{"id":11429,"date":"2022-06-24T00:01:00","date_gmt":"2022-06-23T21:01:00","guid":{"rendered":"http:\/\/blog.ulubat.org\/?p=11429"},"modified":"2022-06-23T21:19:44","modified_gmt":"2022-06-23T18:19:44","slug":"crisprin-tedavi-edebilecegi-ilk-tek-gen-hastaliklari","status":"publish","type":"post","link":"https:\/\/blog.ulubat.org\/index.php\/genel\/crisprin-tedavi-edebilecegi-ilk-tek-gen-hastaliklari\/","title":{"rendered":"CRISPR’\u0131n Tedavi Edebilece\u011fi \u0130lk Tek Gen Hastal\u0131klar\u0131"},"content":{"rendered":"\n
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2020 y\u0131l\u0131nda Nobel Kimya \u00d6d\u00fcl\u00fc\u2019n\u00fc kazanan Emmanuel Charpentier<\/em> ve Jennifer A. Doudna\u2019n\u0131n<\/em> geli\u015ftirdi\u011fi, bilim tarihinde \u00e7\u0131\u011f\u0131r a\u00e7an genom d\u00fczenleme y\u00f6ntemi CRISPR-Cas9<\/em> pek \u00e7ok alanda oldu\u011fu gibi t\u0131p d\u00fcnyas\u0131nda da yeni tedavilerin geli\u015ftirilmesinde \u00f6nemli bir rol \u00fcstleniyor. G\u00fcn\u00fcm\u00fczde tam anlam\u0131yla tedavi edilemeyen ya da tedavisi olmayan onlarca hastal\u0131k i\u00e7in yeni bir umut \u0131\u015f\u0131\u011f\u0131 olan CRISPR teknolojisi bilim insanlar\u0131n\u0131n ellerinde her ge\u00e7en g\u00fcn kayda de\u011fer ba\u015far\u0131lar kazanmaya devam ediyor. Orak h\u00fccreli anemi <\/strong>ve <\/em>\u03b2-talasemi<\/em> <\/strong>de bu grubun i\u00e7inde yer alan iki \u00f6nemli hastal\u0131k. \u00c7al\u0131\u015fmalar g\u00f6steriyor ki her iki hastal\u0131k i\u00e7in de art\u0131k \u00fcmit verici yeni bir tedavi m\u00fcmk\u00fcn olabilir.<\/p>\n<\/div>\n<\/div>\n\n\n

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Orak \u015feklindeki eritrositler<\/strong>
Kaynak: https:\/\/thalassaemia.org.cy\/haemoglobin-disorders\/sickle-cell-disease\/<\/figcaption><\/figure><\/div>\n\n\n

Orak H\u00fccreli Anemi ve \u03b2-Talasemi<\/strong><\/h2>\n\n\n\n

Orak h\u00fccreli anemi ve transf\u00fczyon ba\u011f\u0131ml\u0131 \u03b2-talasemi d\u00fcnyada en s\u0131k g\u00f6r\u00fclen tek gen hastal\u0131klar\u0131 olma \u00f6zelli\u011fi ta\u015f\u0131r. G\u00fcn\u00fcm\u00fczde her y\u0131l yakla\u015f\u0131k olarak 60 bin yeni transf\u00fczyon ba\u011f\u0131ml\u0131 \u03b2-talasemi <\/em>ve 300 bin yeni orak h\u00fccreli anemi hastas\u0131<\/em> tan\u0131 almaktad\u0131r. Her iki hastal\u0131\u011fa da hemoglobin beta alt \u00fcnitesi genindeki (HBB)<\/em> mutasyonlar sebep olur. \u03b2-talasemide, HBB genindeki mutasyonlar beta globin zincirinin \u00fcretiminde azalmaya veya hi\u00e7 \u00fcretilmemeye yol a\u00e7arak alfa ve beta globin dengesizli\u011fi yarat\u0131p efektif olmayan eritropoeze sebep olurlar. Orak h\u00fccreli anemide ise HBB geninde ger\u00e7ekle\u015fen nokta mutasyonu sonucu 6. Pozisyondaki glutamik asidin yerini valin aminoasidi al\u0131r. B\u00f6ylelikle orak \u015feklini alan deoksijenize hemoglobin eritrosit deformasyonuna, hemolize, anemiye, olduk\u00e7a a\u011fr\u0131l\u0131 vazookluzif ataklara, geri d\u00f6n\u00fc\u015f\u00fcms\u00fcz son organ hasarlar\u0131na ve beklenen ya\u015fam s\u00fcresinde k\u0131salmaya sebep olur.<\/p>\n\n\n\n

Transf\u00fczyon ba\u011f\u0131ml\u0131 \u03b2-talasemide ad\u0131ndan da anla\u015f\u0131laca\u011f\u0131 \u00fczere tedavi devaml\u0131 olarak transf\u00fczyon ve demir \u015felasyonudur. Orak h\u00fccreli anemide ise a\u011fr\u0131 y\u00f6netimi, transf\u00fczyon ve hidroksi\u00fcre tedavileri \u00f6n plana \u00e7\u0131kmaktad\u0131r. Allojenik kemik ili\u011fi transplantasyonu her iki hastal\u0131\u011f\u0131 da tamamen iyile\u015ftirebilir fakat tedaviye uygun hastalar\u0131n sadece %20\u2019den az\u0131 insan l\u00f6kosit antijen uyumlu don\u00f6rleri bulabilmektedir.<\/p>\n\n\n\n

\u00c7are Fetal Hemoglobin mi?<\/strong><\/h2>\n\n\n\n

Fetal hemoglobin (HbF) erken gestasyonal d\u00f6nemden postnatal 1 ila 2 ay boyunca yeti\u015fkin HbA \u00fcretilene kadar eritrositlerimizin i\u00e7ini doldurur. Postnatal d\u00f6nemde HBB geni \u00fczerinden beta globin zinciri \u00fcretilmeye ba\u015fland\u0131k\u00e7a HBG geni \u00fczerindeki gama globin \u00fcreten b\u00f6lgeler \u00f6zellikle BCL11A<\/em> adl\u0131 bir transkripsiyon fakt\u00f6r\u00fc arac\u0131l\u0131\u011f\u0131yla bask\u0131lan\u0131rlar ve b\u00f6ylelikle eritrositlerimiz HbA bask\u0131n hale gelir.<\/p>\n\n\n\n

Asl\u0131nda fetal hemoglobinin (HbF)\u2019nin orak h\u00fccreli anemideki rol\u00fc altm\u0131\u015f y\u0131ldan fazla bir s\u00fcre \u00f6nce Dr. Janet Watson\u2019\u0131n yenido\u011fan hastalar\u0131nda daha az semptom olmas\u0131, deoksijenize eritrositlerinin daha uzun s\u00fcrede orakla\u015fmas\u0131 ve hatta orak h\u00fccreli anemi olan annelerinin eritrositleri kadar yayg\u0131n bir \u015fekilde deformasyona u\u011framad\u0131\u011f\u0131n\u0131 g\u00f6zlemlemesiyle ortaya konmu\u015ftu. Watson bu g\u00f6zlemlerine yenido\u011fanlar\u0131n kanlar\u0131ndaki HbF seviyelerinin y\u00fcksekli\u011fini de eklemi\u015fti. Daha sonra yap\u0131lan orak hemoglobin (HbS) jelasyon \u00e7al\u0131\u015fmalar\u0131 g\u00f6sterdi ki HbF, HbS ile etkile\u015fime ge\u00e7miyordu. Bu sayede yenido\u011fanlarda, heterozigot orak h\u00fccreli anemi ve e\u015fli\u011finde kal\u0131tsal s\u00fcrekli HbF tablosu g\u00f6r\u00fclen vakalarda HbS seviyesi \u00e7ok y\u00fcksek olmas\u0131na ra\u011fmen bu hastalar klinik olarak normal olabiliyorlard\u0131. Ayr\u0131ca Senegal ve Suudi-Hintli HBB benzeri gen k\u00fcmesi haplotipli hastalarda da istisnai olarak y\u00fcksek HbF seviyelerine rastlanmaktad\u0131r. Bu hastalar asemptomatik olmamakla birlikte genellikle daha hafif klinik bulgular g\u00f6sterirler.<\/p>\n\n\n\n

HbF, orak h\u00fccreli aneminin klinik ve hematolojik \u015fiddetini azaltmak a\u00e7\u0131s\u0131ndan en g\u00fc\u00e7l\u00fc mod\u00fclat\u00f6r olarak g\u00f6rev yapmaktad\u0131r. Y\u00fcksek HbF seviyeleri \u03b2-talasemi ve orak h\u00fccreli anemi hastalar\u0131nda mortalite ve morbiditeyi iyile\u015ftirme ile ili\u015fkilendirilmi\u015ftir. Ayr\u0131ca orak h\u00fccreli anemide akut a\u011fr\u0131lar\u0131n s\u0131kl\u0131\u011f\u0131n\u0131 azaltmakta, daha az bacak \u00fclseri ve osteonekroz g\u00f6r\u00fclmesine sebep olmakta, genel olarak hastal\u0131\u011f\u0131n \u015fiddetini azaltmaktad\u0131r.<\/p>\n\n\n

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Alfa ve beta gen k\u00fcmelerinin kromozomlar \u00fczerindeki yerle\u015fimi<\/strong>
Kaynak: Molecular basis of \u03b1-thalassemia – Scientific Figure on ResearchGate. Available from: https:\/\/www.researchgate.net\/figure\/Schematic-presentation-of-the-chromosomal-location-of-the-a-and-b-globin-gene-clusters-on_fig1_319971874 [accessed 23 Jun, 2022]<\/em><\/figcaption><\/figure><\/div>\n\n\n

CRISPR ve Yeni Umutlar<\/strong><\/h2>\n\n\n\n

2019 y\u0131l\u0131nda bir grup bilim insan\u0131 yukar\u0131da bahsetti\u011fim sebeplerden dolay\u0131 fetal hemoglobinin orak h\u00fccreli anemi ve \u03b2-talasemi tedavisinde iyi bir se\u00e7enek olabilece\u011fini d\u00fc\u015f\u00fcnd\u00fc. Hipotezleri \u015fu y\u00f6ndeydi: E\u011fer HbF\u2019e sahip hasta yeti\u015fkinlerde klinik seyir daha iyi ve hafifse buna sahip olmayan yeti\u015fkinlerde de d\u0131\u015far\u0131dan HbF \u00fcretimini tetiklemek m\u00fcmk\u00fcn m\u00fcyd\u00fc?<\/em> Tahmin edilebilece\u011fi \u00fczere altm\u0131\u015f y\u0131ldan fazla zamand\u0131r bilinen bir ger\u00e7e\u011fi hipoteze \u00e7eviren ilk bilim insanlar\u0131 de\u011fillerdi. Daha \u00f6nce de pek \u00e7ok farmakolojik ajanla ve \u00e7e\u015fitli y\u00f6ntemlerde bunu denemi\u015f \u00e7al\u0131\u015fmalar mevcuttu. Fakat bu konuda CRISPR\u2019dan faydalanan ilk bilim insanlar\u0131 olacaklard\u0131.<\/p>\n\n\n\n

Deneyler 19 ya\u015f\u0131nda bir \u03b2-talasemi ve 33 ya\u015f\u0131nda bir orak h\u00fccreli anemi hastas\u0131 iki kad\u0131n ile ba\u015flad\u0131. Her iki hastaya da d\u00fczenli olarak kan transf\u00fczyonu yap\u0131lmakta ve her ikisi de hastal\u0131klar\u0131n\u0131n klinik bulgular\u0131n\u0131 g\u00f6stermekteydiler. \u0130lk a\u015famada hastalar\u0131n hematopoetik k\u00f6k h\u00fccre ve progenitor h\u00fccreleri topland\u0131. Arkas\u0131ndan kemoterapi uygulanarak kemik iliklerindeki b\u00fct\u00fcn hematopoetik seriler s\u0131f\u0131rland\u0131. Daha sonra CRISPR-Cas9 y\u00f6ntemi kullan\u0131larak d\u00fczenlenen hematopoetik k\u00f6k h\u00fccre ve progenitor h\u00fccrelerdeki BCL11A\u2019n\u0131n ekspresyonu azalt\u0131l\u0131p fetal hemoglobin (HbF) \u00fcretebilecek k\u00f6k h\u00fccreler elde edildi. Elde edilen bu modifiye h\u00fccreler hastalara tekrardan verildi. Her iki hasta da 12 ayl\u0131k s\u00fcre boyunca %99\u2019dan fazla pansel\u00fclarite sa\u011flay\u0131p fetal hemoglobin seviyelerinde d\u00fczenli bir art\u0131\u015f g\u00f6sterdiler. \u03b2-talasemi hastas\u0131n\u0131n 15 ayl\u0131k, orak h\u00fccreli anemi hastas\u0131n\u0131n ise 9 ayl\u0131k tedavisi sonunda kan transf\u00fczyonuna ihtiya\u00e7lar\u0131 kalmam\u0131\u015ft\u0131. \u00c7al\u0131\u015fman\u0131n ba\u015flamas\u0131n\u0131n \u00fczerinden ge\u00e7en bir y\u0131l\u0131 a\u015fk\u0131n s\u00fcreden sonra verdi\u011fi r\u00f6portajda \u00e7al\u0131\u015fmaya orak h\u00fccreli anemi hastas\u0131 olarak kat\u0131lan Victoria Gray<\/strong> \u201cGayet iyiyim (\u2026) \u015eimdiye kadar orak h\u00fccreli anemiyle ilgili bir s\u0131k\u0131nt\u0131m olmad\u0131 (\u2026) Bu ben ve ailem i\u00e7in \u00e7ok b\u00fcy\u00fck bir \u015fey. \u0130ki y\u0131l boyunca hi\u00e7 hastaneye u\u011framad\u0131\u011f\u0131ma inanam\u0131yorum. Bunun i\u00e7in minnettar\u0131m.\u201d<\/em> ifadelerini kulland\u0131.<\/p>\n\n\n\n

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\u0130ll\u00fcstrasyon\/ Emma Verdet<\/strong><\/figcaption><\/figure>\n\n\n\n

\u00c7al\u0131\u015fma B\u00fcy\u00fcyor!<\/strong><\/h2>\n\n\n\n

\u00c7al\u0131\u015fma sonu\u00e7lar\u0131n\u0131n hem hastalar hem de bilim d\u00fcnyas\u0131 ad\u0131na umut verici olmas\u0131 \u00fczerine ekip hasta say\u0131s\u0131n\u0131 art\u0131rarak 44 \u03b2-talasemi ve 31 orak h\u00fccreli anemi hastas\u0131n\u0131 daha Faz II \u00e7al\u0131\u015fmalar\u0131na dahil etmeye karar verdi. \u015eimdiye kadar 44 \u03b2-talasemi hastas\u0131ndan 42\u2019si kan transf\u00fczyonuna ihtiya\u00e7 duymazken 31 orak h\u00fccreli anemi hastas\u0131n\u0131n hi\u00e7birinde de tedavi ba\u015flad\u0131\u011f\u0131ndan beri vazookluzif ataklara rastlanmad\u0131. 75 hasta \u00fczerinde ger\u00e7ekle\u015ftirilen Faz II \u00e7al\u0131\u015fmalar\u0131n\u0131n sonu\u00e7lar\u0131 15 Haziran\u2019da Avrupa Hematoloji Derne\u011fi\u2019ndeki bir toplant\u0131da sunuldu. Avustralya Ulusal \u00dcniversitesi\u2019nden Gaetan Burgio<\/strong> sonu\u00e7lar i\u00e7in \u201cSonu\u00e7lar CRISPR terapisi i\u00e7in kayda de\u011fer bir ba\u015far\u0131.\u201d<\/em> derken yine de \u00e7al\u0131\u015fman\u0131n t\u00fcm sonu\u00e7lar\u0131n\u0131n yay\u0131nlanmaya ihtiyac\u0131 oldu\u011funun alt\u0131n\u0131 \u00e7izdi.<\/p>\n\n\n\n

Faz III \u00e7al\u0131\u015fmalar\u0131yla bir sonraki a\u015famaya ge\u00e7meyi planlayan ekip 12-35 ya\u015f aras\u0131 hastalar \u00fczerinde elde edilen ba\u015far\u0131n\u0131n sonucunda 12 ya\u015f alt\u0131 \u00e7ocuklar\u0131 da projeye dahil ederek \u00e7al\u0131\u015fmay\u0131 geni\u015fletmeye karar verdiler.<\/p>\n\n\n\n

Ne Kadar G\u00fcvenli?<\/strong><\/h2>\n\n\n\n

Tedavinin g\u00fcvenli\u011fi konusunda \u00e7al\u0131\u015fman\u0131n i\u00e7inde yer alan Londra Imperial College\u2019dan Doktor Josu de la Fuente \u015funlar\u0131 dile getiriyor \u201cKonvensiyonel kemik ili\u011fi transplantasyonun da CRISPR tedavisinin de \u00e7ok ciddi bir dezavantaj\u0131 var. Her ikisinde de insanlar\u0131n var olan kan k\u00f6k h\u00fccrelerini kemoterapi arac\u0131l\u0131\u011f\u0131yla \u00f6ld\u00fcr\u00fcp yenileri i\u00e7in yer a\u00e7mak zorunday\u0131z. Bu da infertilite ba\u015fta olmak \u00fczere pek \u00e7ok \u00f6nemli yan etkiyi beraberinde getiriyor.\u201d<\/em> fakat kendisi ayn\u0131 zamanda gelecekte kan k\u00f6k h\u00fccrelerini \u00f6ld\u00fcrmenin, antikorlar\u0131 da i\u00e7eren yeni bir y\u00f6ntemle, kemoterapiye oranla daha g\u00fcvenli hale gelece\u011fini umut etti\u011fini belirtiyor.<\/p>\n\n\n\n

Ayr\u0131ca g\u00fcn\u00fcm\u00fczde her iki yakla\u015f\u0131m da olduk\u00e7a pahal\u0131 ve \u00fcst d\u00fczey e\u011fitimli personel gerektirmekte. Bu da en az\u0131ndan \u015fimdilik gen d\u00fczenleme y\u00f6nteminin d\u00fcnya \u00e7ap\u0131nda fayda sa\u011flayan bir tedavi y\u00f6ntemi olmas\u0131n\u0131 zorla\u015ft\u0131r\u0131yor. Zaman ge\u00e7tik\u00e7e ve CRISPR\u2019\u0131n t\u0131p d\u00fcnyas\u0131nda kullan\u0131m\u0131 art\u0131k\u00e7a inan\u0131yorum ki bu y\u00f6ntem de en ula\u015f\u0131labilir tedavilerden biri haline gelecektir.<\/p>\n\n\n\n

Son Olarak\u2026<\/strong><\/h2>\n\n\n\n

CRISPR teknolojisi kullan\u0131lmaya ba\u015flad\u0131\u011f\u0131 ilk g\u00fcnden beri etik y\u00f6n\u00fcyle de g\u00fcndeme gelen bir konu olmu\u015ftur. Hatta kimi zaman onunla ba\u015farabileceklerimizden \u00e7ok distopik yan\u0131yla biraz g\u00f6z korkutur hale gelmi\u015ftir. Fakat t\u00fcm d\u00fcnyada ve \u00fclkemizde \u00f6nemli bir sa\u011fl\u0131k sorunu olan \u03b2-talasemi ve orak h\u00fccreli anemi gibi kal\u0131tsal tek gen hastal\u0131klar\u0131na bak\u0131\u015f\u0131 ve tedaviyi bu denli ba\u015far\u0131l\u0131 bir \u015fekilde de\u011fi\u015ftirebilmesi de kesinlikle g\u00f6z ard\u0131 edilmemesi gereken bir noktad\u0131r. Tedavi edilmeyi bekleyen, tedavisi olmayan pek \u00e7ok nadir hastal\u0131k i\u00e7in yeni bir umut \u0131\u015f\u0131\u011f\u0131 olan bu y\u00f6nteme inanmaya ve desteklemeye devam edilmelidir. Etik ilkelerinden \u015fa\u015fmadan ve belli ba\u015fl\u0131 kat\u0131 d\u00fczenlemeler getirerek as\u0131l potansiyeli ortaya kondu\u011funda CRISPR teknolojisi ile \u00f6n\u00fcm\u00fczde t\u0131p d\u00fcnyas\u0131 i\u00e7in \u00e7ok parlak bir gelecek oldu\u011fu beklenen bir ger\u00e7ekliktir.<\/p>\n\n\n\n

Kaynak\u00e7a<\/strong><\/h2>\n\n\n\n

[1] https:\/\/www.newscientist.com\/article\/2324518-children-to-get-crispr-treatment-for-sickle-cell-disease-in-trial\/<\/a><\/p>\n\n\n\n

[2] https:\/\/www.newscientist.com\/article\/2246020-three-people-with-inherited-diseases-successfully-treated-with-crispr\/<\/a><\/p>\n\n\n\n

[3] Akinsheye I, Alsultan A, Solovieff N, et al. Fetal hemoglobin in sickle cell anemia. Blood. 2011;118(1):19-27. doi:10.1182\/blood-2011-03-325258<\/a><\/p>\n\n\n\n

[4] Haydar Frangoul, M.D., David Altshuler, M.D., Ph.D., M. Domenica Cappellini, M.D., Yi-Shan Chen, Ph.D., Jennifer Domm, M.D., Brenda K. Eustace, Ph.D., Juergen Foell, M.D., Josu de la Fuente, M.D., Ph.D., Stephan Grupp, M.D., Ph.D., Rupert Handgretinger, M.D., Tony W. Ho, M.D., Antonis Kattamis, M.D., et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and \u03b2-Thalassemia. N Engl J Med 2021; 384:252-260. DOI: 10.1056\/NEJMoa2031054<\/a><\/p>\n\n\n\n

[5] https:\/\/www.npr.org\/sections\/health-shots\/2021\/12\/31\/1067400512\/first-sickle-cell-patient-treated-with-crispr-gene-editing-still-thriving#:~:text=That%20involved%20doctors%20taking%20cells,more%20easily%20than%20ever%20before<\/a>.<\/p>\n\n\n\n

[6] https:\/\/www.npr.org\/sections\/health-shots\/2019\/12\/25\/784395525\/a-young-mississippi-womans-journey-through-a-pioneering-gene-editing-experiment<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

2020 y\u0131l\u0131nda Nobel Kimya \u00d6d\u00fcl\u00fc\u2019n\u00fc kazanan Emmanuel Charpentier ve Jennifer A. Doudna\u2019n\u0131n geli\u015ftirdi\u011fi, bilim tarihinde \u00e7\u0131\u011f\u0131r a\u00e7an genom d\u00fczenleme y\u00f6ntemi<\/p>\n","protected":false},"author":153,"featured_media":11474,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[1,2173],"tags":[270,149,271,115,2179,84],"acf":[],"views":978,"_links":{"self":[{"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts\/11429"}],"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\/153"}],"replies":[{"embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/comments?post=11429"}],"version-history":[{"count":12,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts\/11429\/revisions"}],"predecessor-version":[{"id":11478,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/posts\/11429\/revisions\/11478"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/media\/11474"}],"wp:attachment":[{"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/media?parent=11429"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/categories?post=11429"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blog.ulubat.org\/index.php\/wp-json\/wp\/v2\/tags?post=11429"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}