A:
DLin-M-C3-DMA(すなわち、(6Z,9Z,28Z,31Z)-ヘプタトリアコンタ-6,9,28,31-テトラエン-19-イル4-(ジメチルアミノ)ブタノエート)の調製は以下のとおりであった。ジクロロメタン(5mL)中の(6Z,9Z,28Z,31Z)-ヘプタトリアコンタ-6,9,28,31-テトラエン-19-オール(0.53g)、4-N,N-ジメチルアミノ酪酸塩酸塩(0.51g)、4-N,N-ジメチルアミノピリジン(0.61g)及び1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(0.53g)の溶液を、室温で一晩撹拌した。溶液を、希塩酸で洗浄し、続いて、希炭酸水素ナトリウム水溶液で洗浄した。有機画分を、無水硫酸マグネシウム上で乾燥させ、ろ過し、溶媒を回転蒸発器において除去した。残渣を、1~5%のメタノール/ジクロロメタン溶出勾配を用いてシリカゲルカラム(20g)に通した。精製された生成物を含有する画分を組み合わせて。溶媒を除去し、無色油(0.54g)を得た。ALNY-100の合成
二口丸底フラスコ(1L)中で、200mlの無水THF中のLiAlH4(3.74g、0.09852mol)の撹拌懸濁液に、70mLのTHF中の514(10g、0.04926mol)の溶液を、窒素雰囲気下で、00Cでゆっくりと加えた。完全に加えた後、反応混合物を室温まで温め、次に、4時間加熱還流させた。反応の進行をTLCによって監視した。(TLCによる)反応の完了後、混合物を00Cに冷却し、飽和Na2SO4溶液の慎重な添加によってクエンチした。反応混合物を室温で4時間撹拌し、ろ過して取り除いた。残渣をTHFで十分に洗浄した。ろ液及び洗浄液を混合し、400mLのジオキサン及び26mLの濃HClで希釈し、室温で20分間撹拌した。揮発性物質を、減圧下で取り除いて、白色の固体として515の塩酸塩を得た。収量:7.12g 1H-NMR(DMSO、400MHz):δ=9.34(broad,2H)、5.68(s,2H)、3.74(m,1H)、2.66~2.60(m,2H)、2.50~2.45(m,5H)。
250mLの二口丸底フラスコ中で、100mLの乾燥DCM中の化合物515の撹拌溶液に、NEt3を加え(37.2mL、0.2669mol)、窒素雰囲気下で0℃に冷却した。50mLの乾燥DCM中のN-(ベンジルオキシ-カルボニルオキシ)-スクシンイミド(20g、0.08007mol)をゆっくりと加えた後、反応混合物を、室温まで温めた。反応(TLCによって2~3時間)の完了後、混合物を、1NのHCl溶液(1×100mL)及び飽和NaHCO3溶液(1×50mL)で連続して洗浄した。次に、有機層を、無水Na2SO4上で乾燥させ、溶媒を蒸発させて、粗材料を得て、それを、シリカゲルカラムクロマトグラフィーによって精製して、粘着性の塊として516を得た。収量:11g(89%)。1H-NMR(CDCl3、400MHz):δ=7.36~7.27(m,5H)、5.69(s,2H)、5.12(s,2H)、4.96(br.,1H)2.74(s,3H)、2.60(m,2H)、2.30~2.25(m,2H)。LC-MS[M+H]-232.3(96.94%)。
シクロペンテン516(5g、0.02164mol)を、500mLの一口丸底フラスコ中で、220mLのアセトン及び水(10:1)の溶液に溶解させ、それに、N-メチルモルホリン-N-オキシド(7.6g、0.06492mol)、続いて、4.2mLの、tert-ブタノール中のOsO4(0.275g、0.00108mol)の7.6%溶液を室温で加えた。反応(約3時間)の完了の後、混合物を、固体Na2SO3の添加によってクエンチし、得られた混合物を、室温で1.5時間撹拌した。反応混合物を、DCM(300mL)で希釈し、水(2×100mL)、続いて、飽和NaHCO3(1×50mL)溶液、水(1×30mL)及び最後に塩水(1×50mL)で洗浄した。有機相を、無水Na2SO4上で乾燥させ、溶媒を減圧下で除去した。粗材料のシリカゲルカラムクロマトグラフィー精製により、ジアステレオマーの混合物を得て、それを、分取HPLCによって分離した。収量:-6gの粗517A-ピーク-1(白色の固体)、5.13g(96%)。1H-NMR(DMSO、400MHz):δ=7.39~7.31(m,5H)、5.04(s,2H)、4.78~4.73(m,1H)、4.48~4.47(d,2H)、3.94~3.93(m,2H)、2.71(s,3H)、1.72~1.67(m,4H)。LC-MS-[M+H]-266.3、[M+NH4+]-283.5存在、HPLC-97.86%。X線により確認された立体化学。
化合物505の合成について記載されるのと同様の手順を用いて、化合物518(1.2g、41%)を無色油として得た。1H-NMR(CDCl3、400MHz):δ=7.35~7.33(m,4H)、7.30~7.27(m,1H)、5.37~5.27(m,8H)、5.12(s,2H)、4.75(m,1H)、4.58~4.57(m,2H)、2.78~2.74(m,7H)、2.06~2.00(m,8H)、1.96~1.91(m,2H)、1.62(m,4H)、1.48(m,2H)、1.37~1.25(br m,36H)、0.87(m,6H)。HPLC-98.65%。
ヘキサン(15mL)中の化合物518(1当量)の溶液を、THF(1M、2当量)中のLAHの氷冷した溶液に滴下して加えた。完全に加えた後、混合物を、0.5時間にわたって40℃で加熱し、次に、氷浴上で再度冷却した。混合物を、飽和Na2SO4水溶液を用いて慎重に加水分解し、次に、セライトを通してろ過し、還元して油にした。カラムクロマトグラフィーにより、純粋な519(1.3g、68%)が得られ、これは、無色油として得られた。13C NMR δ=130.2、130.1(×2)、127.9(×3)、112.3、79.3、64.4、44.7、38.3、35.4、31.5、29.9(×2)、29.7、29.6(×2)、29.5(×3)、29.3(×2)、27.2(×3)、25.6、24.5、23.3、226、14.1;エレクトロスプレーMS(+ve):C44H80NO2についての分子量(M+H)+計算値654.6、実測値654.6。
i.エマルション
本発明の組成物は、エマルションとして、調製され、製剤化され得る。エマルションは、典型的に、1つの液体が、通常、直径が0.1μmを超える液滴の形態の別の液体中に分散された不均一系である(例えば、Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems,Allen,LV.,Popovich NG.,and Ansel HC.,2004,Lippincott Williams & Wilkins(8th ed.),New York,NY;Idson,in Pharmaceutical Dosage Forms,Lieberman,Rieger and Banker(Eds.),1988,Marcel Dekker,Inc.,New York,N.Y.,volume 1,p.199;Rosoff,in Pharmaceutical Dosage Forms,Lieberman,Rieger and Banker(Eds.),1988,Marcel Dekker,Inc.,New York,N.Y.,Volume 1,p.245;Block in Pharmaceutical Dosage Forms,Lieberman,Rieger and Banker(Eds.),1988,Marcel Dekker,Inc.,New York,N.Y.,volume 2,p.335;Higuchi et al.,in Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.,1985,p.301を参照)。エマルションは、多くの場合、互いに親密に混合され及び分散された2つの非混和性液体相を含む二層系である。一般に、エマルションは、油中水(w/o)又は水中油(o/w)の種類のいずれかであり得る。水性相が微小液滴として塊の油相中に微細に分割され及び分散された場合、得られた組成物は、油中水(w/o)エマルションと呼ばれる。代替的に、油相が微小液滴として塊の水性相中に微細に分割され及び分散された場合、得られた組成物は、水中油(o/w)エマルションと呼ばれる。エマルションは、分散相及び活性薬物に加えて追加の構成成分を含むことができ、該構成成分は、水性相、油相中の溶液として、又はそれ自体が別個の相として存在し得る。必要に応じてエマルション中に乳化剤、安定剤、染料、及び抗酸化剤などの医薬賦形剤も存在し得る。医薬エマルションは、例えば、油中水中油(o/w/o)及び水中油中水(w/o/w)エマルションの場合など、3つ以上の相からなる多エマルションであり得る。そのような複合製剤は、多くの場合、単純な二成分エマルションが提供しない所定の利点を提供する。o/wエマルションの個々の油小滴が小さい水小滴を囲い込む多エマルションは、w/o/wエマルションを構成する。同様に、油の連続相中で安定化された水の小球中に囲い込まれた油小滴の系は、o/w/oエマルションを提供する。
本発明の一実施形態において、iRNA及び核酸の組成物は、マイクロエマルションとして製剤化される。マイクロエマルションは、単一の光学的に等方性で且つ熱力学的に安定した液体溶液である、水、油及び両親媒性物質の系として定義され得る(例えば、Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems,Allen,LV.,Popovich NG.,and Ansel HC.,2004,Lippincott Williams & Wilkins(8th ed.),New York,NY;Rosoff,in Pharmaceutical Dosage Forms,Lieberman,Rieger and Banker(Eds.),1988,Marcel Dekker,Inc.,New York,N.Y.,volume 1,p.245を参照)。典型的には、マイクロエマルションは、最初に油を水性界面活性剤溶液中に分散した後、十分な量の第四の構成成分、一般に中間の鎖長のアルコールを加えて透明系を形成することにより調製される。従って、マイクロエマルションは、表面活性分子の界面フィルムにより安定化されている2つの非混和性液体からなる熱力学的に安定な、等方的に透明な分散物として記載されている(Leung and Shah,in:Controlled Release of Drugs:Polymers and Aggregate Systems,Rosoff,M.,Ed.,1989,VCH Publishers,New York,pp.185-215)。マイクロエマルションは通常、油、水、界面活性剤、補助界面活性剤及び電解質を含む3~5つの構成成分の組み合わせを用いて調製される。マイクロエマルションが油中水(w/o)タイプ又は水中油(o/w)タイプのいずれのものであるかは、使用される油及び界面活性剤の特性と、界面活性剤分子の極性頭部及び炭化水素尾部の構造及び幾何学的充填(geometric packing)とに依存する(Schott,in Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.,1985,p.271)。
本発明のRNAi剤は、粒子、例えば、微粒子に組み込まれてもよい。微粒子は、噴霧乾燥によって生成され得るが、凍結乾燥、蒸発、流体床乾燥、真空乾燥、又はこれらの技術の組合せを含む他の方法によって生成されてもよい。
一実施形態において、本発明は、動物の皮膚への、核酸、特にiRNAの効率的な送達を行うために様々な浸透促進剤を用いる。ほとんどの薬剤が、イオン化及び非イオン化の両方の形態で溶液中に存在する。しかしながら、通常、脂溶性又は親油性の薬剤のみが、細胞膜を容易に横断する。横断される膜が浸透促進剤で処理されている場合、非親油性薬剤でも細胞膜を横断することができることが発見されている。細胞膜をわたる非親油性薬剤の拡散の補助に加えて、浸透促進剤は、親油性薬剤の浸透性も向上させる。
本発明の所定の組成物は、製剤中に担体化合物も組み込んでいる。本明細書で使用される「担体化合物」又は「担体」は、不活性(即ち、生物学的活性perseを所有しない)であり得るが、例えば、生物学的に活性な核酸を分解し、又は循環からの核酸の除去を促進することによる、生物学的活性を有する核酸のバイオアベイラビリティを低下させるインビボでのプロセスによって、核酸であると認識される核酸又はその類似体を指すことができる。核酸及び担体化合物の共投与、典型的には過剰な後者の物質による共投与により、おそらくは共通の受容体に対する担体化合物と核酸との競合に起因して、肝臓、腎臓又は他の循環外リザーバ(extracirculatory reservoir)中で回収される核酸の量が実質的に低下し得る。例えば、肝組織内での部分的ホスホロチオエートの回収は、それがポリイノシン酸、デキストラン硫酸塩、ポリシチジル酸(polycytidic acid)又は4-アセトアミド-4’イソチオシアノ-スチルベン-2,2’-ジスルホン酸と共投与された際、低下され得る(Miyao et al.,DsRNA Res.Dev.,1995,5,115-121;Takakura et al.,DsRNA&Nucl.Acid Drug Dev.,1996,6,177-183。
担体化合物とは対照的に、「医薬担体」又は「賦形剤」は、動物に1つ又は複数の核酸を送達するための薬学的に許容され得る溶媒、懸濁剤、又は任意の他の薬理学的に不活性なビヒクルである。賦形剤は、液体又は固体とすることができ、計画された投与方法を考慮に入れて、核酸及び医薬組成物の他の所定の構成成分と組み合わされた際に、所望の嵩、稠度などを提供するように選択される。典型的な医薬担体には、非限定的に、結合剤(例えば、α化トウモロコシ澱粉、ポリビニルピロリドン又はヒドロキシプロピルメチルセルロースなど);充填剤(例えば、乳糖及び他の糖、微結晶セルロース、ペクチン、ゼラチン、硫酸カルシウム、エチルセルロース、ポリアクリレート又はリン酸水素カルシウムなど);滑沢剤(例えば、ステアリン酸マグネシウム、タルク、シリカ、コロイド状二酸化ケイ素、ステアリン酸、金属ステアリン酸塩、水素化植物油、トウモロコシ澱粉、ポリエチレングリコール、安息香酸ナトリウム、酢酸ナトリウムなど);錠剤崩壊剤(例えば、澱粉、澱粉グリコール酸ナトリウムなど);及び湿潤剤(例えば、ラウリル硫酸ナトリウムなど)が挙げられる。
本発明の組成物は更に、医薬組成物中に従来見出される他の補助構成成分も、当技術分野にて確立されたそれらの使用レベルで含有し得る。それ故、例えば、組成物は、例えば、鎮痒薬、収斂薬、局所麻酔薬若しくは抗炎症薬剤などの更なる、適合可能な、医薬的に活性な材料を含有することができ、又は、染料、風味剤、保存剤、抗酸化剤、乳白剤、増粘剤及び安定剤などの、本発明の組成物の様々な剤形を物理的に処方するのに有用な更なる材料を含有することができる。しかしながら、それらの材料は、加えられた際、本発明の組成物の構成成分の生物学的活性を過度に妨害しない必要がある。製剤は滅菌されてもよく、また所望の場合、製剤の核酸と有害に相互作用しない補助剤、例えば滑沢剤、保存剤、安定剤、湿潤剤、乳化剤、浸透圧に影響を与える塩、緩衝液、着色料、調味料及び/又は芳香性物質などと混合される。
本発明は、細胞内でのTMPRSS6(マトリプターゼ-2)の発現の阻害方法を提供する。本方法は、細胞を、細胞内でのTMPRSS6の発現を阻害するのに有効な量のRNAi剤、例えば、二本鎖RNAi剤と接触させ、それにより、細胞内でのTMPRSS6の発現を阻害する工程を含む。
本発明は、TMPRSS6遺伝子発現によって調節され得る疾病及び病態の処置又は予防方法も提供する。例えば、本明細書に記載される組成物は、鉄過剰に関連する疾患、例えば、サラセミア(例えば、β-サラセミア又はα-サラセミア)、原発性ヘモクロマトーシス、続発性ヘモクロマトーシス、重度の若年性ヘモクロマトーシス、赤芽球性ポルフィリン症、鉄芽球性貧血、溶血性貧血、赤血球異形成貧血、又は鎌型赤血球貧血を処置するのに使用され得る。一実施形態において、TMPRSS6 iRNAは、異常ヘモグロビン症を処置するのに使用され得る。本発明のTMPRSS6 iRNAは、慢性アルコール依存症などの、他の病態に起因する鉄のレベルの上昇を処置するのにも使用され得る。
本発明は、iRNA剤のいずれかを使用し、及び/又は本発明の方法のいずれかを行うためのキットも提供する。このようなキットは、1つ又は複数のRNAi剤と、使用説明書、例えば、細胞を、TMPRSS6の発現を阻害するのに有効な量のRNAi剤と接触させることによって、細胞内でのTMPRSS6の発現を阻害するための説明書とを含む。キットは、任意選択で、細胞をRNAi剤と接触させるための手段(例えば、注射器具)、又はTMPRSS6の阻害を測定するための手段(例えば、TMPRSS6 mRNA又はTTRタンパク質の阻害を測定するための手段)を更に含み得る。TMPRSS6の阻害を測定するためのこのような手段は、例えば、血漿試料などの、対象に由来する試料を得るための手段を含み得る。本発明のキットは、任意選択で、RNAi剤を対象に投与するための手段又は治療有効量又は予防的に有効な量を決定するための手段を更に含み得る。
以下の材料及び方法を実施例に使用した。
ABI高容量cDNA逆転写キット(Applied Biosystems,Foster City,CA,Cat #4368813)を用いたcDNA合成
Hep3B細胞(ATCC,Manassas,VA)を、10%のFBS、ストレプトマイシン、及びグルタミン(ATCC)が補充されたEMEM(ATCC)中、5%のCO2の雰囲気下、37℃でほぼコンフルエンスまで増殖させた後、トリプシン処理によりプレートから解放した。ウェル当たり14.8μlのOpti-MEM及び0.2μlのLipofectamine RNAiMax(Invitrogen,Carlsbad CA.cat # 13778-150)を、96ウェルプレート内のウェルごとに5μlの各siRNA二本鎖に加えることによりトランスフェクションを行い、室温で15分間インキュベートした。次に、約2×104個のHep3B細胞を含む、抗生物質を有さない80μlの完全増殖培地を、siRNA混合物に加えた。RNA精製の前に、細胞を、24時間インキュベートした。10nM及び0.1nMの最終二本鎖濃度で単回投与実験を行った。
細胞を採取し、150μlの溶解/結合緩衝液中に溶解させた後、プラットフォームシェーカーを用いて850rpmで5分間混合した(混合速度は、プロセス全体を通して同一であった)。10マイクロリットルの磁気ビーズ及び80μlの溶解/結合緩衝液混合物を丸底プレートに加え、1分間混合した。磁気スタンドを用いて磁気ビーズを捕捉し、ビーズを乱すことなく上清を除去した。上清を除去した後、溶解した細胞を残りのビーズに加え、5分間混合した。上清を除去した後、磁気ビーズを150μlの洗浄緩衝液Aで2回洗浄し、1分間混合した。ビーズを再度捕捉し、上清を除去した。次に、ビーズを150μlの洗浄緩衝液Bで洗浄し、捕捉し、上清を除去した。次に、ビーズを150μlの溶出緩衝液で洗浄し、捕捉し、上清を除去した。ビーズを2分間乾燥させた。乾燥後、50μlの溶出緩衝液を加え、75℃で5分間混合した。ビーズを磁石上で5分間捕捉し、精製されたRNAを含有する50μlの上清を除去し、新たな96ウェルプレートに加えた。
2μlのcDNAを、384ウェルプレート(Roche cat # 04887301001)中で、ウェル当たり、0.5μlのヒトGAPDH TaqMan Probe(Applied Biosystems Cat #4326317E)、0.5μlのヒトTMPRSS6 TaqMan probe(Applied Biosystems cat # Hs00542184_m1)及び5μlのLightcycler 480プローブマスターミックス(Roche Cat #04887301001)を含むマスターミックスに加えた。ΔΔCt(RQ)アッセイを用いて、Roche LC480 Real Time PCRシステム(Roche)中で、リアルタイムPCRを行った。特に断りのない限り、各二本鎖を2つの独立したトランスフェクションにおいて試験し、各トランスフェクションを2回アッセイした。
転写物
NCBI Gene database(http://www.ncbi.nlm.nih.gov/gene/)において注釈付けされたヒト、アカゲザル(アカゲザル(Macaca mulatta))、マウス、及びラットTMPRSS6転写物を標的とするsiRNAを特定するために、siRNA設計を行った。設計には、NCBI RefSeq collectionからの以下の転写物を使用した:ヒト-NM_153609.2;アカゲザル-XM_001085203.2及びXM_001085319.1;マウス-NM_027902.2;ラット-NM_001130556.1。高い霊長類/げっ歯類配列分散のため、限定はされないが、ヒト及びアカゲザル転写物のみ;ヒト、アカゲザル、及びマウス転写物のみ;ヒト、アカゲザル、マウス、及びラット転写物のみ;及びマウス及びラット転写物のみと一致する二本鎖を含むバッチを含むいくつかの別個のバッチで、SiRNA二本鎖を設計した。各設計バッチ(上記)において考慮される、列挙されるヒト転写物及び他の種の転写物と100%の同一性を共有する全てのsiRNA二本鎖を設計した。
合計で39のセンス及び39のアンチセンスに由来するヒト/アカゲザル、6のセンス及び6のアンチセンスに由来するヒト/アカゲザル/マウス、3のセンス及び3のアンチセンスに由来するヒト/アカゲザル/マウス/ラット、及び16のセンス及び16のアンチセンスに由来するマウス/ラットsiRNA 21/23量体オリゴを合成し、GalNAcコンジュゲート二本鎖に形成した。
修飾され、コンジュゲートされたTMPRSS6 siRNA二本鎖も、ヒト細胞株Hep3B内でのトランスフェクションアッセイによって有効性について評価した。TMPRSS6 siRNAを、2つの用量、10nM及び0.1nMでトランスフェクトした。これらのアッセイの結果が、表3に示され、データが、陰性対照siRNA、AD-1955でトランスフェクトした細胞に対して、TMPRSS6を標的とするsiRNAでトランスフェクトした細胞中に残るメッセージの割合±標準偏差(SD)として表される。
AD-59743がTMPRSS6タンパク質の発現を抑制する能力を、AD-59743の投与後の野生型C57BL/6マウスの肝臓中のTMPRSS6及びヘプシジンmRNAのレベルを測定することによって評価した。1、3又は10mg/kgの単回用量のAD-59743を、皮下投与し、マウスを3日目又は7日目に殺処分した。肝臓中のTMPRSS6及びヘプシジンmRNAのレベルを、上述される方法を用いて、qPCRによって測定した。対照群にPBSによる注射を与えた。
この試験の目的は、鉄レベルに対する同時投与されるTMPRSS6特異的siRNA及び鉄キレート剤の影響を試験することであった。この試験では、6週齢の野生型C57BL/6及びサラセミアTh3/+マウス(Douet et al.,Am.J.Pathol.(2011),178(2):774-83)に、3~5ppmの鉄を含有する低鉄食を与えた。マウスに、デフェリプロンを含有する製剤AF-011-46273、250mg/kg/日の用量の鉄キレート剤及び以下の構造:オリゴSeq-センス-uGGuAuuuccuAGGGuAcAdTsdT(配列番号209);オリゴSeq-アンチセンス-UGuACCCuAGGAAAuACcAdTsdT(配列番号210)を有するiRNA剤を静脈内投与した。製剤は、MC-3/DSPC/コレステロール/PEG-DMG 50/10/38.5/1.5も含有していた。肝臓及び脾臓組織を採取し、組織の非ヘム鉄濃度を、既に記載されるように測定した(例えば、Schmidt et al.(2013)Blood 121(7):1200-8;Cook,JD,et al..Tissue iron stores.In:Cook JD,editor.Methods in Hematology.Vol 1.New York,NY:Churchill Livingstone Press;1980.p.104-109を参照)。
転写物
NCBI Gene database(http://www.ncbi.nlm.nih.gov/gene/)において注釈付けされたヒト、カニクイザル(カニクイザル(Macaca fascicularis);これ以降、「カニクイザル(cyno)」)、マウス、及びラットTMPRSS6転写物を標的とするsiRNAを特定するために、siRNA設計を行った。設計には、NCBI RefSeq collectionからの以下の転写物を使用した:ヒト-NM_153609.2;マウス-NM_027902.2;ラット-NM_001130556.1。カニクイザルの場合、転写物の配列は、カニクイザル(M.fascicularis)ゲノムプロジェクト及びNCBIヌクレオチドデータベース(http://macaque.genomics.org.cn/page/species/download.jsp及びhttp://www.ncbi.nlm.nih.gov/nucleotide/)からそれぞれ入手可能な2つの登録番号:“ENSP00000384964[mRNA]遺伝子座=chr10:82446450:82485403:-“及びFR874253.1から構築される配列の、ヒトTMPRSS6とのアラインメントによって得られた。高い霊長類/げっ歯類配列分散のため、限定はされないが、ヒト及びカニクイザル転写物のみ;ヒト、カニクイザル、及びマウス転写物のみ;及びヒト、カニクイザル、マウス、及びラット転写物のみと一致する二本鎖を含むバッチを含むいくつかの別個のバッチで、SiRNA二本鎖を設計した。規定の領域において、各設計バッチ(上記)において考慮される、列挙されるヒト転写物及び他の種の転写物と100%の同一性を共有するほとんどのsiRNA二本鎖を設計した。場合によっては、アンチセンス鎖:標的mRNA相補的塩基対が、GC又はCG対であった場合、二本鎖とmRNA標的との間のミスマッチが、最初のアンチセンス(最後のセンス)位置において許容された。これらの場合、最初のアンチセンス:最後のセンス対においてUA又はAU対を有する二本鎖を設計した。したがって、二本鎖は、相補性を維持したが、標的に対して不一致であった(U:C、U:G、A:C、又はA:G)。
合計で5のセンス及び5のアンチセンスヒト、32のセンス及び32のアンチセンスに由来するヒト/カニクイザル、4のセンス及び4のアンチセンスに由来するヒト/カニクイザル/マウス、8のセンス及び8のアンチセンスに由来するヒト/カニクイザル/マウス/ラット、19のセンス及び19のアンチセンスに由来するヒト/カニクイザル/ラット、2のセンス及び2のアンチセンスに由来するヒト/マウス、及び1のセンス及び1のアンチセンスに由来するヒト/マウス/ラットsiRNA 21/23量体オリゴを合成し、GalNAcコンジュゲート二本鎖に形成した。
単回用量及び用量応答試験のための細胞培養及びトランスフェクション
Hep3B細胞(ATCC,Manassas,VA)を、10%のFBS、ストレプトマイシン、及びグルタミン(ATCC)を補充したDMEM(ATCC)中で、5%のCO2の雰囲気中で、37℃でほぼコンフルエンスまで増殖させた後、トリプシン処理によりプレートから解放した。ウェル当たり14.8μlのOpti-MEM及び0.2μlのLipofectamine RNAiMax(Invitrogen,Carlsbad CA.cat # 13778-150)を、96ウェルプレート内のウェルごとに5μlのsiRNA二本鎖に加えることによりトランスフェクションを行い、室温で15分間インキュベートした。次に、約2×104個のHep3B細胞を含む、抗生物質を有さない80μlの完全増殖培地を、siRNA混合物に加えた。RNA精製の前に、細胞を、24時間インキュベートした。10nM及び0.1nMの最終二本鎖濃度で実験を行った。
細胞を採取し、150μlの溶解/結合緩衝液中に溶解させた後、エッペンドルフサーモミキサー(Eppendorf Thermomixer)を用いて、850rpmで5分間混合した(混合速度は、プロセス全体を通して同一であった)。10マイクロリットルの磁気ビーズ及び80μlの溶解/結合緩衝液混合物を丸底プレートに加え、1分間混合した。磁気スタンドを用いて磁気ビーズを捕捉し、ビーズを乱すことなく上清を除去した。上清を除去した後、溶解した細胞を残りのビーズに加え、5分間混合した。上清を除去した後、磁気ビーズを150μlの洗浄緩衝液Aで2回洗浄し、1分間混合した。ビーズを再度捕捉し、上清を除去した。次に、ビーズを150μlの洗浄緩衝液Bで洗浄し、捕捉し、上清を除去した。次に、ビーズを150μlの溶出緩衝液で洗浄し、捕捉し、上清を除去した。ビーズを2分間乾燥させた。乾燥後、50μlの溶出緩衝液を加え、70℃で5分間混合した。ビーズを磁石上で5分間捕捉した。40μlの上清を除去し、別の96ウェルプレートに加えた。
反応当たり、2μlの10倍緩衝液、0.8μlの25倍dNTP、2μlのランダムプライマー、1μlの逆転写酵素、1μlのRNase阻害剤及び3.2μlのH2Oのマスターミックスを、10μlの総RNAに加えた。以下の工程を介して、Bio-Rad C-1000又はS-1000サーモサイクラー(Hercules,CA)を用いて、cDNAを生成した:25℃で10分間、37℃で120分間、85℃で5秒間、4℃で保持。
2μlのcDNAを、384ウェル50プレート(Roche cat # 04887301001)中で、ウェル当たり、0.5μlのGAPDH TaqMan Probe(Applied Biosystems Cat #4326317E)、0.5μlのTMPRSS6 TaqMan probe(Applied Biosystems cat # Hs00542184_m1)及び5μlのLightcycler 480プローブマスターミックス(Roche Cat #04887301001)を含むマスターミックスに加えた。ΔΔCt(RQ)アッセイを用いて、Roche Lightcycler Real Time PCRシステム(Roche)中でリアルタイムPCRを行った。要約した表中に特に断りのない限り、各二本鎖を2つの独立したトランスフェクションにおいて試験し、各トランスフェクションを2回アッセイした。
雌のC57BL/6マウスに、0.3mg/kg、1.0mg/kg又は3.0mg/kgの用量のAD-60940、又は対照としてPBSのみを単回皮下注射で投与した。3匹のマウスを、様々な時点で、肝臓TMPRSS6 mRNA、肝臓ヘプシジンmRNA、血清ヘプシジン、総血清鉄、及びトランスフェリン飽和度パーセントについて、用量ごとに評価した。1.0mg/kg又は3.0mg/kgのAD-60940又はPBSを与えられたマウスを、0日目(処置前)並びに処置の7、11、14及び21日後に評価した。0.3mg/kgのAD-60940を与えられたマウスを、0日目(処置前)並びに処置の7及び11日後に評価した。肝臓TMPRSS6 mRNA及び肝臓ヘプシジンmRNAレベルを、qPCRによって測定し、GAPDH mRNAレベルに対して正規化し、PBSのみを投与されたマウスにおけるmRNAレベルに対して表した。血清ヘプシジンを、ELISA(Intrinsic Life Sciences)によって測定した。総血清鉄及びトランスフェリン飽和度パーセント(% TfSat)を、Olympus AU400 Serum Chemistry Analyzerを用いて測定した。各データ点が、3匹のマウスの平均値を表す。平均の標準偏差が、エラーバーによって表される。
雌のC57BL/6マウスに、0.3mg/kg、1.0mg/kgの用量のAD-60940、又はPBSのみ(対照として)を、3週間にわたって週に1回、皮下注射で投与し、次に、最後の投与の7日後に殺処分した(図4A)。用量ごとに3匹のマウスを、肝臓TMPRSS6 mRNA、肝臓ヘプシジンmRNA、及びトランスフェリン飽和度パーセントについて評価した。肝臓TMPRSS6 mRNA及び肝臓ヘプシジンmRNAレベルを、qPCRによって測定し、GAPDH mRNAレベルに対して正規化し、PBSのみを投与されたマウスにおけるmRNAレベルに対して表した。トランスフェリン飽和度パーセント(% TfSat)を、Olympus AU400 Serum Chemistry Analyzerを用いて測定した。各データ点が、3匹のマウスの平均値を表す。平均の標準偏差が、エラーバーによって表される。
AD-59743、AD-61002、AD-60940、及び他のTMPRSS6 iRNA剤を用いて生成されたデータを、肝臓TMPRSS6 mRNAレベル及び血清ヘプシジンレベル及びトランスフェリン飽和度パーセントの間の関係を評価するために更に分析した。血清ヘプシジン濃度は、ヒルの式を用いて、TMPRSS6 mRNAレベルに対する非線形関係を示した(図5A)。トランスフェリン飽和度パーセントは、線形単回帰式に当てはめたとき、TMPRSS6 mRNAレベルに対する線形関係を示した(図5B)。TMPRSS6 mRNAレベル及びトランスフェリン飽和度パーセントの間の線形関係は、鉄制限が、AD-60940によって正確にかつ予想どおりに調節され得ることを示す。血清ヘプシジン濃度及び相対的なヘプシジンmRNAレベルも、線形単回帰式に当てはめたとき、線形関係を示した(図5C)。対照的に、トランスフェリン飽和度パーセント及び血清ヘプシジン濃度の間の関係は、非線形であり、ヒルの式に当てはめた(図5D)。
図6に示されるTMPRSS6 siRNA二本鎖を、siRNA二本鎖の投与後に、雌のC57BL/6マウスの肝臓中のTMPRSS6 mRNAのレベルを抑制する能力によって、有効性について評価した。3mg/kgのTMPRSS6 siRNA二本鎖を単回の皮下投与で投与し、マウスを7日後に殺処分した。肝臓中のTMPRSS6 mRNAのレベルを、上述される方法を用いてqPCRによって測定した。対照群のマウスには、PBSの注射を与えた。
図7に示されるTMPRSS6 siRNA二本鎖を、siRNA二本鎖の投与後に、野生型C57BL/6マウスの肝臓中のTMPRSS6 mRNAのレベルを抑制する能力によって、有効性について評価した。0.3mg/kg又は1.0mg/kgのいずれかのTMPRSS6 siRNA二本鎖の皮下投与を、3週間にわたって週に1回投与した。マウスを、最後の投与の7日後に殺処分した。肝臓中のTMPRSS6 mRNAのレベルを、上述される方法を用いて、qPCRによって測定した。対照群のマウスに、PBSの注射を与えた。
AD-60940の投与が、対照と比べて80%超だけTMPRSS6 mRNAを持続的に減少させたという観察に基づいて、様々な化学的修飾を有するAD-60940の親配列に基づいた更なるsiRNAを、Hep3B細胞におけるトランスフェクションによって、10nM及び0.1nMでの単回用量スクリーンにおいて有効性について評価した。これらの剤のセンス鎖及びアンチセンス鎖の配列が、表8に示され、このスクリーンの結果が、表9に示される。表9中のデータは、対照に対して残るメッセージの平均割合として表される。
TMPRSS6を標的とする更なる二本鎖を産生し、以下の材料及び方法を用いて有効性についてインビトロでスクリーニングした。
siRNA設計
センス鎖及びアンチセンス鎖の両方について、19ヌクレオチド長のTMPRSS6二本鎖を、GenBank登録番号NM_153609.3に記載されるヒトTMPRSS6 mRNA配列を用いて設計した。実質的に3209ヌクレオチド転写物全体にわたる、7ヌクレオチドより長い反復を含まない3180の二本鎖を最初に同定した。次に、全ての3180の二本鎖を、各二本鎖位置におけるヌクレオチド対、並びにスクリーニングに使用される用量及び細胞株を評価する線形モデルにしたがって、予測される有効性について採点した。また、二本鎖を、特注の力まかせアルゴリズムを用いて、ヒトRefSeq collectionにおける全ての転写物に対してマッチングさせ、TMPRSS6以外の転写物に対する(鎖当たりの)ミスマッチの最低数を採点した。次に、合成され、スクリーニングされる二本鎖を、以下のスキームにしたがって、3180から選択した:転写物の5’末端から開始して、最も高い予測される有効性を有し、TMPRSS6以外の全ての転写物に対する両方の鎖における少なくとも1つのミスマッチを有し、他の二本鎖組の一部として既に合成及びスクリーニングされていない全ての10±2ヌクレオチドの「ウインドウ」内で二本鎖を選択した。全ての基準を満たす二本鎖が、所与のウインドウ内で同定されない場合、そのウインドウを飛ばした。303の二本鎖を、上記の基準にしたがって選択した。更なる31の二本鎖も選択した。
Hep3B2.1-7細胞を、米国培養細胞系統保存機関(American Type Culture Collection)(Rockville,Md.,cat.No.HB-8064)から入手し、加湿器の付いた培養器(humidified incubator)(Heraeus HERAcell,Kendro Laboratory Products,Langenselbold,Germany)において、5%のCO2の雰囲気下、37℃で、10%のウシ胎仔血清(FCS)(Biochrom AG,Berlin,Germany,cat.No.S0115)及びペニシリン100U/ml、ストレプトマイシン100mg/ml(Biochrom AG,Berlin,Germany,cat.No.A2213)を含有するように補充されたEMEM(ATCC #30-2003)中で培養した。
TMPRSS6 mRNAの測定のために、TMPRSS6についてはQuantigene II Kit及びbDNAについてはQuantigene I Explore Kit(それぞれ、Panomics,Fremont,Calif.,USA,cat.No.15735又はQG0004)の製造業者によって推奨される手順にしたがって、細胞を、トランスフェクションの24時間後に採取し、53℃で溶解させた。その後、50μlの溶解物を、ヒトTMPRSS6に特異的なプローブセットを用いてインキュベートし、10μlの溶解物を、ヒトGAPDHに特異的なプローブセットを用いてインキュベートし、QuantiGeneのための製造業者のプロトコルにしたがって処理した。化学発光を、RLU(相対発光量)としてVictor2-Light(Perkin Elmer,Wiesbaden,Germany)において測定し、ヒトTMPRSS6プローブセットを用いて得られた値を、各ウェルについてそれぞれのヒトGAPDH値に対して正規化し、次に、3つの関連のない対照dsRNAの平均に関連付けた。
Claims (13)
- 細胞内でのTMPRSS6(マトリプターゼ-2)遺伝子の発現を阻害するための二本鎖RNAi剤であって、前記二本鎖RNAi剤が、二本鎖領域を形成するセンス鎖及びアンチセンス鎖を含み、前記センス鎖が、
5’-CUUCUUCUGGUUCAUUCUCCA-3’(配列番号223)
のヌクレオチド配列を含み、前記アンチセンス鎖が、
5’-UGGAGAAUGAACCAGAAGAAGCA-3’(配列番号292)
のヌクレオチド配列を含み、
前記センス鎖が21~30ヌクレオチド長であり、及びアンチセンス鎖が23~30ヌクレオチド長であり、
前記センス鎖の前記ヌクレオチドの全て及び前記アンチセンス鎖の前記ヌクレオチドの全てが、修飾ヌクレオチドであり、
前記センス鎖が、3’末端において二価又は三価の分枝鎖状リンカーを介して結合された、1つ又は複数のGalNAc誘導体を含むリガンドにコンジュゲートされる、
二本鎖RNAi剤。 - 前記修飾ヌクレオチドの少なくとも1つが、3’末端デオキシ-チミン(dT)ヌクレオチド、2’-O-メチル修飾ヌクレオチド、2’-フルオロ修飾ヌクレオチド、2’-デオキシ-修飾ヌクレオチド、固定ヌクレオチド、非塩基性ヌクレオチド、2’-アミノ-修飾ヌクレオチド、2’-アルキル-修飾ヌクレオチド、モルホリノヌクレオチド、ホスホロアミデート、非天然塩基を含むヌクレオチド、5’-ホスホロチオエート基を含むヌクレオチド、5’リン酸又は5’リン酸模倣体を含むヌクレオチド、及びコレステリル誘導体又はドデカン酸ビスデシルアミド基に結合された末端ヌクレオチドからなる群から選択される、請求項1に記載の二本鎖RNAi剤。
- 少なくとも1つの鎖が、少なくとも1つまたは少なくとも2つのヌクレオチドの3’オーバーハングを含む、請求項1に記載の二本鎖RNAi剤。
- 前記センス鎖が21~25または21~23のヌクレオチド長であり、及び前記アンチセンス鎖が23~25ヌクレオチド長である、請求項1に記載の二本鎖RNAi剤。
- 前記センス鎖が21ヌクレオチド長であり、及び前記アンチセンス鎖が23ヌクレオチド長である、請求項4に記載の二本鎖RNAi剤。
- 少なくとも1つのホスホロチオエート又はメチルホスホネートヌクレオチド間結合を更に含む、請求項1に記載の二本鎖RNAi剤。
- 前記RNAi剤が、6~8つのホスホロチオエートヌクレオチド間結合を含む、請求項8に記載の二本鎖RNAi剤。
- 請求項1に記載の二本鎖RNAi剤を含む医薬組成物。
- TMPRSS6に関連する疾患に罹患しているヒト対象の処置方法への使用のための、請求項1に記載の二本鎖RNAi剤、又は請求項10に記載の医薬組成物。
- 前記ヒトが、遺伝性ヘモクロマトーシス、β-サラセミア、赤芽球性ポルフィリン症、パーキンソン病、アルツハイマー病又はフリードライヒ運動失調症から選択される疾患に罹患している、請求項11に記載の二本鎖RNAi剤、又は医薬組成物。
- 前記二本鎖RNAi剤、又は医薬組成物が、皮下投与又は静脈内投与されるものである、請求項11又は12に記載の二本鎖RNAi剤、又は医薬組成物。
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