JPWO2018199121A1 - 炎症性腸疾患の予防又は治療剤 - Google Patents
炎症性腸疾患の予防又は治療剤 Download PDFInfo
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Abstract
Description
項1. miR-29a及び/又はmiR-29bを炭酸アパタイト粒子に担持させた複合粒子を含み、
全身投与される、炎症性腸疾患の予防又は治療剤。
項2. 血管内投与又は皮下投与によって投与される、項1に記載の炎症性腸疾患の予防又は治療剤。
項3. 炭酸アパタイト粒子の平均粒子径が400〜3000 nmである、項1又は2に記載の炎症性腸疾患の予防又は治療剤。
項4. miR-29a及び/又はmiR-29bを炭酸アパタイト粒子に担持させた複合粒子の、
全身投与される、炎症性腸疾患の予防又は治療剤の製造のための使用。
項5. 前記全身投与が、血管内投与又は皮下投与である、項4に記載の使用。
項6. 前記炭酸アパタイト粒子の平均粒子径が400〜3000 nmである、項4又は5に記載の使用。
項7. miR-29a及び/又はmiR-29bを炭酸アパタイト粒子に担持させた複合粒子を、炎症性腸疾患の予防又は治療が求められる患者に全身投与する、炎症性腸疾患の予防又は治療方法。
項8. 前記全身投与が、血管内投与又は皮下投与である、項7に記載の方法。
項9. 前記炭酸アパタイト粒子の平均粒子径が400〜3000 nmである、項7又は8に記載の方法。
本発明の予防又は治療剤は、miRNAとして、miR-29a及び/又はmiR-29bを含む。miR-29a及びmiR-29bをノックアウトさせたマウスでは、硫酸デキストラン(DSS)によって誘発される大腸炎を悪化させることが報告されているが(非特許文献8)、これらのmiRNAが、樹状細胞において、IL-6、TGF-β、IL12 p40及びIL23 p19等のサイトカインの発現量を低下させる作用があることについては、従来知られていない。
成熟型has-miR-29a(sense):5'-UAG CAC CAU CUG AAA UCG GUU A-3'(配列番号1)
成熟型has-miR-29a(antisense):5'-UAA CCG AUU UCA GAU GGU GCU A-3'(配列番号2)
成熟型has-miR-29b(sense):5'-UAG CAC CAU UUG AAA UCA GUG UU-3'(配列番号3)
成熟型has-miR-29b(antisense):5'-AAC ACU GAU UUC AAA UGG UGC UA-3'(配列番号4)
炭酸アパタイトは、水酸アパタイト(Ca10(PO4)6(OH)2)の水酸基の一部をCO3で置換した構造を有し、一般式Ca10-mXm(PO4)6(CO3)1-nYnで表される化合物である。ここで、Xは、炭酸アパタイトにおけるCaを部分的に置換し得る元素であり、例えば、Sr、Mn、希土類元素等が挙げられる。mは、通常0以上1以下の正数であり、好ましくは0以上0.1以下であり、より好ましくは0以上0.01以下であり、更に好ましくは0以上0.001以下である。Yは、炭酸アパタイトにおけるCO3を部分的に置換しうる基又は元素であり、OH、F、Cl等が挙げられる。nは、通常0以上0.1以下の正数であり、好ましくは0以上0.01以下であり、より好ましくは0以上0.001以下であり、更に好ましくは0以上0.0001以下である。
水槽の温度:例えば5〜45℃、好ましくは10〜35℃、更に好ましくは20〜30℃
高周波出力:例えば10〜500W、好ましくは20〜400W、更に好ましくは30〜300W、より好ましくは40〜100W。
発振周波数:例えば10〜60Hz、好ましくは20〜50Hz、更に好ましくは30〜40Hz。
処理時間:例えば、30秒〜30分、好ましくは1〜20分、更に好ましくは3〜10分。
本発明の予防又は治療剤では、miR-29a及び/又はmiR-29bが炭酸アパタイト粒子に担持されて複合化した複合粒子を使用する。このようにmiR-29a及び/又はmiR-29bを炭酸アパタイト粒子に複合化させることによって、miR-29a及び/又はmiR-29bを、炎症性腸疾患の患部に送達させるだけでなく、樹状細胞に効率的に取り込ませることが可能になる。また、当該複合粒子は、細胞内に導入された後に、細胞内でmiR-29a及び/又はmiR-29bが炭酸アパタイト粒子から遊離できるので、miR-29a及び/又はmiR-29bに所望の活性を発揮させることができる。
miR-29a及び/又はmiR-29bを担持した炭酸アパタイト粒子の複合粒子は、炎症性腸疾患の症状を効果的に治癒又は改善できるので、本発明の予防又は治療剤は、炎症性腸疾患は治療用途に使用できる。また、炎症性腸疾患は再発と寛解を繰り返しながら、徐々に進行することもあるので、本発明の予防又は治療剤は、炎症性腸疾患の予防や再発防止のために使用することもできる。
本発明の予防又は治療剤は、全身投与により投与される。局所投与では、樹状細胞に対してmiR-29a及び/又はmiR-29bを送達することができないが、全身投与することによって、前記miRNAの一部を患部に直接送達すると共に、前記miRNAの一部を樹状細胞に効率的に取り込ませることが可能になる。
試験例6以外では、以下の方法で製造したmiRNA及び炭酸アパタイトの複合体を使用した。先ず、無機水溶液(NaHCO3; 44 mM, NaH2PO4; 0.9 mM, CaCl2; 1.8 mM, pH 7.5)を調製した。この無機水溶液50mlにmiRNA100μgを添加し、37℃で30分間インキュベートした。その後、12,000rpm×3分で遠沈して、60μgのmiRNAを含むペレット(miRNAを炭酸アパタイト粒子に内包させた複合粒子;miRNA/sCA複合体)を得た。当該ペレットに200μLとなるように生理食塩水(0.5重量%アルブミン含有)を添加して分散させ、これを超音波振動処理(38 kHz, 80 W)に10分間かけて、直ちに試験に使用した。なお、得られたmiRNA/sCA複合体は、平均粒径が400〜2000nmであることがゼータサイザーナノZS(マルバーン)を用いた動的光散乱法粒子計測(DLS)において確認されている。
7週齢のBALB/cマウス(日本クレア株式会社)に、デキストラン硫酸(DSS)2重量%を含む水を7日間飲水させて、炎症性腸炎を発症させ、DSS誘導マウス腸炎モデルを作成した。当該DSS誘導マウス腸炎モデルに、MIRTX/sCA複合体又はAlexa647-miRNA/sCA複合体を、miRNAの投与量が60μg/マウスとなるように、尾静脈投与した。
7週齢のBALB/cマウス(日本クレア株式会社)を表2に示す6つの群に分けた。各群のマウスに表2に示す条件でDSSとmiRNA/sCA複合体又はmiRNAの投与を行った。
<粘膜ダメージ>
0:normal
1:3-10 intraepithelial lymphocytes (IEL)/high power field (HPF) and focal damage
2:10 IEL/HPF and rare crypt abscesses
3:10 IEL/HPF, multiple crypt abscesses and erosion/ulceration
<粘膜下組織ダメージ>
0:normal or widely scattered leukocytes
1:focal aggregates of leukocytes
2:diffuse leukocyte infiltration with expansion of submucosa
3:diffuse leukocyte infiltration
<筋層ダメージ>
0:normal or widely scattered leukocytes
1:widely scattered leukocyte aggregates between muscle layers
2:leukocyte infiltration with focal effacement of the muscularis
3:extensive leukocyte infiltration with transmural effacement of the muscularis
7週齢のBALB/cマウス(日本クレア株式会社)に、DSS 2重量%を含む水を7日間飲水させて、炎症性腸炎を発症させ、DSS誘導マウス腸炎モデルを作成した。当該DSS誘導マウス腸炎モデルに、Alexa647-miRNA/sCA複合体を、miRNAの投与量が60μg/マウスとなるように尾静脈投与した。Alexa647-miRNA/sCA複合体の投与から4時間後にマウスから大腸を取り出し、炎症が一番強く現れる直腸部位について凍結切片を作成し、抗CD11c抗体及びDAPIを用いて免疫染色(CD11cは緑色)を行い、蛍光顕微鏡及びコンフォーカル顕微鏡にて観察を行った。また、比較のために、DSSを投与していない正常マウスを使用したこと以外は、前記と同条件で試験を行った。
7週齢のBALB/cマウス(日本クレア株式会社)に、DSS 2重量%を含む水を7日間飲水させて、炎症性腸炎を発症させ、DSS誘導マウス腸炎モデルを作成した。当該DSS誘導マウス腸炎モデルに、sCA-miR-29a/sCA複合体又はsCA-miR-29b/sCA複合体を、miRNAの投与量が1回当たり60μg/マウスとなるように、1日目、2日目、及び3日目に尾静脈投与し、4日目にマウスから大腸を取り出した。当該大腸の粘膜から粘膜固有層細胞(Lamina propria cells)を抽出し、抗CD11c抗体とautoMACS Pro Separatorを用いて、CD11c陽性細胞を分離した。得られたCD11c陽性細胞からRNAを抽出した。次いで、定量RT-PCRで各種サイトカイン(IL12 p40、IL23 p19、IL-6、及びTGF-β)の発現量を測定した(n=3)。なお、各サイトカインの発現量の定量は、β-actinを内部標準として使用し、β-actin量に対する各サイトカインの発現量の相対値として求めた。
7週齢のBALB/cマウス(日本クレア株式会社)を表3に示す4つの群に分けた。各群のマウスに表3に示す条件でDSSとmiRNA/sCA複合体の投与を行った。
7週齢のBALB/cマウス(日本クレア株式会社)を表4に示す4つの群(各群n=3)に分けた。各群のマウスに表4に示す条件でDSSとmiRNA/sCA複合体の投与を行った。
7週齢のBALB/cマウス(日本クレア株式会社)に、DSS 2重量%を含む水を7日間飲水させて、炎症性腸炎を発症させ、DSS誘導マウス腸炎モデルを作成した。当該DSS誘導マウス腸炎モデルに、Alexa647 conjugated miR-29b/sCA複合体を、miRNAの投与量が60μg/マウスとなるように皮下投与した。
(1)miR-29b/sCA複合体の調製
先ず、無機水溶液(NaHCO3; 44 mM, NaH2PO4; 0.9 mM, CaCl2; 1.8 mM, pH 7.5)を調製した。この無機水溶液50mlにmiR-29b 100μgを添加し、37℃で30分間インキュベートした。その後、12,000rpm×3分で遠沈して、60μgのmiRNAを含むペレット(miRNAを炭酸アパタイト粒子に内包させた複合粒子;miRNA/sCA複合体)を得た。当該ペレットに200μLとなるように生理食塩水(0.5重量%アルブミン含有)を添加して分散させ、これを超音波振動処理(38 kHz, 80 W)を行った後に、メンブレンフィルターによって、50 nm超且つ約3000nm以下の粒子(以下、miR-29b/sCA複合体(>50nm))と10 nm以上50 nm以下の粒子(以下、miR-29b/sCA複合体(≦50nm))に分離して、直ちに試験に使用した。
8週齢のBALB/cAJclマウス(雌)を表5に示す3つの群(各群当たり2匹)に分けた。各群のマウスに表5に示す条件でDSSとmiR-29b/sCA複合体の投与を行った。
<粘膜固有層の傷害の判定基準>
0点:正常所見。
1点:強拡大1視野(high power field;HPF)当たり、3〜10個の上皮ない細胞(intraepithelial lymphocytes;IEL)の存在、局所の粘膜障害が認められる。
2点:HPF当たり10個以上のIELと、陰窩膿瘍が僅かに認められる。
3点:HPF当たり10個以上のIELと、陰窩膿瘍の散在、及び糜爛・潰瘍が僅かに認められる。
<粘膜下層の傷害の判定基準>
0点:正常、又は好中球浸潤像がわずかに散見される。
1点:局所の好中球浸潤が認められる。
2点:瀰漫性に好中球浸潤を認め、粘膜下層の拡大を伴う。
3点:粘膜下層全体に好中球浸潤が認められる。
<筋層の傷害の判定基準>
0点:正常、又は好筋層の一部に好中球が散見される。
1点:筋層は保持されているが、筋層間に瀰漫性に好中球浸潤が認められる。
2点:好中球浸潤のため、筋層の配列の乱れが認められる。
3点:広範な好中球浸潤のため、貫壁性に筋層の配列の乱れが認められる。
HE染色して観察した結果を図12のaに示す。図12のaから分かるように、DSS+sCA(>50nm)-miR-29b群及びDSS+sCA(≦50nm)-miR-29b群では、DSS群に比べて大腸の粘膜構造の破壊の程度が低くなっており、特にDSS+sCA(>50nm)-miR-29b群では、DSS+sCA(≦50nm)-miR-29b群に比べて、大腸の粘膜構造の破壊の程度が格段低くなっていた。
7週齢のBALB/cマウス(日本クレア株式会社)に、DSS 2重量%を含む水を7日間飲水させて、炎症性腸炎を発症させ、DSS誘導マウス腸炎モデルを作成した。当該DSS誘導マウス腸炎モデルに、Alexa647-miRNA/sCA複合体を、miRNAの投与量が60μg/マウスとなるように皮下投与した。Alexa647-miRNA/sCA複合体の投与から4時間後にマウスから大腸を取り出し、炎症が一番強く現れる直腸部位の凍結切片を作成し、抗CD11c抗体及びDAPIを用いて免疫染色(CD11cは緑色)を行い、蛍光顕微鏡にて観察を行った。
7週齢のBALB/cマウス(日本クレア株式会社)に、デキストラン硫酸(DSS)2重量%を含む水を7日間飲水させて、炎症性腸炎を発症させ、DSS誘導マウス腸炎モデルを作成した。当該DSS誘導マウス腸炎モデルに、MIRTX/sCA複合体を、miRNAの投与量が60μg/マウスとなるように、皮下脈投与した。
7週齢のBALB/cマウス(日本クレア株式会社)を表6に示す4つの群(各群n=5)に分けた。各群のマウスに表6に示す条件でDSSとmiRNA/sCA複合体の投与を行った。
Claims (9)
- miR-29a及び/又はmiR-29bを炭酸アパタイト粒子に担持させた複合粒子を含み、
全身投与される、炎症性腸疾患の予防又は治療剤。 - 血管内投与又は皮下投与によって投与される、請求項1に記載の炎症性腸疾患の予防又は治療剤。
- 前記炭酸アパタイト粒子の平均粒子径が400〜3000 nmである、請求項1又は2に記載の炎症性腸疾患の予防又は治療剤。
- miR-29a及び/又はmiR-29bを炭酸アパタイト粒子に担持させた複合粒子の、
全身投与される、炎症性腸疾患の予防又は治療剤の製造のための使用。 - 前記全身投与が、血管内投与又は皮下投与である、請求項4に記載の使用。
- 前記炭酸アパタイト粒子の平均粒子径が400〜3000 nmである、請求項4又は5に記載の使用。
- miR-29a及び/又はmiR-29bを炭酸アパタイト粒子に担持させた複合粒子を、炎症性腸疾患の予防又は治療が求められる患者に全身投与する、炎症性腸疾患の予防又は治療方法。
- 前記全身投与が、血管内投与又は皮下投与である、請求項7に記載の方法。
- 前記炭酸アパタイト粒子の平均粒子径が400〜3000 nmである、請求項7又は8に記載の方法。
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CN110494147B (zh) | 2023-10-20 |
EP3616702A1 (en) | 2020-03-04 |
WO2018199121A1 (ja) | 2018-11-01 |
EP3616702B1 (en) | 2022-12-14 |
US20200188423A1 (en) | 2020-06-18 |
CN110494147A (zh) | 2019-11-22 |
US11298370B2 (en) | 2022-04-12 |
EP3616702A4 (en) | 2021-02-10 |
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