Mayar da magungunan rigakafin tabo a cikin RDEB (2023)

Masu bincike sun gano cewa kwayoyi guda biyu (givinostat da valproic acid) sun taimaka wajen samar da kwayoyin fata na RDEB da ke girma a cikin dakin gwaje-gwaje. Valproic acid kuma ya sami damar rage alamun RDEB waɗanda ke shafar idanu, gashi da fata. Valproic acid an yarda da shi kuma ana amfani dashi ko'ina don wasu yanayi. Wannan aikin yana ba da shaida don tallafawa sake dawowa don jinkirin farawa da ci gaba da bayyanar cututtuka a cikin mutanen da ke zaune tare da RDEB.

Masu bincike sun buga bita na aikin su akan fibrosis na fata a cikin 2021.

Dokta Daniele Castiglia masanin ilimin kwayoyin halitta ne kuma Daraktan dakin gwaje-gwaje na kwayoyin halitta da kwayoyin halitta a Istituto Dermopatico dell'Immacolata, IDI-IRCCS a Roma. Yana da fiye da shekaru 20 yana aiki a fagen EB da sauran genodermatoses waɗanda ke samun takamaiman ƙwarewar da suka shafi tushen kwayoyin halitta da haɗin gwiwar genotype-phenotype. Ayyukan bincikensa yana mai da hankali kan salon salula da hanyoyin ƙwayoyin cuta na rikice-rikice na EB don bayyana sabbin maƙasudai don hanyoyin magance cututtukan cututtukan.

"Shawarwarinmu na nufin gwada yiwuwar warkewa na magungunan epigenetic guda biyu, waɗanda aka riga aka yi amfani da su a matakan asibiti a cikin wasu cututtukan fibrotic."

- Dr Daniele Castiglia

Taken Bayar: Ƙwararrun magungunan anti-fibrotic na histone deacetylase inhibitors (HDACi) don recessive dystrophic epidermolysis bullosa.

Bincike ya nuna cewa kura-kuran kwayoyin halitta da ke haifar da rashin collagen VII ba shine kawai dalilin tsananin cutar ba a cikin recessive dystrophic epidermolysis bullosa (RDEB). Sauran kwayoyin halitta, da ake kira 'genes modifier', (genes masu tasiri ko canza bayanin wani jinsin), kuma suna iya inganta ko cutar da cututtuka dangane da ayyukansu. Wadannan kwayoyin halitta masu gyara da tasirin su ana iya yin niyya ta hanyar warkewa (don gwadawa da nemo magani) don rage bayyanar cututtuka da yiwuwar canza yanayin cutar. Ana iya yin wannan ban da niyya ga kuskuren asali na asali.

Canje-canje na gado ko "epigenetic" sune waɗanda ke canza kunna kwayoyin halitta ba tare da canza DNA ɗin mu ko jerin kwayoyin halitta ba. Suna iya ɗaukar alhakin bambance-bambance a cikin kwayoyin halitta masu gyara.

Babban damuwa a cikin RDEB shine kasancewar kumburi da fibrosis mai ci gaba na fata da mucosae (kogon baki, esophagus, da dai sauransu) wanda ke haifar da matsaloli masu tsanani, irin su mitten deformities (fusion na yatsunsu), m (narrowing na esophagus) da kuma EB hade da ciwon daji. An danganta shi da wannan, sunadaran da ake kira TGF-β wanda ke kunna amsawar tantanin halitta da yawa, yana haifar da siginar kwayoyin da ke da alhakin RDEB fata fibrosis farawa da ci gaba.

Sakamakon gwaji ya nuna cewa sauye-sauye na epigenetic na iya rinjayar rashin lafiyar RDEB ta hanyar ƙarfafa sel zuwa fibrosis lokacin da fata ta ji rauni kuma wannan zai iya zama manufa don magani. Wannan rukunin ya gano cewa ƙananan ƙwayoyi da ke da alaƙa da nau'in nau'in canjin epigenetic guda ɗaya da ake kira histone acetylation (kwayoyin da ke tasiri akan yadda DNA ke ninka fiye da kwayoyin halitta) na iya rage RDEB fibrosis da aikin TGF-β.

Wannan shawarar tana nufin gwada hanyoyin warkewa ko yuwuwar jiyya na magungunan “epigenetic” guda biyu, waɗanda aka riga aka yi amfani da su a asibiti a cikin wasu cututtukan fibrotic, a cikin raguwa da jinkirta rikice-rikice masu alaƙa da cuta a cikin ƙirar dakin gwaje-gwaje na RDEB.

DNA (jan kirtani) an nannade shi a kusa da histones (blue beads). Ƙwaƙwalwar DNA tana haɗuwa da kwayoyin halitta marasa aiki yayin da gyare-gyaren tarihi, wanda ake kira acetylation (Ac) yana ba da damar DNA ta zama ƙasa taƙunta, matsayi wanda yawanci yana ba da damar kunna kwayoyin halitta. Ta hanyar hana histone deacetylases (HDACs), magungunan epigenetic, kamar givinostat da valproic acid, suna ba da damar haɓakar acetylation na histone, don haka inganta maganganun kwayoyin halitta. Za a iya kunna ƙwayoyin gyare-gyare tare da tasirin anti-fibrotic.

Ƙungiyar za ta binciki iyawar waɗannan "epidrugs" don daidaita maganganun kwayoyin halitta don taimakawa wajen magance fibrosis a cikin fata na RDEB. Magunguna guda biyu da za a gwada a cikin wannan yanki na bincike sune givinostat, mai hana histone deacetylation (HDACi) wanda ke cikin gwaji na asibiti don yanayi da yawa, da kuma maganin da aka amince da shi da ake kira valproic acid wanda ke da lasisi don wasu yanayin kiwon lafiya, dukansu sun sani. don samun tasirin antifibrotic da aka nuna a cikin bincike na baya. Sakamako daga wannan binciken da fatan zai haifar da ƙarin gwaji na asibiti mai yiwuwa sake dawowa ko sake amfani da kwayoyi don magance fibrosis na RDEB da matsalolin da ke tattare da shi.

Yawancin abubuwan lura sun tabbatar da cewa adadin collagen VII ba shine kawai dalilin tsananin cutar ba a cikin marasa lafiya na dystrophic epidermolysis bullosa (RDEB); wasu kwayoyin halitta, da ake kira genes modifier, na iya inganta ko kara tsananta bayyanar cututtuka dangane da ko sun fi ko žasa aiki. Saboda haka, kwayoyin halitta masu gyara da tasirin su za a iya niyya ta hanyar warkewa don rage alamun bayyanar cututtuka da inganta yanayin cutar.

Babban damuwa a cikin RDEB shine kasancewar kumburi da fibrosis na ci gaba (induration) na fata da mucosae (kogon baki, esophagus, da dai sauransu) wanda ke haifar da bayyanar cututtuka mai tsanani, irin su mitten deformities, tsaurara da ciwon daji. TGF-β, furotin da ke kunna amsawar salula da yawa, yana haifar da siginar kwayoyin da ke da alhakin RDEB fata fibrosis farawa da ci gaba.

Canje-canje na gado waɗanda ke canza kunna kwayoyin halitta ba tare da canza jerin DNA ɗinmu ba ana san su da canje-canjen epigenetic. Suna iya ɗaukar alhakin bambance-bambance a cikin kwayoyin halitta masu gyara da kuma cikin bayyanar asibiti a cikin daidaikun RDEB.

Mun gano cewa ƙananan ƙwayoyi masu niyya ga babban canjin epigenetic, histone acetylation, na iya rage RDEB fibroblast fibrosis da TGF-β aiki.

Shawarar mu tana nufin gwada yuwuwar hanyoyin warkewa na magungunan epigenetic guda biyu, waɗanda aka riga aka yi amfani da su a matakan asibiti a cikin wasu cututtukan fibrotic, a ragewa da jinkirta bayyanar cututtuka na samfurin RDEB. Mun gano cewa daya daga cikin magungunan biyu yana iya magance fibrosis na fata da ci gaba da cututtuka ta hanyar rage mummunan bayyanar cututtuka irin su asarar lambobi da tabo na corneal. Ana ci gaba da gudanar da bincike don gano illolin ƙwayoyin cuta da kuma salon salula na sarrafa magunguna. (Daga rahoton ci gaba na 2022).

Yawancin abubuwan lura sun tabbatar da cewa adadin collagen VII ba shine kawai dalilin tsananin cutar ba a cikin marasa lafiya na dystrophic epidermolysis bullosa (RDEB); wasu kwayoyin halitta, da ake kira "genes modifier", na iya inganta ko kara tsananta bayyanar cututtuka dangane da ko sun fi ko žasa aiki. Don haka, kwayoyin halitta masu gyara da tsarinsu da ayyukansu za a iya niyya ta hanyar warkewa don rage alamun cututtuka da inganta yanayin cutar. Alal misali, canje-canje a cikin bayyanar cututtuka na decorin da TGF-β, kwayoyin halitta guda biyu da ke cikin microenvironment na fata, an ruwaito su a cikin RDEB kamar yadda aka danganta da rashin lafiyar cututtuka, kuma binciken guda biyu ya nuna cewa isar da decorin a cikin fata wanda RDEB ke inganta phenotype. ta hanyar magance ayyukan TGF-β, wanda ya wuce gona da iri yana haifar da siginar kwayoyin da ke da alhakin farawar fibrosis na fata da ci gaba. Lalle ne, babban damuwa a cikin RDEB shine kasancewar kumburi da fibrosis na ci gaba (induration) na fata da mucosae (rashin baki, esophagus) wanda ke haifar da bayyanar cututtuka mai tsanani, irin su mitten deformities, tsaurara da ciwon daji.

Canje-canje na gado waɗanda ke canza ayyukan kwayoyin halitta ba tare da canza jerin DNA ba an san su da canje-canjen epigenetic. Suna iya ɗaukar alhakin bambance-bambance a cikin kwayoyin halitta masu gyara da bayyanar asibiti a cikin daidaikun RDEB. Sakamakon aikinmu yana nuna cewa babban canjin epigenetic, wanda aka sani da histone acetylation, an canza shi a cikin fata na RDEB. Bayan haka, mun gano "magungunan epigenetic" guda biyu (givinostat da valproic acid) waɗanda suka yi niyya ga histone acetylation kuma sun gano cewa duka biyun suna iya magance halayen profibrotic na fibroblasts na al'ada daga mutane RDEB, gami da rage ayyukan TGF-β.

Shawarar tamu ta kasance da nufin gwada ƙarfin waɗannan magunguna guda biyu, waɗanda aka riga aka gwada su a cikin wasu cututtukan fibrotic a matakin farko, a ragewa da jinkirta bayyanar cutar RDEB a cikin ƙirar linzamin kwamfuta na RDEB. Mun gano cewa valproic acid ya iya magance fibrosis na fata da kuma magance matsalolin cututtuka da kyau, kamar asarar lambobi da tabo na corneal. Wannan miyagun ƙwayoyi yana aiki ta hanyar magance tasirin TGF-β, (ƙaddamar da matrix mara kyau, haɓaka haɓakar ƙwayoyin cuta, kunna hanyoyin siginar profibrotic da protumorigenic). Kamar yadda aka yarda da valproic acid kuma ana amfani da shi sosai a cikin aikin asibiti don yanayin da ba fata ba, ana iya sake dawo da shi don magance farkon da ci gaban fibrosis kuma a cikin daidaikun RDEB. (Daga rahoton ƙarshe na 2023.)