JP2021531805A - 皮膚をインスリン産生組織にリプログラミングするための組成物および方法 - Google Patents
皮膚をインスリン産生組織にリプログラミングするための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2018年8月1日に出願された米国仮特許出願第62/713,239号の利益を主張し、その全体が参照により本明細書に組み込まれる。
本出願は、2019年8月1日作成の「321501−2330 Sequence Listing_ST25」と題するASCII.txtファイルとして電子形式で出願された配列表を含む。配列表の内容は、その全体が本明細書に組み込まれる。
「対象」という用語は、投与または治療の標的である任意の個体を指す。対象は、脊椎動物、例えば、哺乳動物であり得る。このため、対象は、ヒトまたは獣医学的患者であり得る。「患者」という用語は、臨床医、例えば、医師の治療下にある対象を指す。
分数W/Zの100倍
式中、Wは、配列アライメントプログラムのCおよびDのアライメントによる同一性照合としてスコアされたヌクレオチドまたはアミノ酸の数であり、Zは、Dにおけるヌクレオチドまたはアミノ酸の総数である。配列Cの長さが配列Dの長さに等しくない場合、Dに対するCの配列同一性%は、Cに対するDの配列同一性%に等しくないことが理解されよう。当該技術分野の技能の範囲内の様々な方法で、例えば、BLAST、BLAST−2、ALIGN、ALIGN−2、またはMegalign(DNASTAR)ソフトウェアなどの公的に入手可能なコンピュータソフトウェアを使用して、配列同一性パーセントを決定する目的のためのアライメントを得ることができる。
Pdx1、Ng3、Mafa、およびTcf3(「PMN−T因子」)からなる群から選択されるタンパク質をコードする核酸配列を含むポリヌクレオチドを開示する。Pdx1、Ng3、Mafa、およびTcf3をコードするアミノ酸配列および核酸配列は、当該技術分野で既知である。
MNGEEQYYAATQLYKDPCAFQRGPAPEFSASPPACLYMGRQPPPPPPHPFPGALGALEQGSPPDISPYEVPPLADDPAVAHLHHHLPAQLALPHPPAGPFPEGAEPGVLEEPNRVQLPFPWMKSTKAHAWKGQWAGGAYAAEPEENKRTRTAYTRAQLLELEKEFLFNKYISRPRRVELAVMLNLTERHIKIWFQNRRMKWKKEEDKKRGGGTAVGGGGVAEPEQDCAVTSGEELLALPPPPPPGGAVPPAAPVAAREGRLPPGLSASPQPSSVAPRRPQEPR(配列番号1)、または配列番号1に対して、少なくとも65%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の配列同一性を有するアミノ酸配列を含む。
ATGAACGGCGAGGAGCAGTACTACGCGGCCACGCAGCTTTACAAGGACCCATGCGCGTTCCAGCGAGGCCCGGCGCCGGAGTTCAGCGCCAGCCCCCCTGCGTGCCTGTACATGGGCCGCCAGCCCCCGCCGCCGCCGCCGCACCCGTTCCCTGGCGCCCTGGGCGCGCTGGAGCAGGGCAGCCCCCCTGACATCTCCCCGTACGAGGTGCCCCCCCTCGCCGACGACCCCGCGGTGGCGCACCTTCACCACCACCTCCCGGCTCAGCTCGCGCTCCCCCACCCGCCCGCCGGGCCCTTCCCGGAGGGAGCCGAACCGGGCGTCCTGGAGGAGCCCAACCGCGTCCAGCTGCCTTTCCCATGGATGAAGTCTACCAAAGCTCACGCGTGGAAAGGCCAGTGGGCAGGCGGCGCCTACGCTGCGGAGCCGGAGGAGAACAAGCGGACGCGCACGGCCTACACGCGCGCACAGCTGCTAGAGCTGGAGAAGGAGTTCCTATTCAACAAGTACATCTCACGGCCGCGCCGGGTGGAGCTGGCTGTCATGTTGAACTTGACCGAGAGACACATCAAGATCTGGTTCCAAAACCGCCGCATGAAGTGGAAAAAGGAGGAGGACAAGAAGCGCGGCGGCGGGACAGCTGTCGGGGGTGGCGGGGTCGCGGAGCCTGAGCAGGACTGCGCCGTGACCTCCGGCGAGGAGCTTCTGGCGCTGCCGCCGCCGCCGCCCCCCGGAGGTGCTGTGCCGCCCGCTGCCCCCGTTGCCGCCCGAGAGGGCCGCCTGCCGCCTGGCCTTAGCGCGTCGCCACAGCCCTCCAGCGTCGCGCCTCGGCGGCCGCAGGAACCACGA(配列番号2)、またはストリンジェントなハイブリダイゼーション条件下で配列番号2からなる核酸配列にハイブリダイズする核酸配列を含む。
MTPQPSGAPTVQVTRETERSFPRASEDEVTCPTSAPPSPTRTRGNCAEAEEGGCRGAPRKLRARRGGRSRPKSELALSKQRRSRRKKANDRERNRMHNLNSALDALRGVLPTFPDDAKLTKIETLRFAHNYIWALTQTLRIADHSLYALEPPAPHCGELGSPGGSPGDWGSLYSPVSQAGSLSPAASLEERPGLLGATSSACLSPGSLAFSDFL(配列番号3)、または配列番号3に対して、少なくとも65%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の配列同一性を有するアミノ酸配列を含む。
ATGACGCCTCAACCCTCGGGTGCGCCCACTGTCCAAGTGACCCGTGAGACGGAGCGGTCCTTCCCCAGAGCCTCGGAAGACGAAGTGACCTGCCCCACGTCCGCCCCGCCCAGCCCCACTCGCACACGGGGGAACTGCGCAGAGGCGGAAGAGGGAGGCTGCCGAGGGGCCCCGAGGAAGCTCCGGGCACGGCGCGGGGGACGCAGCCGGCCTAAGAGCGAGTTGGCACTGAGCAAGCAGCGACGGAGTCGGCGAAAGAAGGCCAACGACCGCGAGCGCAATCGAATGCACAACCTCAACTCGGCACTGGACGCCCTGCGCGGTGTCCTGCCCACCTTCCCAGACGACGCGAAGCTCACCAAGATCGAGACGCTGCGCTTCGCCCACAACTACATCTGGGCGCTGACTCAAACGCTGCGCATAGCGGACCACAGCTTGTACGCGCTGGAGCCGCCGGCGCCGCACTGCGGGGAGCTGGGCAGCCCAGGCGGTTCCCCCGGGGACTGGGGGTCCCTCTACTCCCCAGTCTCCCAGGCTGGCAGCCTGAGTCCCGCCGCGTCGCTGGAGGAGCGACCCGGGCTGCTGGGGGCCACCTCTTCCGCCTGCTTGAGCCCAGGCAGTCTGGCTTTCTCAGATTTTCTG(配列番号4)、またはストリンジェントなハイブリダイゼーション条件下で配列番号4からなる核酸配列にハイブリダイズする核酸配列を含む。
MAAELAMGAELPSSPLAIEYVNDFDLMKFEVKKEPPEAERFCHRLPPGSLSSTPLSTPCSSVPSSPSFCAPSPGTGGGGGAGGGGGSSQAGGAPGPPSGGPGAVGGTSGKPALEDLYWMSGYQHHLNPEALNLTPEDAVEALIGSGHHGAHHGAHHPAAAAAYEAFRGPGFAGGGGADDMGAGHHHGAHHAAHHHHAAHHHHHHHHHHGGAGHGGGAGHHVRLEERFSDDQLVSMSVRELNRQLRGFSKEEVIRLKQKRRTLKNRGYAQSCRFKRVQQRHILESEKCQLQSQVEQLKLEVGRLAKERDLYKEKYEKLAGRGGPGSAGGAGFPREPSPPQAGPGGAKGTADFFL(配列番号5)、または配列番号5に対して、少なくとも65%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の配列同一性を有するアミノ酸配列を含む。
ATGGCCGCGGAGCTGGCGATGGGCGCCGAGCTGCCCAGCAGCCCGCTGGCCATCGAGTACGTCAACGACTTCGACCTGATGAAGTTCGAGGTGAAGAAGGAGCCTCCCGAGGCCGAGCGCTTCTGCCACCGCCTGCCGCCAGGCTCGCTGTCCTCGACGCCGCTCAGCACGCCCTGCTCCTCCGTGCCCTCCTCGCCCAGCTTCTGCGCGCCCAGCCCGGGCACCGGCGGCGGCGGCGGCGCGGGGGGCGGCGGCGGCTCGTCTCAGGCCGGGGGCGCCCCCGGGCCGCCGAGCGGGGGCCCCGGCGCCGTCGGGGGCACCTCGGGGAAGCCGGCGCTGGAGGATCTGTACTGGATGAGCGGCTACCAGCATCACCTCAACCCCGAGGCGCTCAACCTGACGCCCGAGGACGCGGTGGAGGCGCTCATCGGCAGCGGCCACCACGGCGCGCACCACGGCGCGCACCACCCGGCGGCCGCCGCAGCCTACGAGGCTTTCCGCGGCCCGGGCTTCGCGGGCGGCGGCGGAGCGGACGACATGGGCGCCGGCCACCACCACGGCGCGCACCACGCCGCCCACCACCACCACGCCGCCCACCACCACCACCACCACCACCACCACCATGGCGGCGCGGGACACGGCGGTGGCGCGGGCCACCACGTGCGCCTGGAGGAGCGCTTCTCCGACGACCAGCTGGTGTCCATGTCGGTGCGCGAGCTGAACCGGCAGCTCCGCGGCTTCAGCAAGGAGGAGGTCATCCGGCTCAAGCAGAAGCGGCGCACGCTCAAGAACCGCGGCTACGCGCAGTCCTGCCGCTTCAAGCGGGTGCAGCAGCGGCACATTCTGGAGAGCGAGAAGTGCCAACTCCAGAGCCAGGTGGAGCAGCTGAAGCTGGAGGTGGGGCGCCTGGCCAAAGAGCGGGACCTGTACAAGGAGAAATACGAGAAGCTGGCGGGCCGGGGCGGCCCCGGGAGCGCGGGCGGGGCCGGTTTCCCGCGGGAGCCTTCGCCGCCGCAGGCCGGTCCCGGCGGGGCCAAGGGCACGGCCGACTTCTTCCTG(配列番号6)、またはストリンジェントなハイブリダイゼーション条件下で配列番号6からなる核酸配列にハイブリダイズする核酸配列を含む。
MNQPQRMAPVGTDKELSDLLDFSMMFPLPVTNGKGRPASLAGAQFGGSGLEDRPSSGSWGSGDQSSSSFDPSRTFSEGTHFTESHSSLSSSTFLGPGLGGKSGERGAYASFGRDAGVGGLTQAGFLSGELALNSPGPLSPSGMKGTSQYYPSYSGSSRRRAADGSLDTQPKKVRKVPPGLPSSVYPPSSGEDYGRDATAYPSAKTPSSTYPAPFYVADGSLHPSAELWSPPGQAGFGPMLGGGSSPLPLPPGSGPVGSSGSSSTFGGLHQHERMGYQLHGAEVNGGLPSASSFSSAPGATYGGVSSHTPPVSGADSLLGSRGTTAGSSGDALGKALASIYSPDHSSNNFSSSPSTPVGSPQGLAGTSQWPRAGAPGALSPSYDGGLHGLQSKIEDHLDEAIHVLRSHAVGTAGDMHTLLPGHGALASGFTSPMSLGGRHAGLVGGSHPEDGLAGSTSLMHNHAALPSQPGTLPDLSRPPDSYSGLGRAGATAAASEIKREEKEDEENTSAADHSEEEKKELKAPRARTSPDEDEDDLLPPEQKAEREKERRVANNARERLRVRDINEAFKELGRMCQLHLNSEKPQTKLLILHQAVSVILNLEQQVRERNLNPKAACLKRREEEKVSGVVGDPQMVLSAPHPGLSEAHNPAGHM(配列番号7)、または配列番号7に対して、少なくとも65%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の配列同一性を有するアミノ酸配列を含む。
MNQPQRMAPVGTDKELSDLLDFSMMFPLPVTNGKGRPASLAGAQFGGSGLEDRPSSGSWGSGDQSSSSFDPSRTFSEGTHFTESHSSLSSSTFLGPGLGGKSGERGAYASFGRDAGVGGLTQAGFLSGELALNSPGPLSPSGMKGTSQYYPSYSGSSRRRAADGSLDTQPKKVRKVPPGLPSSVYPPSSGEDYGRDATAYPSAKTPSSTYPAPFYVADGSLHPSAELWSPPGQAGFGPMLGGGSSPLPLPPGSGPVGSSGSSSTFGGLHQHERMGYQLHGAEVNGGLPSASSFSSAPGATYGGVSSHTPPVSGADSLLGSRGTTAGSSGDALGKALASIYSPDHSSNNFSSSPSTPVGSPQGLAGTSQWPRAGAPGALSPSYDGGLHGLQSKIEDHLDEAIHVLRSHAVGTAGDMHTLLPGHGALASGFTGPMSLGGRHAGLVGGSHPEDGLAGSTSLMHNHAALPSQPGTLPDLSRPPDSYSGLGRAGATAAASEIKREEKEDEENTSAADHSEEEKKELKAPRARTSSTDEVLSLEEKDLRDRERRMANNARERVRVRDINEAFRELGRMCQMHLKSDKAQTKLLILQQAVQVILGLEQQVRERNLNPKAACLKRREEEKVSGVVGDPQMVLSAPHPGLSEAHNPAGHM(配列番号8)、または配列番号8に対して、少なくとも65%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の配列同一性を有するアミノ酸配列を含む。
ATGAACCAGCCGCAGAGGATGGCGCCTGTGGGCACAGACAAGGAGCTCAGTGACCTCCTGGACTTCAGCATGATGTTCCCGCTGCCTGTCACCAACGGGAAGGGCCGGCCCGCCTCCCTGGCCGGGGCGCAGTTCGGAGGTTCAGGTCTTGAGGACCGGCCCAGCTCAGGCTCCTGGGGCAGCGGCGACCAGAGCAGCTCCTCCTTTGACCCCAGCCGGACCTTCAGCGAGGGCACCCACTTCACTGAGTCGCACAGCAGCCTCTCTTCATCCACATTCCTGGGACCGGGACTCGGAGGCAAGAGCGGTGAGCGGGGCGCCTATGCCTCCTTCGGGAGAGACGCAGGCGTGGGCGGCCTGACTCAGGCTGGCTTCCTGTCAGGCGAGCTGGCCCTCAACAGCCCCGGGCCCCTGTCCCCTTCGGGCATGAAGGGGACCTCCCAGTACTACCCCTCCTACTCCGGCAGCTCCCGGCGGAGAGCGGCAGACGGCAGCCTAGACACGCAGCCCAAGAAGGTCCGGAAGGTCCCGCCGGGTCTTCCATCCTCGGTGTACCCACCCAGCTCAGGTGAGGACTACGGCAGGGATGCCACCGCCTACCCGTCCGCCAAGACCCCCAGCAGCACCTATCCCGCCCCCTTCTACGTGGCAGATGGCAGCCTGCACCCCTCAGCCGAGCTCTGGAGTCCCCCGGGCCAGGCGGGCTTCGGGCCCATGCTGGGTGGGGGCTCATCCCCGCTGCCCCTCCCGCCCGGTAGCGGCCCGGTGGGCAGCAGTGGAAGCAGCAGCACGTTTGGTGGCCTGCACCAGCACGAGCGTATGGGCTACCAGCTGCATGGAGCAGAGGTGAACGGTGGGCTCCCATCTGCATCCTCCTTCTCCTCAGCCCCCGGAGCCACGTACGGCGGCGTCTCCAGCCACACGCCGCCTGTCAGCGGGGCCGACAGCCTCCTGGGCTCCCGAGGGACCACAGCTGGCAGCTCCGGGGATGCCCTCGGCAAAGCACTGGCCTCGATCTACTCCCCGGATCACTCAAGCAATAACTTCTCGTCCAGCCCTTCTACCCCCGTGGGCTCCCCCCAGGGCCTGGCAGGAACGTCACAGTGGCCTCGAGCAGGAGCCCCCGGTGCCTTATCGCCCAGCTACGACGGGGGTCTCCACGGCCTGCAGAGTAAGATAGAAGACCACCTGGACGAGGCCATCCACGTGCTCCGCAGCCACGCCGTGGGCACAGCCGGCGACATGCACACGCTGCTGCCTGGCCACGGGGCGCTGGCCTCAGGTTTCACCAGTCCCATGTCGCTGGGTGGGCGGCACGCAGGCCTGGTTGGAGGCAGCCACCCCGAGGACGGCCTCGCAGGCAGCACCAGCCTCATGCACAACCACGCGGCCCTCCCCAGCCAGCCAGGCACCCTCCCTGACCTGTCTCGGCCTCCCGACTCCTACAGTGGGCTAGGGCGAGCAGGTGCCACGGCGGCCGCCAGCGAGATCAAGCGGGAGGAGAAGGAGGACGAGGAGAACACGTCAGCGGCTGACCACTCGGAGGAGGAGAAGAAGGAGCTGAAGGCCCCCCGGGCCCGGACCAGCCCAGACGAGGACGAGGACGACCTTCTCCCCCCAGAGCAGAAGGCCGAGCGGGAGAAGGAGCGCCGGGTGGCCAATAACGCCCGGGAGCGGCTGCGGGTCCGTGACATCAACGAGGCCTTTAAGGAGCTGGGGCGCATGTGCCAACTGCACCTCAACAGCGAGAAGCCCCAGACCAAACTGCTCATCCTGCACCAGGCTGTCTCGGTCATCCTGAACTTGGAGCAGCAAGTGCGAGAGCGGAACCTGAATCCCAAAGCAGCCTGTTTGAAACGGCGAGAAGAGGAAAAGGTGTCAGGTGTGGTTGGAGACCCCCAGATGGTGCTTTCAGCTCCCCACCCAGGCCTGAGCGAAGCCCACAACCCCGCCGGGCACATG(配列番号9)、またはストリンジェントなハイブリダイゼーション条件下で配列番号9からなる核酸配列にハイブリダイズする核酸配列を含む。
ATGAACCAGCCGCAGAGGATGGCGCCTGTGGGCACAGACAAGGAGCTCAGTGACCTCCTGGACTTCAGCATGATGTTCCCGCTGCCTGTCACCAACGGGAAGGGCCGGCCCGCCTCCCTGGCCGGGGCGCAGTTCGGAGGTTCAGGTCTTGAGGACCGGCCCAGCTCAGGCTCCTGGGGCAGCGGCGACCAGAGCAGCTCCTCCTTTGACCCCAGCCGGACCTTCAGCGAGGGCACCCACTTCACTGAGTCGCACAGCAGCCTCTCTTCATCCACATTCCTGGGACCGGGACTCGGAGGCAAGAGCGGTGAGCGGGGCGCCTATGCCTCCTTCGGGAGAGACGCAGGCGTGGGCGGCCTGACTCAGGCTGGCTTCCTGTCAGGCGAGCTGGCCCTCAACAGCCCCGGGCCCCTGTCCCCTTCGGGCATGAAGGGGACCTCCCAGTACTACCCCTCCTACTCCGGCAGCTCCCGGCGGAGAGCGGCAGACGGCAGCCTAGACACGCAGCCCAAGAAGGTCCGGAAGGTCCCGCCGGGTCTTCCATCCTCGGTGTACCCACCCAGCTCAGGTGAGGACTACGGCAGGGATGCCACCGCCTACCCGTCCGCCAAGACCCCCAGCAGCACCTATCCCGCCCCCTTCTACGTGGCAGATGGCAGCCTGCACCCCTCAGCCGAGCTCTGGAGTCCCCCGGGCCAGGCGGGCTTCGGGCCCATGCTGGGTGGGGGCTCATCCCCGCTGCCCCTCCCGCCCGGTAGCGGCCCGGTGGGCAGCAGTGGAAGCAGCAGCACGTTTGGTGGCCTGCACCAGCACGAGCGTATGGGCTACCAGCTGCATGGAGCAGAGGTGAACGGTGGGCTCCCATCTGCATCCTCCTTCTCCTCAGCCCCCGGAGCCACGTACGGCGGCGTCTCCAGCCACACGCCGCCTGTCAGCGGGGCCGACAGCCTCCTGGGCTCCCGAGGGACCACAGCTGGCAGCTCCGGGGATGCCCTCGGCAAAGCACTGGCCTCGATCTACTCCCCGGATCACTCAAGCAATAACTTCTCGTCCAGCCCTTCTACCCCCGTGGGCTCCCCCCAGGGCCTGGCAGGAACGTCACAGTGGCCTCGAGCAGGAGCCCCCGGTGCCTTATCGCCCAGCTACGACGGGGGTCTCCACGGCCTGCAGAGTAAGATAGAAGACCACCTGGACGAGGCCATCCACGTGCTCCGCAGCCACGCCGTGGGCACAGCCGGTGACATGCACACGCTGCTGCCTGGCCACGGGGCGCTGGCCTCAGGTTTCACCGGCCCCATGTCACTGGGCGGGCGGCACGCAGGCCTGGTTGGAGGCAGCCACCCCGAGGACGGCCTCGCAGGCAGCACCAGCCTCATGCACAACCACGCGGCCCTCCCCAGCCAGCCAGGCACCCTCCCTGACCTGTCTCGGCCTCCCGACTCCTACAGTGGGCTAGGGCGAGCAGGTGCCACGGCGGCCGCCAGCGAGATCAAGCGGGAGGAGAAGGAGGACGAGGAGAACACGTCAGCGGCTGACCACTCGGAGGAGGAGAAGAAGGAGCTGAAGGCCCCCCGGGCCCGGACCAGCAGTACGGACGAGGTGCTGTCCCTGGAGGAGAAAGACCTGAGGGACCGGGAGAGGCGCATGGCCAATAACGCGCGGGAGCGGGTGCGCGTGCGGGATATTAACGAGGCCTTCCGGGAGCTGGGGCGCATGTGCCAGATGCACCTCAAGTCGGACAAAGCGCAGACCAAGCTGCTCATCCTGCAGCAGGCCGTGCAGGTCATCCTGGGGCTGGAGCAGCAGGTGCGAGAGCGGAACCTGAATCCCAAAGCAGCCTGTTTGAAACGGCGAGAAGAGGAAAAGGTGTCAGGTGTGGTTGGAGACCCCCAGATGGTGCTTTCAGCTCCCCACCCAGGCCTGAGCGAAGCCCACAACCCCGCCGGGCACATG(配列番号10)、またはストリンジェントなハイブリダイゼーション条件下で配列番号10からなる核酸配列にハイブリダイズする核酸配列を含む。
また、Pdx1、Ng3、Mafa、およびTcf3をコードする核酸配列を含むポリヌクレオチドを、皮膚細胞内に細胞内送達することを含む、皮膚細胞をインスリン産生細胞にリプログラミングする方法も開示する。いくつかの実施形態において、核酸配列は、非ウイルスベクターに存在する。いくつかの実施形態において、核酸配列は、発現制御配列に作動可能に連結されている。他の実施形態において、核酸は、2つ以上の発現制御配列に作動可能に連結されている。
図1A〜1Eは、糖尿病マウスを(皮膚への深部局所ナノエレクトロインジェクションによって)異なる遺伝子カクテルで1回治療した研究の結果を示す。血糖(y軸)を、1週目(治療後)から14週目まで(x軸)測定した。結果は、同時にまたは順次送達したPNM−Tカクテルが、対照/未治療マウスおよびカクテルの他の並べ替えと比較して、より制御されたグルコースレベル(すなわち、マウスが開始したベースラインとより同様)を支持することができたことを示す。
Claims (15)
- Pdx1をコードする第1の核酸配列、Ng3をコードする第2の核酸配列、Mafaをコードする第3の核酸配列、およびTcf3をコードする第4の核酸配列を含む、非ウイルスベクター。
- 前記第1、第2、第3、および第4の核酸配列のそれぞれが、発現制御配列に作動可能に連結されている、請求項1に記載の非ウイルスベクター。
- 前記第1、第2、第3、および第4の核酸配列のそれぞれが、単一発現制御配列に作動可能に連結されている、請求項2に記載の非ウイルスベクター。
- 前記非ウイルスベクターが、pIRES−hrGFP−2a、pCMV6、pMAX、pCAG、pAd−IRES−GFP、およびpCDNA3.0の群から選択されるプラスミドを含む、請求項2または3に記載の非ウイルスベクター。
- 前記ポリヌクレオチドが、細胞内送達に好適なリポソーム、微小粒子、またはナノ粒子内に封入される、請求項2〜4のいずれか一項に記載の非ウイルスベクター。
- 皮膚細胞をインスリン産生細胞にリプログラミングする方法であって、
(a)Pdx1、Ng3、Mafa、およびTcf3タンパク質、またはPdx1、Ng3、Mafa、およびTcf3をコードするポリヌクレオチドを、前記皮膚細胞内に細胞内送達すること、または
(b)前記皮膚細胞を、Pdx1、Ng3、Mafa、およびTcf3タンパク質、またはPdx1、Ng3、Mafa、およびTcf3をコードするポリヌクレオチドを含有または発現する細胞から産生された細胞外小胞に曝露することを含む、方法。 - 前記タンパク質またはポリヌクレオチドが、順次投与される、請求項6に記載の方法。
- 請求項1〜5のいずれか一項に記載の非ウイルスベクターを、前記体細胞内に細胞内送達することを含む、請求項6に記載の方法。
- 細胞内送達が、三次元ナノチャネルエレクトロポレーションを含む、請求項6〜8のいずれか一項に記載の方法。
- 細胞内送達が、組織ナノトランスフェクション装置による送達を含む、請求項6〜8のいずれか一項に記載の方法。
- 細胞内送達が、深部局所組織ナノエレクトロインジェクション装置による送達を含む、請求項6〜8のいずれか一項に記載の方法。
- 対象における糖尿病を治療するための方法であって、請求項6〜11のいずれか一項に記載の方法を使用して、前記対象における有効量の皮膚細胞をインスリン産生細胞にリプログラミングすることを含む、方法。
- 前記対象が、インスリン依存性糖尿病を有する、請求項12に記載の方法。
- 前記対象が、インスリン抵抗性糖尿病を有する、請求項12に記載の方法。
- 前記対象が、治療中に70〜130mg/dLの空腹時血糖レベルを有する、請求項13または14に記載の方法。
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