Tabo a cikin RDEB (2023)

Nirogacestat, wani magani da aka amince da shi kwanan nan a Amurka don kula da wani nau'in girma mara kyau (ciwon daji na desmoid) wanda ba shi da alaƙa da EB, an gwada shi. Ya sanya sel fata girma a cikin dakin gwaje-gwaje daga mutanen da ke da RDEB mafi koshin lafiya kuma ana iya sake yin su don rage alamun cutar ga mutanen da ke zaune tare da EB.

Masu bincike sun buga sakamakon su a cikin Journal of Investigative Dermatology a cikin 2024 kuma sun gabatar da takardar izinin mallaka mai suna "Masu hana Gamma-asiri don amfani da su a cikin maganin epidermolysis bullosa".

Kwayoyin fata (fibroblasts) daga mutanen da ke da RDEB ana girma a cikin dakin gwaje-gwaje kuma ana bincika matakan da nau'ikan kwayoyin da ake kira microRNAs da suke samarwa. Matsayin waɗannan kwayoyin halitta a cikin sarrafa tabo (fibrosis) na iya sa su zama manufa don maganin EB. An zaɓi ƙwayoyin microRNA guda huɗu don ƙarin bincike saboda suna nan a mafi girma (uku daga cikin huɗun) ko ƙananan matakan a cikin sel daga mutanen da ke da RDEB. An nuna su suna shafar fibrosis da matakai na kumburi.

Na dabam, an nuna wani magani da ake ƙera don magance ciwon daji a matsayin magani mai mahimmanci don rage tabo a cikin RDEB.

Wannan bayanan, wanda mai binciken ya bayar a cikin 2022, yana kwatanta aikin da ake ci gaba:

Farfesa Giovanna Zambruno (dama) tare da Dr Angelo Giuseppe Condorelli a dakin al'adun cell a Bambino Gesù Children's Hospital. Dokta Condorelli shine mai binciken bayan digiri na biyu da ke kula da aikin a kowace rana a cikin dakin gwaje-gwaje.

Jagoran Bincike:

Dr Giovanna Zambruno, mai ba da shawara, Bambino Gesù Children's Hospital, IRCCS, Rome, Italiya

Dr. Zambruno ta kammala karatun digiri a fannin likitanci a Jami'ar Pavia, Italiya (1982) kuma ta kammala horar da zama a fannin ilimin fata da kuma Venereology a 1985 a wannan Jami'ar. Bayan hadin gwiwar bincike a dakin gwaje-gwaje na INSERM na binciken cututtukan fata da na rigakafi da kuma a Sashen Nazarin cututtukan fata na Jami'ar Claude Bernard, Lyon, Faransa (1985-1986), ta zama ma'aikaci a Sashen Nazarin cututtukan fata, Jami'ar Modena, inda ta kafa. rukunin bincikenta na farko. A cikin 1995, ta koma Istituto Dermopatico dell'Immacolata (IDI), inda ta kasance Darakta na Laboratory of Molecular and Cell Biology (1995-2015) sannan kuma Daraktan Kimiyya (2017-2018). A halin yanzu ita ce mai ba da shawara a Asibitin Yara na Bambino Gesù, Rome, inda take haɗin gwiwa tare da Rukunin Pathology da Dermatology da Sashen Binciken Halittu da Rare Diseases. A cikin shekaru 25 da suka gabata ayyukanta na asibiti da na bincike sun mai da hankali kan cututtukan fata da ba kasafai ba, musamman gadar epidermolysis bullosa. Ta rubuta fiye da 270 wallafe-wallafe a cikin mujallun da aka yi bita na tsara, 80 daga cikinsu akan epidermolysis bullosa.

Masu bincike tare:

Dr Teresa Odorisio, Laboratory of Molecular and Cell Biology, IDI-IRCCS, Rome, Italy
Mai haɗin gwiwa: Farfesa Leena Bruckner-Tuderman, Jami'ar Universitätsklinikum Freiburg - Hautklinik, Jamus

"Runi- da kumburi-kore fibrosis ne akai-akai da kuma ci gaba siffa a cikin RDEB. Yana da alhakin samuwar hannun mittens, ƙwanƙwasa gaɓoɓi da ƙumburi na mucosal, kuma yana da tasiri a cikin haɓakar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta da wuri. Magance fibrosis yana wakiltar dabara don inganta yanayin cututtuka da ingancin rayuwar marasa lafiya. A karon farko, nazarin mu zai bincika matakan magana na adadi mai yawa na miRNA da aikinsu a cikin RDEB fibrosis. Binciken miRNA zai zama wurin farawa don ganowa da kuma raba sabbin dabarun magunguna / hanya don gaba, sabbin dabarun rigakafin fibrotic.

– Dr Giovanna Zambruno

Taken Grant: MicroRNAs a cikin dystrophic epidermolysis bullosa fibrosis: bayanin martaba, aiki da hangen nesa na warkewa

DNA ɗinmu ta ƙunshi kwayoyin halitta waɗanda ke adana bayanan don gina sunadaran da ke samar da jikinmu. Ana rubuta umarnin DNA cikin ƙwayoyin RNA da ake kira messenger RNAs (mRNAs), waɗanda ke samar da waɗannan sunadaran (fassara). Duk da haka, wasu RNA, waɗanda ake kira RNA waɗanda ba codeing ba, ba a fassara su cikin sunadarai amma suna daidaita adadin sunadaran da aka samar. MicroRNAs (miRNAs) RNA ne marasa coding waɗanda ke toshe samar da furotin ta hanyar mu'amala da takamaiman mRNAs. MiRNAs sune manyan masu kula da duk hanyoyin nazarin halittu kuma aikinsu mara kyau yana ba da gudummawa ga cututtuka da yawa, gami da cututtukan fata na fibrotic (scarring).

A cikin recessive dystrophic epidermolysis bullosa (RDEB) rashin jin daɗi ba tare da jurewa ba yana haifar da fibrosis mai tsanani wanda ke taka muhimmiyar rawa wajen haɓakar rikice-rikicen cututtuka. Ƙungiyarmu ta lura cewa wasu miRNA sun fi yawa a cikin fibroblasts daga marasa lafiya na RDEB (RDEBFs) kuma suna yin aikin pro-fibrotic a cikin vitro. Dangane da waɗannan karatun farko, aikin na yanzu yana nufin gano ƙarin miRNAs dysregulated a cikin RDEBFs da kuma nuna rawar da suke takawa a cikin mahimman hanyoyin fibrotic kamar samarwa da sakin mahimman ƙwayoyin pro-fibrotic (misali ma'aunin haɓaka mai canzawa-b1) da dermal. (fatar) taurin kai. Wannan binciken zai ba da gudummawa don faɗaɗa ilimi game da cututtukan cututtukan cututtuka da gano sabbin miRNAs da maƙasudin miRNA a matsayin maƙasudin sabbin hanyoyin kwantar da hankali don iyakance fibrosis.

DNA ɗinmu ta ƙunshi kwayoyin halitta waɗanda ke adana bayanan don gina sunadaran da ke samar da jikinmu. Ana rubuta umarnin DNA cikin ƙwayoyin RNA da ake kira messenger RNAs (mRNAs), waɗanda ke samar da sunadarai. Duk da haka, dangin ƙananan RNA, da ake kira microRNAs, ba su zama sunadaran ba amma suna tsara adadin sunadaran da aka samar. MicroRNAs suna toshe samar da furotin ta hanyar yin hulɗa tare da takamaiman mRNAs, waɗanda aka ayyana azaman maƙasudin microRNA. MicroRNAs sune manyan masu kula da duk hanyoyin nazarin halittu kuma rashin aikin su yana ba da gudummawa ga cututtuka da yawa, gami da recessive dystrophic epidermolysis bullosa (RDEB) da matsanancin rikice-rikice na asibiti, kamar kumburin fata, fibrosis da ci gaban kansa.

A cikin fibrotic kyallen takarda, fibroblasts suna samar da adadi mai yawa na sunadaran "fibrotic", galibi collagens, waɗanda aka ajiye a waje da sel, kuma suna nuna haɓakar haɓakar nama da ke kewaye da su, wanda ke haifar da taurin nama da rashin aiki. Nazarinmu na baya ya nuna cewa microRNA mai suna miR-145-5p, ya fi yawa a cikin fibroblasts daga marasa lafiya na RDEB kuma ya nuna rawar da yake takawa a cikin hanyoyin fibrotic. A cikin wannan aikin mun kimanta ɗimbin ɗaruruwan microRNA guda ɗaya kuma mun fara bincika ayyukansu. Mun gano rukuni na 36 microRNAs da aka soke su a cikin RDEB fibroblasts (wato kwayoyin aƙalla sau biyu fiye da ƙasa da yawa dangane da sel daga masu ba da gudummawa lafiya). Bayan haka, mun zaɓi don ƙarin bincike microRNA guda huɗu, waɗanda ke cikin ƙara ko rage adadin a cikin ƙwayoyin RDEB idan aka kwatanta da sarrafawa. Mun lura cewa gyare-gyaren magunguna na waɗannan microRNAs na iya magance samar da sunadaran fibrotic na yau da kullun ta RDEB fibroblasts.

Hakazalika, mun zurfafa nazarinmu akan sabon tsarin kwayoyin halitta da aka gano da ke cikin RDEB fibrosis, mai suna Notch pathway. Hanya ta salon salula ta ƙunshi tsari mai tsari na ayyuka da takamaiman ƙwayoyin cuta (mai suna mambobi), haifar da al'amuran rayuwa daban-daban, kamar rarraba tantanin halitta, motsi ko fibrosis. Nazarinmu ya nuna cewa hanawar hanyar Notch ta hanyoyi daban-daban, gami da magunguna da ake samu a kasuwa amma har zuwa yau ana amfani da su don magance cututtuka daban-daban daga RDEB, da alama yana rage halayen pro-fibrotic da yawa a cikin ƙwayoyin RDEB. A cikin daki-daki, RDEB fibroblasts da aka bi da su tare da takamaiman kwayoyin da ke rage ayyukan Notch suna nuna raguwar iyawa i) don kwangilar gels collagen (wanda ke wakiltar samfurin iyawar fibroblasts don rage ƙwayar da ke kewaye), ii) don saka sunadaran "fibrous" (collagens) a wajen tantanin halitta, iii) don ɓoye mafi mahimmancin kwayoyin fibrotic, watau canza girma factorbeta1, iv) don motsawa. da kuma yaɗuwa, da (v) don samar da nau'ikan ƙwayoyin cuta masu yawa waɗanda galibi suna da yawa a cikin kyallen jikin fibrotic. Haɗe tare, bayananmu suna goyan bayan dacewar ilimin halitta na hanyar Notch a cikin hanyoyin cututtukan da ke da alaƙa da RDEB, da hana ta azaman ingantacciyar hanyar warkewa don magance fibrosis na fata. (Daga rahoton ci gaba na 2022).

Kayan kwayoyin halittar mu (jerin DNA da RNA) suna adanawa da watsa bayanan don samar da dukkan sassan jiki, gami da sunadarai da enzymes, da aiwatar da kowane muhimmin tsari. Adadin da ya dace da aikin kowane kwayoyin halitta yana da mahimmanci don tabbatar da aikin nama da gabobin jiki kuma, don haka, don kiyaye lafiya. Musamman, yawan furotin ana sarrafa su ta hanyar hanyoyin kwayoyin halitta daban-daban, gami da aikin microRNAs - dangi mai fadi (> membobi 2500) na gajerun kwayoyin RNA tare da ayyuka na tsari.

MicroRNAs suna dakatar da samar da furotin ta hanyar hana “canzawa” samfuran furotin, da ake kira RNAs Messenger (mRNAs), zuwa sunadaran. Kowane microRNA yana daidaita takamaiman saitin mRNAs/protein, wanda aka ayyana azaman maƙasudin microRNA ta hanyar dogaro da tantanin halitta da mahallin. Rashin aiki na MicroRNAs yana ba da gudummawa ga cututtuka iri-iri, gami da nau'in dystrophic na epidermolysis bullosa (RDEB) da rikice-rikicensa na asibiti, kamar kumburi, fibrosis da ci gaban kansa.

A cikin fibrotic kyallen takarda, babban dermal-mazaunin sel, da ake kira fibroblasts, suna samar da adadi mai yawa na sunadaran "fibrous" da kwayoyin "pro-fibrotic", wanda ke taimakawa wajen taurin fata da rashin aikin fibroblast.

A cikin wannan binciken, mun gano kuma mun bincika aikin nazarin halittu na microRNA guda biyu, miR-129-1-3p da miR-210-3p, waɗanda aka gano suna dysregulated a cikin fibroblasts da aka samu daga marasa lafiya tare da RDEB (RDEB-FBs). Musamman, an ƙara adadin miR-210-3p a cikin RDEB-FBs yayin da aka rage miR-129-1-3p idan aka kwatanta da sel daga masu ba da gudummawa lafiya. A cikin RDEB-FBs, hanawa na pharmacological na miR-210-3p ta hanyar kwayoyin da aka ayyana "anti-miR" ya rage ikon RDEB-FBs don motsawa, abin da ake kira "yawan ƙaura", da kuma haɗa pro-fibrotic sunadaran. , ciki har da rukuni na kwayoyin da ke da hannu a cikin amsawar salula zuwa lalacewa mai lalacewa. A cikin gwaje-gwaje daban-daban, haɓakar matakan miR-129-1-3p ta hanyar ƙwayar cuta da aka ayyana "mimic" (miR-129-1-3p-mimic) rage ƙanƙantar ƙwayar ƙwayar cuta - alama ce ta pro-fibrotic fibroblasts - kuma an rage shi. Maganar zaɓi na pro-fibrotic sunadaran. Waɗannan binciken suna nuna tasirin anti-fibrotic na miR-129-1-3p kuma, bi da bi, mummunan tasirin raguwar sa a cikin fibroblasts marasa lafiya.

Daga baya, mun gano kuma mun inganta ingantaccen furotin pro-fibrotic novel wanda miR-129-1-3p ya tsara, ma'ana cewa ƙananan matakan miR-129-1-3p (kamar yadda muka lura a cikin RDEB fibroblasts) sun dace da manyan matakan wannan sabon miR. -129-1-3p manufa ta kwayoyin halitta.

A layi daya, mun kammala binciken da ke kwatanta aikin pro-fibrotic na membobin hanyar NOTCH a cikin RDEB fibrosis. A cikin daki-daki, bincikenmu da aka samu a cikin fibroblasts daga marasa lafiya tare da RDEB sun nuna cewa hanawar NOTCH siginar cascade ta PF-03084014 (nirogacestat), kwayar halittar dangin gamma-secretase inhibitors, da alama tana haɓaka halayen fibrotic daban-daban waɗanda suka fito daga ƙaddamar da collagen zuwa ga ɓoye na fibrosis-inducing factor TGF-ß1 da kuma samar da pro-fibrotic sunadaran. Na bayanin kula, PF-03084014 an amince da shi kwanan nan ta FDA don maganin ciwace-ciwacen daji da kuma sayar da shi azaman Ogsiveo TM ta SpringWorks Therapeutics Inc. A nan gaba, ana iya amfani da wannan miyagun ƙwayoyi da kyau don sake dawowa don amfani da shi azaman wakili na anti-fibrotic a RDEB. A ƙarshe, bayananmu suna goyan bayan mahimmancin ilimin halitta na hanyar NOTCH a cikin hanyoyin cututtukan da ke da alaƙa da RDEB, da hana ta ta takamaiman ƙwayoyin cuta azaman ingantaccen dabarun warkewa don magance fibrosis na fata a cikin RDEB. (Daga rahoton karshe na 2024).