{"id":623,"date":"2019-03-09T01:03:32","date_gmt":"2019-03-08T22:03:32","guid":{"rendered":"http:\/\/blog.ulubat.org\/?p=623"},"modified":"2019-04-07T23:22:01","modified_gmt":"2019-04-07T20:22:01","slug":"tibbin-gelecegi-crispr-cas9-teknolojisi","status":"publish","type":"post","link":"https:\/\/blog.ulubat.org\/index.php\/genel\/tibbin-gelecegi-crispr-cas9-teknolojisi\/","title":{"rendered":"T\u0131bb\u0131n Gelece\u011fi: CRISPR\/Cas9 Teknolojisi"},"content":{"rendered":"\n

Sevgili okur! \u00c7ay\u0131n\u0131, kahveni al\u0131p en iyi rahat etti\u011fin pozisyona ge\u00e7meni tavsiye ederim. \u015eimdi daha \u00f6nce hi\u00e7 duymad\u0131ysan ufkunu a\u00e7acak, duyduysan ufkunu geni\u015fletecek bir konu hakk\u0131ndaki bu yaz\u0131 seni bekliyor. L\u00fctfen arada s\u0131k\u0131l\u0131p yar\u0131m b\u0131rakma. Sonuna kadar sabret zira pi\u015fman olmayacaks\u0131n. <\/p>\n\n\n\n

CRISPR-\nCas       Sistemi, CRISPRs<\/em> ve Cas9<\/em>\ngenlerinden olu\u015fan ve prokaryotik t\u00fcrlerde yabanc\u0131 DNA molek\u00fcllerini yok etmek\nsuretiyle istilac\u0131 t\u00fcrlere kar\u015f\u0131 imm\u00fcn yan\u0131t olu\u015fturan bir sistemdir (1). Bu\nsistemde birtak\u0131m de\u011fi\u015fiklikler yap\u0131larak insan h\u00fccrelerinde DNA yap\u0131s\u0131n\u0131n\nde\u011fi\u015ftirilebilece\u011finin ve b\u00f6ylelikle genetik hastal\u0131klar\u0131n tedavi\nedilebilece\u011finin anla\u015f\u0131lmas\u0131 \u00fczerine 21. y\u00fczy\u0131l\u0131n en heyecan verici bilimsel\ngeli\u015fmesi olan CRISPR\/Cas9 teknolojisi ortaya \u00e7\u0131km\u0131\u015ft\u0131r. Bu teknoloji sayesinde\nCRISPR\/Cas sisteminin bile\u015fenleri \u00e7e\u015fitli gen b\u00f6lgelerine y\u00f6nlendirilerek bozuk\ngenler kesilebilir, DNA\u2019ya yeni genler eklenebilir, mutasyonlu alleller normal\nalleller haline d\u00f6n\u00fc\u015ft\u00fcr\u00fclebilir ya da istenilen genlerin ekspresyonu art\u0131r\u0131l\u0131p-azalt\u0131labilir\n(2,3). Ayr\u0131ca son yay\u0131nlar bu teknoloji sayesinde \u00e7ift zincir k\u0131r\u0131\u011f\u0131 yapmadan\ntek bir n\u00fckleotitte de de\u011fi\u015fiklik yap\u0131labilece\u011fini (4), (L\u00fctfen bu c\u00fcmlenin\na\u011f\u0131rl\u0131\u011f\u0131n\u0131n fark\u0131na var. Genetik hastal\u0131klar\u0131n yakla\u015f\u0131k yar\u0131s\u0131 tek n\u00fckleotit\nhatalar\u0131ndan kaynaklanmaktad\u0131r.) DNA\u2019y\u0131 kesmeden istenilen genlerin\nsusturulabilece\u011fini (5) ve sadece DNA\u2019n\u0131n de\u011fil RNA\u2019n\u0131n da d\u00fczenlenebilece\u011fini (6)\n(Son 2 ifade ile \u015funu anlatmak istiyorum: Sadece genomda de\u011fil epigenomda da\nde\u011fi\u015fiklik yapabiliriz.) bildirmektedir. <\/p>\n\n\n\n

CRISPR\/Cas9\nteknolojisi Stanford \u00dcniversitesi\u2019nden Jennifer Doudna ve arkada\u015flar\u0131\ntaraf\u0131ndan 2013 y\u0131l\u0131nda ke\u015ffedilmi\u015ftir. Ard\u0131ndan Doudna, patentini ald\u0131. Ama\nHarvard \u00dcniversitesi\u2019nden Feng Zang de bu teknolojinin uygulanmas\u0131 ile ilgili\n\u00f6nemli \u00e7al\u0131\u015fmalara imza att\u0131 ve o da \u00e7al\u0131\u015fmalar\u0131 ile ilgili patent ald\u0131. \u0130kisi\nde milyar dolarl\u0131k de\u011feri olan \u015firketler kurdular ve ayn\u0131 zamanda Emmanuelle\nCharpentier ile birlikte Nobel \u00d6d\u00fcl\u00fcn\u00fcn de en b\u00fcy\u00fck adaylar\u0131 aras\u0131ndalar. Tabi\n\u00e7al\u0131\u015fmalar sadece ABD\u2019de yap\u0131lm\u0131yor. \u00c7in de bu teknolojinin kullan\u0131m\u0131 konusunda\niddial\u0131. (Haberlerde okumu\u015fsunuzdur. \u00c7inli bir bilim insan\u0131(!) HIV\u2019e kar\u015f\u0131\ndiren\u00e7 kazand\u0131rtt\u0131\u011f\u0131 iki bebe\u011fin D\u00fcnya\u2019ya geldi\u011fini iddia etti. Nas\u0131l olabilir\nbu? Elbette ki CRISPR\/Cas9 ile.) 2. D\u00fcnya Sava\u015f\u0131 sonras\u0131 ABD ile Sovyetler\nuzaya \u00e7\u0131kma yar\u0131\u015f\u0131nda idi. \u015eimdi de ABD ile \u00c7in aras\u0131nda hastal\u0131klar\u0131 tedavi\netmek i\u00e7in benzer bir yar\u0131\u015f\u0131n oldu\u011funu s\u00f6yleyebilirim. Dolay\u0131s\u0131yla bizler de bu\nyar\u0131\u015fa dahil olmal\u0131y\u0131z. Bir yerden ba\u015flamak gerekiyorsa o da hi\u00e7 ku\u015fkusuz\nokumakt\u0131r. \u00d6nce okuyal\u0131m, d\u00fc\u015f\u00fcnelim. Ard\u0131ndan fikirler ortaya \u00e7\u0131kacakt\u0131r. Haydi\nokumaya devam J<\/p>\n\n\n\n

Bu\nteknolojiye neden milyar dolarl\u0131k yat\u0131r\u0131mlar yap\u0131l\u0131yor? Neden \u00fclkeler adeta\nbirbirleri ile yar\u0131\u015f\u0131yor? \u00c7\u00fcnk\u00fc 21. Y\u00fczy\u0131l\u0131n en heyecan verici bilimsel\ngeli\u015fmelerinden biri olan CRISPR\/Cas9 teknolojisi gelecek i\u00e7in \u00e7ok b\u00fcy\u00fck\numutlar vaat etmektedir. Sadece genetik hastal\u0131klar olarak d\u00fc\u015f\u00fcnmeyin. Kanser,\nkalp damar hastal\u0131klar\u0131, n\u00f6rodejeneratif hastal\u0131klar vb. hastal\u0131klarda da\nk\u0131saca t\u00fcm t\u0131pta kullan\u0131m potansiyeli bar\u0131nd\u0131rmaktad\u0131r. Bu potansiyelleri\nke\u015ffedecek bilim insanlar\u0131 aras\u0131nda neden bizler de yer almayal\u0131m? <\/p>\n\n\n\n

\u015eimdi\nsizlere bu teknolojinin kullan\u0131ld\u0131\u011f\u0131 baz\u0131 bilimsel \u00e7al\u0131\u015fmalardan bahsedece\u011fim.\nMalumunuzdur ki CRISPR\/Cas9 teknolojisi bir derya deniz. Yap\u0131lan herbir \u00e7al\u0131\u015fma\nayr\u0131 ayr\u0131 irdelenmeyi hak ediyor. Ama yaz\u0131 \u00e7ok uzar ve amac\u0131ndan sapabilir. O\ny\u00fczden sizlere \u0131\u015f\u0131k tutabilmek i\u00e7in yakla\u015f\u0131k 3 y\u0131ld\u0131r okudu\u011fum yay\u0131nlardan\nse\u00e7mece olarak baz\u0131lar\u0131n\u0131 burada payla\u015faca\u011f\u0131m. Hemen hemen hepsi \u00e7ok y\u00fcksek\netki fakt\u00f6rl\u00fc dergilerde yay\u0131mland\u0131. Konu hakk\u0131nda daha derin okumalar i\u00e7in\nkaynak\u00e7adan yararlanabilirsiniz.<\/p>\n\n\n\n

Bu\nteknoloji, bir\u00e7ok n\u00f6rolojik hastal\u0131k da dahil olmak \u00fczere halihaz\u0131rda tedavi\nse\u00e7ene\u011fi olmayan hastal\u0131klar\u0131n iyile\u015ftirilmesinde (7), n\u00f6ronal i\u015flevlerle\ndavran\u0131\u015flar\u0131n ve n\u00f6robiyolojik hastal\u0131klar\u0131n alt\u0131nda yatan genetik ve\nepigenetik mekanizmalar\u0131n anla\u015f\u0131lmas\u0131nda b\u00fcy\u00fck bir potansiyel bar\u0131nd\u0131rmaktad\u0131r\n(8). Duchenne Musk\u00fcler Distrofi\u2018li (DMD) farelerde hatal\u0131 distrofin geni\nkesilmi\u015f ve yeniden tamir mekanizmas\u0131 ile tekrardan genin ekspresyonu sa\u011flanm\u0131\u015f\n(9). \u0130n vitro yap\u0131lan ba\u015fka bir \u00e7al\u0131\u015fmada ise kardiyomyositlerde sorunlu ekzon\nb\u00f6lgeleri hedef al\u0131narak DMD ile ili\u015fkili kardiyak anormalliklerin\nd\u00fczeltilebilece\u011fi bildirilmi\u015f (10). Yine in vitro olarak; Frajil X sendromundan\nsorumlu FMR1 genindeki CGG tekrar\u0131 (11) ve huntington hastal\u0131\u011f\u0131ndan sorumlu\nhuntingtin genindeki CAG tekrar\u0131 \u00f6nlenmi\u015f (12). Uyar\u0131lm\u0131\u015f Pluripotent K\u00f6k\nH\u00fccrelerden ve fibroblastlardan insan n\u00f6ron h\u00fccrelerinin yeniden programlanmas\u0131\nba\u015far\u0131lm\u0131\u015f (13). \u00c7e\u015fitli n\u00f6rolojik hastal\u0131klar\u0131n tedavisi i\u00e7in otolog Schwann\nh\u00fccrelerinin ve mezenkimal k\u00f6k h\u00fccrelerin daha etkin d\u00fczenlenebilece\u011fi\nbildirilmi\u015f (14). SCN1A fonksiyon kayb\u0131 mutasyonunun neden oldu\u011fu epilepsilerin\npatofizyolojisi ayd\u0131nlat\u0131lm\u0131\u015f (15). Yine CRISPR\/Cas9 teknolojisini kullanarak\nkanal mutasyonlar\u0131n\u0131n tamir edilip, kanalopatilerin tamamen tedavi\nedilebilece\u011fi \u00f6ng\u00f6r\u00fcl\u00fcyor (16). Sinaptotagmin I’in (Syt1) hedeflendi\u011fi bir\n\u00e7al\u0131\u015fmada ise fare hipokampusunun dentat girusundaki inhibit\u00f6r uyar\u0131 uyar\u0131larak\ndentat girusun \u00f6\u011frenme ve afektif s\u00fcre\u00e7lerde belirgin d\u00fczenleyici rollere sahip\noldu\u011fu bulunmu\u015f. Bu \u00e7al\u0131\u015fma, CRISPR\/Cas9 teknolojisinin memeli beynindeki gen\nfonksiyonunun daha h\u0131zl\u0131 ara\u015ft\u0131r\u0131lmas\u0131 i\u00e7in yararl\u0131 bir ara\u00e7 olabilece\u011fini\ng\u00f6stermekte (17). Yine CRISPR\/Cas9 sayesinde alzaymer, parkinson, amiyotrofik\nlateral skleroz, spinal musk\u00fcler atrofi ve ataksi-telanjiektazi gibi\nn\u00f6rodejeneratif bozukluklarda daha k\u0131sa s\u00fcrede ve daha etkin hayvan modelleri\nolu\u015fturulabilece\u011fi bildirilmi\u015f (18).<\/p>\n\n\n\n

Ding\nve ark. farelerde y\u00fcksek LDL seviyesi ile ili\u015fkili olan PCSK9 genini sayesinde\nmutasyona u\u011fratmay\u0131 ba\u015fard\u0131lar (19), daha sonraki \u00e7al\u0131\u015fmalar\u0131nda ise ayn\u0131\nba\u015far\u0131y\u0131 in vivo insan hepatositlerinde tekrarlad\u0131lar (20), kalp yetmezli\u011finde\nkalbin i\u015flevini art\u0131rabilmek amac\u0131yla SERCA2a geninin hedef al\u0131nd\u0131\u011f\u0131 \u00e7al\u0131\u015fmalar\nfaz 2\u2019ye kadar ilerlemi\u015ftir (21), akut allograft reddine y\u00f6nelik de CD4+\nyard\u0131mc\u0131 T lenfositlerin tepkisini hafifletmek i\u00e7in yine CRISPR\/Cas9\nteknolojisi kullan\u0131larak MHC2 molek\u00fcllerinin hedef al\u0131nmas\u0131 planlanmaktad\u0131r (22),\nXie ve ark. ise PRKAG2 genindeki mutasyon ile ili\u015fkili PRKAG2 kardiyak sendroma\ny\u00f6nelik fare deneylerinde ba\u015far\u0131l\u0131 sonu\u00e7lar elde etmi\u015flerdir (23). Ayr\u0131ca\nCRISPR\/Cas9 teknolojisi, kalp-damar hastal\u0131klar\u0131nda insan genetik varyasyonunun\ni\u015fleyi\u015fini incelemek i\u00e7in deney hayvanlar\u0131n\u0131n h\u0131zl\u0131 ve etkili bi\u00e7imde \u00fcretimini\nde kolayla\u015ft\u0131racakt\u0131r (24).  <\/p>\n\n\n\n

Bu\nteknoloji \u00f6zellikle kanserle ilgili \u00e7al\u0131\u015fmalarda yo\u011fun bir \u015fekilde\nkullan\u0131lmaktad\u0131r. \u00d6rne\u011fin: Fare melanoma h\u00fccrelerindeki PTPN2 geninin\nimm\u00fcnoterapilere diren\u00e7te rol ald\u0131\u011f\u0131 ke\u015ffedildi (25). <\/strong>\u0130nsan metastatik melanoma ve akci\u011fer kanseri h\u00fccrelerinde ise\nimm\u00fcnoterapilere dirence APLNR genindeki mutasyonlar\u0131n neden olabilece\u011fi\nsaptand\u0131 (26).Prostat ve karaci\u011fer\nkanseri farelerinde ise MAN2A1-FER f\u00fczyon geninin kesilmesinin t\u00fcm\u00f6r y\u00fck\u00fcnde\nazalma sa\u011flad\u0131\u011f\u0131 bildirildi (27). Fare embriyonik fibroblast h\u00fccrelerindeki\nTUDOR-SN geninin kesilmesi ile h\u00fccre b\u00fcy\u00fcmesinin yava\u015flad\u0131\u011f\u0131 tespit edildi (28).\nOrganoidler \u00fczerinde yap\u0131lan bir \u00e7al\u0131\u015fmada ise MLH1 VE NTHL1 genlerindeki\nmutasyonlar\u0131n kolon kanseri ve meme kanseri geli\u015fimine neden oldu\u011fu g\u00f6zlemlendi\n(29). Dahas\u0131 CRISPR\/Cas9 tekni\u011fi ile \u00fcretilen CAR-T h\u00fccrelerinin (CAR-T h\u00fccre\ntedavisi baz\u0131 hematolojik malinitelerin tedavisinde FDA onay\u0131 alm\u0131\u015ft\u0131r. Belki\nde kanser imm\u00fcnoterapisinde en heyecan verici geli\u015fmelerden biridir. \u0130lerleyen\nzamanlarda bu konu hakk\u0131nda da yazaca\u011f\u0131m.) geleneksel y\u00f6ntemlerle \u00fcretilen\nCAR-T h\u00fccrelerine k\u0131yasla kanser h\u00fccrelerine kar\u015f\u0131 daha etkin oldu\u011fu bildirildi\n(30). Ayr\u0131ca CRISPR\/Cas9 teknolojisi kullan\u0131larak deneysel \u00e7al\u0131\u015fmalar i\u00e7in\n\u00e7e\u015fitli kanser modelleri de olu\u015fturulmaktad\u0131r (31). Bu geli\u015fmelerin yan\u0131 s\u0131ra\n2016 itibariyle CRISPR\/Cas9 teknolojisinin kullan\u0131ld\u0131\u011f\u0131 ilk klinik deney\nakci\u011fer kanseri hastalar\u0131nda ba\u015flad\u0131 (32) ve 2018 itibariyle 20\u2019den fazla\nklinik deney devam etmekteydi (33). \u015eubat 2019\u2019da da beta talasemi ve orak\nh\u00fccreli anemi hastal\u0131klar\u0131nda yine CRISPR\/Cas9 teknolojisinin kullan\u0131laca\u011f\u0131\nfaz1\/2 \u00e7al\u0131\u015fmalar\u0131 ba\u015fland\u0131 (34). \u015eayet bu yazd\u0131klar\u0131mdan sonra CRISPR\/Cas9\nteknolojisi ilginizi \u00e7ektiyse (ya da halihaz\u0131rda ilginizi \u00e7ekmekteyse) NEJM\ndergisinde yay\u0131mlanm\u0131\u015f \u00e7ok yeni iki yaz\u0131y\u0131 da okuman\u0131z\u0131 tavsiye ederim. (35,36)<\/p>\n\n\n\n

Tabi\nolaya hep beyaz taraf\u0131ndan bakmayal\u0131m. CRISPR\/Cas9 teknolojisi ile ilgili derin\nendi\u015feler de mevcut. Bunlardan en \u00f6nemli ikisi \u015fu: etik ve g\u00fcvenirlilik. Genoma\nbilhassa embriyonel d\u00f6nemde m\u00fcdahale etmek etik olarak \u00e7ok tart\u0131\u015fmal\u0131 bir konu.\n Bir de bu teknoloji ile hedef b\u00f6lgelere\n%100 \u00f6zg\u00fcll\u00fckte m\u00fcdahale edebilmemiz \u015fu an i\u00e7in m\u00fcmk\u00fcn de\u011fil. K\u00fc\u00e7\u00fck bir hata\npay\u0131n\u0131n olmas\u0131 bile geri d\u00f6n\u00fc\u015fs\u00fcz hasarlara sebep olabilir. O y\u00fczden heyecanl\u0131\nolmak kadar temkinli olmak da \u00f6nemli. Ama gelecek ad\u0131na bilimden \u00fcmit duydu\u011fumu\nbelirtmek isterim.<\/p>\n\n\n\n

Sonu\u00e7\nolarak mevcut veriler yak\u0131n bir gelecekte CRISPR\/Cas9 teknolojisinin klinikte\nyayg\u0131n olarak kullan\u0131labilece\u011fini ve CRISPR\/Cas9teknolojisine dayal\u0131\nyakla\u015f\u0131mlar\u0131n geni\u015f bir tedavi potansiyeli bar\u0131nd\u0131rd\u0131\u011f\u0131n\u0131 g\u00f6stermektedir. Gelece\u011fin\nhekimleri olarak bizler de bu tedavi y\u00f6ntemine kendimizi haz\u0131rlamal\u0131y\u0131z. Hatta\nve hatta bizzat bu alandaki \u00e7al\u0131\u015fmalara dahil olmal\u0131y\u0131z.  Bu yaz\u0131 ile CRISPR\/Cas9 teknolojisi ve bu\nteknolojinin t\u0131ptaki kullan\u0131m olanaklar\u0131 hakk\u0131nda umar\u0131m bir fark\u0131ndal\u0131k\nolu\u015fturabilmi\u015fimdir. Sa\u011fl\u0131cakla ve bilimle kal\u0131n. <\/p>\n\n\n\n

Kaynak\u00e7a:<\/strong><\/p>\n\n\n\n

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    Sevgili okur! \u00c7ay\u0131n\u0131, kahveni al\u0131p en iyi rahat etti\u011fin pozisyona ge\u00e7meni tavsiye ederim. \u015eimdi daha \u00f6nce hi\u00e7 duymad\u0131ysan ufkunu a\u00e7acak,<\/p>\n","protected":false},"author":61,"featured_media":1214,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[1,19],"tags":[],"acf":[],"views":1275,"_links":{"self":[{"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts\/623"}],"collection":[{"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/users\/61"}],"replies":[{"embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/comments?post=623"}],"version-history":[{"count":5,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts\/623\/revisions"}],"predecessor-version":[{"id":631,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts\/623\/revisions\/631"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/media\/1214"}],"wp:attachment":[{"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/media?parent=623"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/categories?post=623"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/tags?post=623"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}