JP2017510296A - 錐体細胞における増強された遺伝子発現のための組成物および方法 - Google Patents
錐体細胞における増強された遺伝子発現のための組成物および方法 Download PDFInfo
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Abstract
Description
米国特許法§119(e)にしたがって、この出願は、2014年3月17日に出願された米国仮特許出願第61/954,330号および2015年3月2日に出願された米国仮特許出願第62/127,185号(これらの完全な開示は、参考として本明細書に援用される)の出願日に対する優先権を主張する。
この出願に伴う配列表が、紙でのコピーの代わりにテキストフォーマットで提供され、これは、ここで参考として本明細書に援用される。この配列表を含むテキストファイルの名称は、AVBI_005_02WO_ST25.txtである。このテキストファイルは、308KBであり、2015年3月17日に作成されたものであり、そしてEFS−Webを介して電子的に提出される。
本発明は、網膜障害の遺伝子療法に関する。
眼の視覚障害は、多くの場合、錐体細胞における公知の一次的欠陥に関する。これらとしては、スタルガルト黄斑ジストロフィー、錐体ジストロフィー、錐体杆体ジストロフィー、脊髄小脳失調症7型、およびバルデー・ビードル症候群−1などの黄斑ジストロフィー、ならびに1色覚(achromotopsia)、青錐体1色覚(blue cone monochromacy)、1型色覚(protan defect)、2型色覚(deutan defect)、および3型色覚(tritan defect)を含めた色覚障害が挙げられる。
「ベクター」とは、本明細書で使用される場合、ポリヌクレオチドを含むまたはポリヌクレオチドと結合し、ポリヌクレオチドの細胞への送達を媒介するために使用することができる高分子または高分子の結合体(association)を指す。例示的なベクターとしては、例えば、プラスミド、ウイルスベクター、リポソーム、および他の遺伝子送達ビヒクルが挙げられる。
本開示は、錐体細胞において遺伝子を発現させるためのポリヌクレオチドカセットおよび発現ベクターを提供する。例えば、個体における、例えば、錐体細胞障害を治療または予防するための、錐体細胞における遺伝子の発現の促進においてこれらの組成物を使用する方法も提供される。これらおよび他の本発明の目的、利点および特徴は、以下により十分に記載されている組成物および方法の詳細を読めば、当業者には明白になるであろう。
本開示の一部の態様では、錐体細胞において導入遺伝子を発現させるための組成物が提供される。「錐体細胞」は、本明細書では、「錐体光受容体」または「錐体」とも称され、比較的明るい光の中で最もよく機能する、眼の網膜内の光受容体細胞の亜型を意味する。錐体は、特定の波長の光に対して感受性であり、したがって、色の知覚を支持する。さらに、錐体は、杆体光受容体よりも刺激に対して速く応答し、杆体よりも像内の細かい詳細および迅速な変化を知覚し、したがって、読書や運転などの視覚的な細部が最も重要になる活動のために高い視力を維持する。錐体は、網膜の断面において、それらの外節が錐体様形状であることによって容易に同定可能である。錐体はまた、網膜内でのそれらの位置によっても容易に同定可能であり、最も高密度の錐体は、「中心窩(fovea centralis)」または「中心窩(foveal pit)」と称される網膜の黄斑の中心に位置する1.5mmの凹部に存在する。
(a)錐体細胞におけるコード配列の発現を促進するプロモーター領域と、
(b)プロモーター領域に作動可能に連結したコード配列と
を含む。
別の例として、一部の実施形態では、ポリヌクレオチドカセットは、
(a)網膜錐体細胞におけるコード配列の発現を促進するプロモーター領域と、
(b)翻訳開始配列と、
(c)プロモーター領域に作動可能に連結したコード配列と
を含む。
第3の例として、一部の実施形態では、ポリヌクレオチドカセットは、
(a)網膜錐体細胞におけるコード配列の発現を促進するプロモーター領域と、
(b)5’非翻訳領域と、
(c)翻訳開始配列と、
(d)プロモーター領域に作動可能に連結したコード配列と
を含む。
第4の例として、一部の実施形態では、ポリヌクレオチドカセットは、
(a)網膜錐体細胞におけるコード配列の発現を促進するプロモーター領域と、
(b)5’非翻訳領域と、
(c)イントロンと、
(d)翻訳開始配列と、
(e)プロモーター領域に作動可能に連結したコード配列と
を含む。
第5の例として、一部の実施形態では、ポリヌクレオチドカセットは、
(a)網膜錐体細胞におけるコード配列の発現を促進するプロモーター領域と、
(b)5’非翻訳領域と、
(c)イントロンと、
(d)翻訳開始配列と、
(e)ポリアデニル化配列と
を含む。
(a)配列番号7(配列番号6)Homo sapiensオプシン1(錐体色素)、短波長感受性(OPN1SW)、mRNA NCBI Reference Sequence:NM_001708.2;
(b)配列番号9(配列番号8)Homo sapiensオプシン1(錐体色素)、中波長感受性(OPN1MW)、mRNA NCBI Reference Sequence:NM_000513.2;
(c)配列番号11(配列番号10)Homo sapiensオプシン1(錐体色素)、長波長感受性(OPN1LW)、mRNA NCBI Reference Sequence:NM_020061.4;
(d)配列番号13(配列番号12)ATP結合性カセット網膜遺伝子(ABCR)遺伝子(NM_000350);
(e)配列番号15(配列番号14)網膜色素上皮に特異的65kDタンパク質遺伝子(RPE65)(NM._000329);
(f)配列番号17(配列番号16)網膜結合性タンパク質1遺伝子(RLBP1)(NM._000326);
(g)配列番号19(配列番号18)ペリフェリン/網膜変性症遅延遺伝子(NM_000322);
(h)配列番号21(配列番号20)アレスチン(SAG)(NM_000541);
(i)配列番号23(配列番号22)アルファ−トランスデューシン(GNAT1)(NM_000172);
(j)配列番号24 グアニル酸シクラーゼ活性化因子1A(GUCA1A)(NP_000400.2);
(k)配列番号25 網膜特異的グアニル酸シクラーゼ(GUCY2D)(NP_000171.1);
(l)配列番号26&27 錐体環状ヌクレオチドゲーティング陽イオンチャネルのアルファサブユニット(CNGA3)(NP_001073347.1またはNP_001289.1);
(m)配列番号28 ヒト錐体トランスデューシンアルファサブユニット(不完全1色覚(incomplete achromotopsia));
(n)配列番号29 錐体cGMP特異的3’,5’−環状ホスホジエステラーゼサブユニットアルファ’、タンパク質(錐体ジストロフィー4型);
(o)配列番号30 網膜錐体ロドプシン感受性cGMP3’,5’−環状ホスホジエステラーゼサブユニットガンマ、タンパク質(網膜錐体ジストロフィー3A型);
(p)配列番号31 錐体杆体ホメオボックス、タンパク質(錐体杆体ジストロフィー);
(q)配列番号32 錐体光受容体環状ヌクレオチドゲーティングチャネルベータサブユニット、タンパク質(1色覚);
(r)配列番号33 錐体光受容体cGMPゲーティング陽イオンチャネルベータ−サブユニット、タンパク質(全色盲(total color blindness)、例えば、Pingelapese Islandersの間での);
(s)配列番号35(配列番号34)網膜色素変性症1(常染色体優性)(RP1);
(t)配列番号37(配列番号36)網膜色素変性症GTPアーゼ調節因子相互作用タンパク質1(RPGRIP1);
(u)配列番号39(配列番号38)PRP8;
(v)配列番号41(配列番号40)中心体タンパク質290kDa(CEP290);
(w)配列番号43(配列番号42)IMP(イノシン5’−一リン酸)デヒドロゲナーゼ1(IMPDH1)、転写物改変体1;
(x)配列番号45(配列番号44)アリール炭化水素受容体相互作用タンパク質様1(AIPL1)、転写物改変体1;
(y)配列番号47(配列番号46)レチノールデヒドロゲナーゼ12(オールトランス/9−シス/11−シス)(RDH12);
(z)配列番号49(配列番号48)レーバー先天黒内障5(LCA5)、転写物バリアント1;および
(aa)例示的なOPN1LW/OPN1MW2多形体(OPN1LW(Lオプシン)ポリペプチド配列と比較;数字の左側のアミノ酸はLオプシン配列に存在する残基であり、数字はLオプシンにおける残基番号であり、数字の右側の残基はLオプシンからの変異(variation)である。これらの実施形態による多形体は、Thr65Ile;Ile111Val;Ser116Tyr;Leu153Met;Ile171Val;Ala174Val;Ile178Val;Ser180Ala;Ile230Thr;Ala233Ser;Val236Met;Ile274Val;Phe275Leu;Tyr277Phe;Val279Phe;Thr285Ala;Pro298Ala;Tyr309Pheから選択されるアミノ酸置換のうちの1つまたは複数を含み得る;
(ab)追加的なオプシン配列変異1(配列番号61);
(ac)追加的なオプシン配列変異2(配列番号62);
(ad)追加的なオプシン配列変異3(配列番号63);
(ae)追加的なオプシン配列変異4(配列番号64);
(af)追加的なオプシン配列変異5(配列番号65);
(ag)追加的なオプシン配列変異6(配列番号65);
(ah)追加的なオプシン配列変異7(配列番号66);
(ai)追加的なオプシン配列変異8(配列番号67);
(aj)追加的なオプシン配列変異9(配列番号68);
(ak)hCHR2(チャネルロドプシン)(配列番号69);
(al)NpHR(ハロロドプシン)(配列番号70);および
(am)eGFP(配列番号71)。
一部の実施形態では、導入遺伝子によりコードされるコード配列は、上または本明細書に開示されている配列によりコードされるポリペプチドに対して少なくとも85%配列同一性、例えば、少なくとも90%配列同一性、例えば、少なくとも95%配列同一性、少なくとも98%配列同一性、または少なくとも99%配列同一性を有するポリペプチドをコードする。したがって、例えば、コード配列は、OPN1LW、OPNIMW、またはOPN1SWによりコードされるポリペプチドに対して少なくとも85%、少なくとも90%、少なくとも95%同一性、少なくとも98%配列同一性、または少なくとも99%配列同一性を有する錐体オプシンをコードする。一部の実施形態では、コード配列は、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号34、配列番号36、配列番号38、配列番号40、配列番号42、配列番号44、配列番号46、配列番号48、配列番号61、配列番号62、配列番号63、配列番号64、配列番号65、配列番号66、配列番号67、配列番号68、配列番号69、配列番号70、または配列番号71に対して少なくとも85%、90%、95%、98%または少なくとも99%の配列同一性を有する。
上で示唆した通り、本発明の一部の態様では、例えば、遺伝子が細胞の生存能力および/または機能に対して有する効果を決定するために、錐体細胞障害を治療するなどのために、主題のポリヌクレオチドカセットを使用して、遺伝子を動物の錐体細胞に送達する。したがって、本発明の一部の態様では、錐体細胞における導入遺伝子の発現をもたらす組成物は遺伝子送達ベクターであり、当該遺伝子送達ベクターは本開示のポリヌクレオチドカセットを含む。
上で示唆した通り、本明細書では集合的に「主題の組成物」と称される主題のポリヌクレオチドカセットおよび遺伝子送達ベクターを、動物の錐体細胞における導入遺伝子の発現において用途が見いだされている。例えば、主題の組成物は、例えば、錐体細胞の生存能力および/または機能に対する遺伝子の効果を決定するための研究において使用することができる。別の例として、主題の組成物は、例えば、錐体細胞障害を治療するための医薬に使用することができる。したがって、本発明の一部の態様では、錐体細胞において遺伝子を発現させるための方法であって、錐体細胞を本開示の組成物と接触させるステップを含む方法が提供される。一部の実施形態では、接触させるステップをin vitroで行う。一部の実施形態では、接触させるステップをin vivoで行う、すなわち、主題の組成物を被験体に投与する。
錐体杆体ジストロフィー、錐体ジストロフィー、スタルガルト黄斑ジストロフィー、および1色覚などの黄斑ジストロフィー;1型色覚、2型色覚、および3型色覚などの色覚障害;ならびに加齢黄斑変性症、黄斑部毛細血管拡張症、網膜色素変性症、糖尿病性網膜症、網膜静脈閉塞症、緑内障、ソースビー眼底変性症、成人卵黄様黄斑ジストロフィー、ベスト病、およびX連鎖性網膜分離症などの中心黄斑の視覚障害を含めた多くの錐体光受容体に関連する障害を治療するための新しい療法が必要とされている。これらの視覚障害は錐体光受容体の機能および/または生存能力の喪失に関連するので、これらの障害は、錐体光受容体に治療用遺伝子を送達して錐体の生存能力および機能をレスキューすることによって治療可能であり得ることが仮定される。
AAV2の定向進化により、野生型AAV2よりも良好に光受容体に形質導入することが可能なウイルス改変体「7m8」の同定が導かれた(DalkaraらSci Transl Med 2013年)。しかし、網膜は、杆体と錐体の2つの型の光受容体を含有し、AAV2−7m8により錐体光受容体それ自体に、およびより詳細には、窩の高度に錐体が豊富な領域内の錐体光受容体に形質導入することが可能かどうかを実証した報告は存在しない。この可能性を試験するために、本発明者らは、GFPに作動可能に連結した遍在するプロモーターCMVの発現カセットを有するAAV2−7m8をアフリカミドリザルの網膜に硝子体内注射によって送達した。硝子体内に送達されたAAV2−7m8.CMV.GFPにより、霊長類の中心窩(中心窩の中心にある直径0.35mmの杆体が存在しない網膜の領域)および傍中心窩(凹部の縁)内の網膜細胞への形質導入が、硝子体内に送達されたAAV2または網膜細胞への形質導入が当技術分野において以前示されている他のAAV改変体よりも効率的になされると思われた。AAV2−7m8によっても試験した他のAAVによっても、霊長類窩の錐体、小窩を取り囲み、窩の傾きを形成する直径1.5mmの錐体が豊富な網膜の領域への形質導入はできないと思われた(図5)。
in vitroでのWERI−RB−1細胞における導入遺伝子発現。ShaabanおよびDeeb、1998年;IOVS 39巻(6号)885〜896頁に記載されている方法に従って、錐体光受容体色素細胞を発現するWERI−Rb−1網膜芽細胞腫細胞に、本開示のポリヌクレオチドカセットをトランスフェクトする。クローニング(Maniatisら)などの、分子生物学の十分に確立された技法を使用して、または新規のDNA合成により、ポリヌクレオチドカセットをプラスミドDNAとしてトランスフェクトする。全ての調節エレメントをカセット内に配置し、増強型GFPタンパク質を駆動するために使用する。次いで、非ウイルストランスフェクションに関する確立された技法を使用して、例えば、脂質に基づくトランスフェクション試薬(Altogen Biosystems、NV)またはリポフェクタミンLTX(Life Technologies)を使用してプラスミドDNAを細胞に導入する。次いで、細胞を72時間にわたって培養し、フローサイトメトリーおよび蛍光顕微鏡を使用してeGFP発現を測定する。本発明のポリヌクレオチドカセット(すなわち、錐体光受容体での発現のために設計した構築物)をトランスフェクトした細胞における導入遺伝子発現を、最適化されていない対応物(すなわち、pR2.1に基づくもの)と比較し、改善されたエレメントを有するカセットからのほうが強力であることが見いだされる。
Claims (57)
- 哺乳動物の網膜の錐体細胞における導入遺伝子の増強された発現のためのポリヌクレオチドカセットであって、
(a)網膜錐体細胞に特異的なプロモーター領域と、
(b)前記プロモーター領域に作動可能に連結したコード配列と、
(c)ポリアデニル化部位と
を含む、ポリヌクレオチドカセット。 - 前記プロモーター領域が、配列番号1、配列番号2、配列番号3、配列番号53、配列番号54、配列番号55、配列番号79、配列番号80、配列番号81、配列番号82、および配列番号83からなる群より選択される配列、またはその機能性断片に対して85%またはそれ超の配列同一性を有するポリヌクレオチド配列を含む、請求項1に記載のポリヌクレオチドカセット。
- 前記プロモーター領域が、配列番号55の全長またはその機能性断片に対して85%またはそれ超の配列同一性を有するポリヌクレオチド配列から本質的になる、請求項2に記載のポリヌクレオチドカセット。
- 前記コード配列の5’側にある非翻訳領域をコードするポリヌクレオチド配列を含む、請求項1から3のいずれか一項に記載のポリヌクレオチドカセット。
- 前記コード配列の5’側にある非翻訳領域をコードする前記ポリヌクレオチド配列が、配列番号56、配列番号57、配列番号58、配列番号84、配列番号85、配列番号86、配列番号87、配列番号88、および配列番号89からなる群より選択される配列、またはその断片に対して85%またはそれ超の配列同一性を有する配列を含む、請求項4に記載のポリヌクレオチドカセット。
- 前記コード配列の5’側にある前記非翻訳領域が、ポリヌクレオチドATGを含まない、請求項4または5に記載のポリヌクレオチドカセット。
- 前記コード配列の5’側にある非翻訳領域をコードする前記ポリヌクレオチド配列が、配列番号85もしくは配列番号86の全長、またはその断片に対して85%またはそれ超の配列同一性を有する配列から本質的になる、請求項4に記載のポリヌクレオチドカセット。
- イントロンをさらに含む、請求項1から7のいずれか一項に記載のポリヌクレオチドカセット。
- 前記イントロンが、配列番号5、配列番号59、および配列番号60からなる群より選択される配列に対して85%またはそれ超の配列同一性を有する配列を含む、請求項8に記載のポリヌクレオチドカセット。
- 前記イントロンが、前記コード配列の5’側にある非翻訳領域をコードする前記ポリヌクレオチド配列内に位置する、請求項9に記載のポリヌクレオチドカセット。
- 翻訳開始配列をさらに含む、請求項1から10のいずれか一項に記載のポリヌクレオチドカセット。
- 前記翻訳開始配列が、配列番号72または配列番号73から本質的になるポリヌクレオチド配列を含む、請求項11に記載のポリヌクレオチドカセット。
- 配列番号52またはその機能性断片に対して85%またはそれ超の配列同一性を有するエンハンサー配列をさらに含む、請求項1から12のいずれか一項に記載のポリヌクレオチドカセット。
- 前記エンハンサー配列が、配列番号51の全長に対して85%またはそれ超の配列同一性を有する配列から本質的になる、請求項13に記載のポリヌクレオチドカセット。
- 前記コード配列の発現が、哺乳動物の錐体細胞に導入した際、前記プロモーター領域を配列番号1のプロモーター領域で置き換えた場合の前記コード配列の発現よりも大きい、請求項1から14のいずれか一項に記載のポリヌクレオチドカセット。
- a)AAVカプシドタンパク質と、
b)AAV ITRが隣接した請求項1から15までのいずれか一項に記載のポリヌクレオチドカセットと
を含む、組換えアデノ随伴ウイルス(rAAV)。 - 請求項1から15のいずれか一項に記載のポリヌクレオチドカセットまたは請求項16に記載のrAAVと医薬賦形剤とを含む医薬組成物。
- 錐体細胞において導入遺伝子を発現させるための方法であって、
1つまたは複数の錐体細胞に、請求項1から15までのいずれか一項に記載のポリヌクレオチドカセットまたは請求項16に記載の組換えアデノ随伴ウイルスを有効量で接触させるステップ
を含み、前記導入遺伝子が、1つまたは複数の前記錐体細胞において検出可能なレベルで発現される、方法。 - 前記錐体細胞における発現を検出するステップを含み、発現が、前記錐体細胞の60%またはそれ超で検出される、請求項18に記載の方法。
- 前記導入遺伝子が、錐体細胞において特異的に検出可能なレベルで発現される、請求項19に記載の方法。
- 錐体細胞障害に対する治療または予防を必要とする哺乳動物における錐体細胞障害を治療または予防するための方法であって、前記哺乳動物の眼に請求項17に記載の医薬組成物を有効量で投与するステップを含み、コード配列が治療用遺伝子産物をコードするものである、方法。
- 前記錐体細胞障害が、黄斑ジストロフィー、色覚障害、または中心黄斑の視覚障害である、請求項21に記載の方法。
- 前記色覚障害が、1色覚、青錐体1色覚、1型色覚、2型色覚、および3型色覚からなる群より選択される、請求項22に記載の方法。
- 疾患の症状の変化を検出するステップをさらに含み、前記変化が、前記哺乳動物の色を知覚する能力の増大を含む、請求項22または23に記載の方法。
- 前記黄斑ジストロフィーが、スタルガルト黄斑ジストロフィー、錐体ジストロフィー、錐体杆体ジストロフィー、脊髄小脳失調症7型、およびバルデー・ビードル症候群−1からなる群より選択される、請求項21に記載の方法。
- 前記中心黄斑の視覚障害が、加齢黄斑変性症、黄斑部毛細血管拡張症、網膜色素変性症、糖尿病性網膜症、網膜静脈閉塞症、緑内障、ソースビー眼底変性症、成人卵黄様黄斑ジストロフィー、ベスト病、杆体錐体ジストロフィー、レーバー先天性黒内障、およびX連鎖性網膜分離症からなる群より選択される、請求項21に記載の方法。
- 疾患の症状の変化を検出するステップをさらに含み、前記変化が、前記哺乳動物の視力喪失の速度の低減を含む、請求項25または26に記載の方法。
- 哺乳動物の網膜の錐体細胞における導入遺伝子の増強された発現のためのポリヌクレオチドカセットであって、
(a)網膜錐体細胞に特異的なプロモーター領域と、
(b)前記プロモーター領域に作動可能に連結したコード配列と、
(c)ポリアデニル化部位と
を含む、ポリヌクレオチドカセット。 - 哺乳動物の網膜の錐体細胞における導入遺伝子の増強された発現のためのポリヌクレオチドカセットであって、
(a)網膜錐体細胞に特異的なプロモーター領域と、
(b)5’非翻訳領域と、
(c)イントロンと、
(d)翻訳開始配列と、
(e)前記プロモーター領域に作動可能に連結したコード配列と、
(f)ポリアデニル化部位と
を含む、ポリヌクレオチドカセット。 - 転写開始部位と前記翻訳開始部位との間の配列が、ポリヌクレオチドATGを含有しない、請求項28または29に記載のポリヌクレオチドカセット。
- 前記プロモーター領域が492塩基対未満の長さである、請求項28または29に記載のポリヌクレオチドカセット。
- 前記プロモーター領域を用いた前記コード配列の発現が、配列番号1として列挙されているプロモーター領域を用いた発現よりも大きい、請求項28または29に記載のポリヌクレオチドカセット。
- 転写開始部位と前記コード配列の末端との間の配列が、500ヌクレオチド超の長さである前記導入遺伝子のオープンリーディングフレーム以外のオープンリーディングフレームを含有しない、請求項28または29に記載のポリヌクレオチドカセット
- 転写開始部位と前記コード配列の末端との間の配列が、250ヌクレオチド超の長さである前記導入遺伝子のオープンリーディングフレーム以外のオープンリーディングフレームを含有しない、請求項28または29に記載のポリヌクレオチドカセット。
- 転写開始部位と前記コード配列の末端との間の配列が、100ヌクレオチド超の長さである前記導入遺伝子のオープンリーディングフレーム以外のオープンリーディングフレームを含有しない、請求項28または29に記載のポリヌクレオチドカセット。
- 前記コード配列についてのオープンリーディングフレーム以外に273bp超のオープンリーディングフレームを含有しない、請求項28または29に記載のポリヌクレオチドカセット。
- 前記コード配列が、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号24、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33、配列番号35、配列番号37、配列番号39、配列番号41、配列番号43、配列番号45、配列番号47、配列番号49、ならびに(i)Thr65Ile(ii)Ile111Val(iii)Ser116Tyr(iv)Leu153Met(v)Ile171Val(vi)Ala174Val(vii)Ile178Val(viii)Ser180Ala(ix)Ile230Thr(x)Ala233Ser(xi)Val236Met(xii)Ile274Val(xiii)Phe275Leu(xiv)Tyr277Phe(xv)Val279Phe(xvi)Thr285Ala(xvii)Pro298Ala、および(xviii)Tyr309Pheからなる群より選択される配列番号11の多形体からなる群より選択されるポリペプチドを含む治療用タンパク質をコードする、請求項28または29に記載のポリヌクレオチドカセット。
- 前記コード配列が、配列番号61、配列番号62、配列番号63、配列番号64、配列番号65、配列番号66、配列番号67、配列番号68、配列番号69、配列番号70、および配列番号71からなる群より選択されるポリヌクレオチド、ならびに(i)Thr65Ile(ii)Ile111Val(iii)Ser116Tyr(iv)Leu153Met(v)Ile171Val(vi)Ala174Val(vii)Ile178Val(viii)Ser180Ala(ix)Ile230Thr(x)Ala233Ser(xi)Val236Met(xii)Ile274Val(xiii)Phe275Leu(xiv)Tyr277Phe(xv)Val279Phe(xvi)Thr285Ala(xvii)Pro298Ala、および(xviii)Tyr309Pheからなる群より選択される配列番号11の多形体をコードするポリヌクレオチドを含む、請求項28または29に記載のポリヌクレオチドカセット。
- 前記プロモーター領域が、配列番号1、配列番号2、配列番号3、配列番号53、配列番号54、および配列番号55からなる群より選択される配列を含む、請求項28または29に記載のポリヌクレオチドカセット。
- 哺乳動物における錐体細胞遺伝子療法のための方法であって、錐体細胞遺伝子療法を必要とする哺乳動物の眼に、
(a)網膜錐体細胞に特異的なプロモーター領域と、
(b)前記プロモーター領域に作動可能に連結した、治療薬をコードするコード配列と
を含むポリヌクレオチドカセットを含む組換え遺伝子送達ベクターを投与するステップを含み、
前記哺乳動物の錐体細胞における前記治療薬のin vivo発現が、錐体細胞遺伝子療法を必要とする前記哺乳動物の治療に役立つ、方法。 - 哺乳動物における錐体細胞遺伝子療法のための方法であって、錐体細胞遺伝子療法を必要とする前記哺乳動物の眼に、
(a)網膜錐体細胞に特異的なプロモーター領域と、
(b)5’非翻訳領域と、
(c)イントロンと、
(d)翻訳開始配列と、
(e)前記プロモーター領域に作動可能に連結した、治療薬をコードするコード配列と
を含むポリヌクレオチドカセットを含む組換え遺伝子送達ベクターを投与するステップを含み、
前記哺乳動物の錐体細胞における前記治療薬のin vivo発現が、錐体細胞遺伝子療法を必要とする前記哺乳動物の治療に役立つ、方法。 - 前記遺伝子療法が、錐体細胞障害の治療に役立つ、請求項40または41に記載の方法。
- 前記遺伝子療法が、分泌タンパク質の送達に役立つ、請求項40または41に記載の方法。
- 前記イントロンが、配列番号5、配列番号59、および配列番号60からなる群より選択されるポリヌクレオチドを含む、請求項41に記載の方法。
- 前記錐体細胞障害が、青錐体1色覚、1型2色覚、2型2色覚、1型3色覚、2型3色覚、1色覚、不完全1色覚、杆体錐体変性症、網膜色素変性症(RP)、黄斑変性症、錐体ジストロフィー、失明、スタルガルト病、およびレーバー先天性黒内障からなる群より選択される、請求項42に記載の方法。
- 前記プロモーターが、配列番号1、配列番号2、配列番号3、配列番号52、配列番号53、配列番号54、および配列番号55からなる群より選択される配列を含む、請求項40または41に記載の方法。
- 前記遺伝子送達ベクターが、前記プロモーターの上流にエンハンサーエレメントをさらに含み、前記遺伝子が前記エンハンサーエレメントに作動可能に連結している、請求項40または41に記載の方法。
- 前記遺伝子送達ベクターが、スプライスドナー/アクセプター領域を含むイントロンをさらに含み、前記イントロンが、前記プロモーター領域の下流に位置し、かつ遺伝子の上流に位置する、請求項40に記載の方法。
- 前記コード配列が、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号24、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33、配列番号35、配列番号37、配列番号39、配列番号41、配列番号43、配列番号45、配列番号47、配列番号49、ならびに:(i)Thr65Ile(ii)Ile111Val(iii)Ser116Tyr(iv)Leu153Met(v)Ile171Val(vi)Ala174Val(vii)Ile178Val(viii)Ser180Ala(ix)Ile230Thr(x)Ala233Ser(xi)Val236Met(xii)Ile274Val(xiii)Phe275Leu(xiv)Tyr277Phe(xv)Val279Phe(xvi)Thr285Ala(xvii)Pro298Ala、および(xviii)Tyr309Pheからなる群より選択される配列番号11の多形体からなる群より選択されるポリペプチドを含む治療用タンパク質をコードする、請求項40または41に記載の方法。
- 前記コード配列が、配列番号61、配列番号62、配列番号63、配列番号64、配列番号65、配列番号66、配列番号67、配列番号68、配列番号69、配列番号70、および配列番号71からなる群より選択されるポリヌクレオチドを含む治療用タンパク質をコードする、請求項40に記載の方法。
- 前記遺伝子送達ベクターが、組換えアデノ随伴ウイルス(AAV)遺伝子送達ベクターを含む、請求項40、41または46に記載の方法。
- 前記哺乳動物において視覚的能力を回復させる、請求項40、41または46に記載の方法。
- 前記哺乳動物が、青錐体1色覚、1型2色覚、2型2色覚、1型3色覚、2型3色覚に罹患している霊長類であり、前記霊長類が、前記療法の結果として新しい色を見ることが可能になる、請求項40、41または46に記載の方法。
- 前記プロモーターが、配列番号1、配列番号2、配列番号3、配列番号52、配列番号53、配列番号54、および配列番号55からなる群より選択される配列を含み、遺伝子が、配列番号7、配列番号9、配列番号11、ならびに(i)Thr65Ile(ii)Ile111Val(iii)Ser116Tyr(iv)Leu153Met(v)Ile171Val(vi)Ala174Val(vii)Ile178Val(viii)Ser180Ala(ix)Ile230Thr(x)Ala233Ser(xi)Va1236Met(xii)Ile274Val(xiii)Phe275Leu(xiv)Tyr277Phe(xv)Va1279Phe(xvi)Thr285Ala(xvii)Pro298Ala、および(xviii)Tyr309Pheからなる群より選択される配列番号11の多形体からなる群より選択される配列を含むポリペプチドをコードする、請求項40または41に記載の方法。
- 前記哺乳動物が、光受容体は健康である視覚障害を有する霊長類である、請求項40または41に記載の方法。
- 請求項1、28、または29のいずれか一項に記載のポリヌクレオチドカセットを含むパッケージされたウイルス粒子を含む製剤。
- 請求項1、28、または29のいずれか一項に記載のポリヌクレオチドカセットを用いてトランスフェクトまたは形質導入された組換え宿主細胞。
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