Fahimtar cututtukan iska a cikin JEB (2023)

Jarirai 3 da ke da alamun iska sun yi gwajin kwayoyin halitta wanda ya nuna goma sha uku daga cikinsu suna da JEB, biyu suna da EBS kuma daya yana da RDEB. Wani ƙayyadadden ƙwayar laminin (LAMA3) yana da canje-canjen kwayoyin halitta a cikin goma daga cikin marasa lafiya, yana nuna cewa, ko da yake hanyar iska na iya shafar wasu nau'in EB wannan alamar ta fi dacewa idan canjin kwayoyin halitta ya kasance a cikin LAMAXNUMX. Canje-canjen kwayoyin halitta a cikin kwayoyin laminin suna hana furotin laminin yin su kuma suna haifar da alamun JEB saboda ƙwayoyin fata ba za su iya tsayawa da kyau ba tare da shi ba.

An yi amfani da biopsies na hanyar jirgin sama daga huɗu daga cikin marasa lafiya don haɓaka ƙwayoyin EB na iska a cikin dakin gwaje-gwaje. Masu bincike sun nuna cewa sun rasa furotin laminin da aka yi daga kwayoyin LAMA3. Idan aka kwatanta da sel daga mutanen da ba tare da EB ba, ƙwayoyin 'hanyar iska EB' ba su da kyau wajen manne wa tasa al'adun tantanin halitta. An ƙirƙiri maganin ƙwayar cuta don sanya ƙwayar halittar LAMA3 mai aiki a cikin sel 'tashin iska EB'. Lokacin da sel suka fara yin furotin daga sabon kwayar halitta, sun zama masu kyau kamar ƙwayoyin EB waɗanda ba na EB ba a manne wa tasa al'adun tantanin halitta.

A nan gaba, waɗannan ƙwayoyin za su buƙaci girma ta hanyar da likitocin fiɗa za su iya amfani da su don maye gurbin gurɓatattun hanyoyin iska a cikin marasa lafiya na EB. Don tabbatar da cewa hakan mai yuwuwa ne, masu bincike sun yi aiki akan tsari, ta yin amfani da tallafin da aka buga na 3D don haɓaka ƙwayoyin hanyar iska zuwa cikin grafts da dasa su cikin nasara.

Wannan maganin kwayoyin halitta yana buƙatar ƙarin haɓakawa kafin ya iya taimakawa mutanen da ke da alamun hanyar iska ta EB amma wannan binciken ya nuna cewa irin wannan magani yana yiwuwa.

An buga sakamakon wannan aikin a cikin 2024: Maganar Lentiviral na nau'in daji na LAMA3A yana mayar da mannewar tantanin halitta a cikin ƙwayoyin basal na iska daga yara masu epidermolysis bullosa kuma an bayyana shi a cikin labarin sharhi: Na LAMA3 da LAMB3: Wani sabon labari na maganin ƙwayar cuta don epidermolysis bullosa. Har ila yau, epidermolysisbullosanews.com ya rufe aikin a cikin labarin harshe na fili: Hanyar maganin kwayar halitta da kwayar halitta tana nuna alkawari ga yaran EB.

An yi amfani da kwayar cutar da aka gyara don samun nasarar sanya kwayoyin halittar laminin da ke aiki cikin sel da aka girma daga biopsies na marasa lafiya. An sake maimaita wannan tsari kuma an inganta shi don nemo hanya mafi kyau don shigar da sabon kwayar halitta a cikin sel da yawa gwargwadon yiwuwa. Masu bincike na iya nuna cewa ana yin furotin laminin a cikin sel marasa lafiya bayan wannan magani kuma sel suna manne tare da kyau.

An yi zane-zanen furotin kuma an nuna sun dace da girma Layer na ƙwayoyin fata akan. Wannan tsari na iya yin dashen da za a gwada don ganin ko ƙwayoyin sun tsira. Idan yana aiki, za a iya ƙirƙira sassan jikin marasa lafiya.

Jagoran Bincike:

Mr Colin Butler, Pediatric ENT Fellow / Babban Babban Malami, UCL Great Ormond Street Institute of Child Health, London

Colin Butler kwararre ne a asibitin Great Ormond Street kuma yana da sha'awar kula da yara masu mahimmancin matsalolin hanyar iska. Ya gudanar da aikin tiyata a wannan yanki kuma yana da gogewa wajen dashen fata zuwa hanyar iska. Yanzu yana cikin ƙungiyar da ke kula da yaran da ke da EB da ke shafar hanyar iska. PhD ɗin sa ya kasance a cikin maganin farfadowa kuma an ba shi kyautar haɗin gwiwar Wellcome hanyar bincike don faɗaɗa manya manyan ƙwayoyin sel zuwa hanyoyin maganin epithelial don hanyar iska. Ya buga da yawa a filin jirgin sama kuma yana da gogewa wajen haɓaka kayayyaki daga 'bench zuwa gefen gado'.

Masu nema:

Farfesa Sam Janes, Shugaban Sashen Bincike na Numfashi a UCL; Farfesa Paolo De Coppi, Kwararren Neonatal a UCL - Tare da haɗin gwiwar: Dr Gabriela Petrof, Dr Anna Martinez, Mr Richard Hewitt (Likitan Otolaryngologist Ear Nose and Throat GOSH)

“EB da ke shafar hanyar iska wani lamari ne da ba kasafai ba amma ga wadanda abin ya shafa yanayin yana haifar da matsananciyar matsalar numfashi saboda tabon. Wadanda abin ya shafa suna da bututun numfashi da suke kanana da zai yi kama da numfashi ta bambaro. Zaɓuɓɓukan asibiti suna da ƙayyadaddun iyaka tare da hanya ɗaya tilo da za a magance kunkuntar hanyar iska ita ce faɗaɗa hanyar iska tare da balloon. Yayin da dilation zai iya taimakawa wajen rage raguwa nan da nan, ƙarin rauni yana haifar da ƙarin tabo. Wannan binciken yana nufin fahimtar wannan tsari da haɓaka hanyoyin magance shi, musamman ta hanyar haɓaka sabbin hanyoyin haɓaka fata na musamman don hanyar iska. Fatan ita ce ta hanyar magance hanyar iska, za a iya kaiwa ga sauran wurare ta hanyar amfani da irin wannan fasaha. Samun damar yin maganin tabon iska da mucosa na iska wanda aka yi daga jikin majiyyaci zai canza da gaske yadda za mu iya magance wannan cuta.”

- Dr Colin Butler

Taken Grant: Haɗaɗɗen cell epithelial na numfashi da jiyya don inganta alamun numfashi a cikin yara tare da junctional epidermolysis bullosa (JEB)

Epidermolysis bullosa (EB) cuta ce ta kwayoyin halitta inda marasa lafiya ke fama da kyallen kyallen takarda masu rauni wanda ke raɗaɗi da tabo tare da ƙarancin rauni. Ya fi shafar fata na waje, duk da haka, akwatin murya da bututun iska na iya tasiri sosai. Zaɓuɓɓukan jiyya don hanyar iska EB suna da iyaka sosai kuma galibi waɗanda abin ya shafa za su sami wahalar haɗiye kuma suna iya fuskantar matsanancin wahalar numfashi daga tabo ta iska. Ƙarshe na toshewar iska yana haifar da buƙatar tracheostomy, hanyar likita don taimakawa wajen buɗe hanyar iska. Binciken da aka yi a wannan yanki ya gano cewa fatalwar fata a cikin hanyar iska na iya samar da yiwuwar isar da kwayoyin halittar da aka gyara ta hanyar iska don taimakawa wajen samar da yiwuwar maganin cutar iska a cikin EB.

Halin da za a mayar da hankali a kai a cikin wannan aikin shine kwayoyin LAMA3, wanda ke da alhakin gina jiki na laminin. Wannan furotin yana da mahimmanci don taimaka wa sel su haɗu da juna don samar da ƙarfi ga fata da sauran kyallen takarda da aka samu a cikin hanyoyin iska, da kuma shiga cikin tsarin warkar da rauni. Aikin a nan yana nufin gano ko tushen jiyya na iya taimakawa tare da gyara layin jirgin da EB ya shafa. Za a yi amfani da kwayoyin halitta daga hanyar iska da kuma kwayar halittar LAMA sannan a gyara a waje da jiki a sake dawo da ita don ganin ko wannan dabarar za ta yi aiki don dakatar da cutar ta iska.

Babban makasudi 3 na wannan aikin shine isar da kayan aikin dakin gwaje-gwaje don samfurin cutar ta hanyar iska ta EB, da kuma amfani da kayan aikin gyaran kwayoyin halitta don gyara layin jirgin da EB ya shafa.

Manufa 1: Fahimtar zurfin zurfi game da epithelium (nama) waɗanda ke shafar hanyoyin iska a cikin junctional EB;

Manufa 2: Ƙirƙirar hanyoyin da za a iya amfani da su don gyaran kwayoyin halittar LAMA3 ta amfani da ƙwayoyin cuta, ( ƙwayoyin cuta da aka yi amfani da su azaman hanyar sadar da ingantaccen kwayar halitta);

Manufa 3: Gwaji don ganin yadda ake karɓar maganin da aka gyara na LAMA3 a cikin tsarin rayuwa.

Waɗannan gabaɗayan manufofin su ne don taimakawa samar da matukin jirgi ko bayanan farko game da hanyoyin da aka tsara don cutar ta hanyar iska ta EB da kuma samar da albarkatu da ba kasafai ba na layin salula na farko, (ƙwararrun sel don haɓaka fahimtar kimiyya), don haɓaka dabarun magani na keɓaɓɓen.

Wannan bincike na iya buɗe yiwuwar gyara nau'ikan EB wanda kuma ya shafi sauran kyallen takarda a cikin jiki, ciki har da corneal (ido) epithelium da mucous membranes na aerodigestive fili, (hanci, lebe, baki, harshe, makogwaro, muryoyin murya da babba. wani bangare na esophagus da bututun iska).

Ikon samar da layukan salula don cutar ta iska a cikin EB ta yin amfani da wannan fasaha kuma za ta buɗe haƙiƙan gwajin ƙwayar cuta na keɓaɓɓen don tantance yawan ƙananan ƙwayoyin ƙwayoyin cuta. Wannan yana nufin gano takamaiman magani ga mutum ta amfani da bayanan da aka tattara daga wannan binciken.

Epidermolysis bullosa (EB) rukuni ne na cututtukan fata da ba kasafai ba kuma ya haɗa da rabuwar nama tare da samuwar blister a cikin nau'ikan fata daban-daban. A cikin nau'in EB mafi tsanani, wanda ake kira junctional EB, wasu marasa lafiya da abin ya shafa suna haifar da matsalolin hanyar iska baya ga raunukan fata. Samuwar blister tare da tabo da kauri suna faruwa a cikin babbar hanyar iska kuma hakan yana toshe hanyar iska. Ko da bayan an cire kyallen da ke toshewa, hanyar iskar da ta lalace tana fuskantar ƙarin rauni saboda sake kamuwa da cuta kuma a ƙarshe tana haifar da jijiyar iska, wanda zai iya zama ba za a iya warkewa ba. Yawan mace-mace na marasa lafiya na EB tare da shigar da jirgin sama ya sa mu samar da magani. A cikin ƙungiyar majiyyatan mu a Babban Asibitin Titin Ormond, mun gano cewa majinyatan EB da ke da hanyar iska suna ɗaukar maye gurbi na DNA a cikin kwayar halitta mai suna LAMA3. Ƙungiyarmu ta ciro kuma ta girma ƙwayoyin hanyar iska na marasa lafiya a cikin dakin gwaje-gwaje. An shigar da kwafin DNA na LAMA3 mai aiki a cikin kwayoyin halittar waɗannan sel. Sakamakonmu ya nuna cewa wannan maganin kwayoyin halitta zai iya mayar da kwayoyin marasa lafiya na EB zuwa aiki na yau da kullum idan aka kwatanta da sel daga mutane na al'ada. Mataki na gaba na aikinmu zai kasance yana haɓaka ingancin hanyar maganin kwayoyin halitta da inganta hanyar tiyata don sadar da ƙwayoyin da aka gyara zuwa manyan hanyoyin iska. (Daga rahoton ci gaba na 2022).

Masu bincike a Jami'ar College London da Great Ormond Street Hospital for Children (GOSH) an ba su tallafin DEBRA don aikin su na inganta rayuwar majinyatan EB da ke fama da matsalolin babbar hanyar iska.

A cikin kashi na farko na binciken su, masana kimiyya sun mayar da hankali kan fahimtar takamaiman bukatun majinyatan EB da ake magana a kai ga sashen kunne, hanci, da makogwaro a GOSH. Binciken ya haɗa da marasa lafiya 15, maza da mata, tare da matsakaicin shekaru fiye da watanni 9 a lokacin da aka ba da izini. Daga cikin waɗannan marasa lafiya, an gano nau'ikan nau'ikan EB daban-daban, tare da Junctional Epidermolysis Bullosa-Simplex (JEB-S) wanda ya fi kowa. Binciken kwayoyin halitta na wannan rukunin marasa lafiya ya nuna cewa tara daga cikin 14 marasa lafiya suna da bambance-bambancen cututtuka a cikin takamaiman kwayar halitta, LAMA3, yana nuna cewa wannan kwayar halitta tana da wani hali na haifar da matsalolin iska.

Ƙungiyar binciken ta sami nasarar kafa al'adun tantanin halitta daga biopsies na iska daga marasa lafiya hudu tare da 'takar iska EB', ba su damar yin nazarin sel a cikin dakin gwaje-gwaje. Sun gano cewa akwai karancin kwayoyin halittar LAMA3 da furotin a cikin sel a cikin al'ada, kuma sel sun kasa yin aiki da jita-jita na al'adun filastik da kuma sel daga masu ba da gudummawar EB. Wannan yana nuna cewa ƙirar tantanin halitta yana da amfani don ƙarin nazarin hanyar iska ta EB, kuma ana iya amfani da ita don gwada yuwuwar hanyoyin warkewa.

Gina kan fahimtar da aka samu daga Aim 1, ƙungiyar binciken sannan ta samar da ƙwayoyin cuta na lentiviral don isar da LAMA3 zuwa sel epithelial na iska wanda aka girma cikin al'adar tantanin halitta. Aikace-aikacen vector na LAMA3 zuwa sel masu haƙuri na EB na iska ya haifar da karuwa mai yawa a cikin LAMA3 RNA da bayanin furotin. Mafi mahimmanci, gyaran gyare-gyaren sel na EB marasa lafiya na iska sun nuna ingantattun haɗe-haɗe na tantanin halitta, kuma sun kasance kwatankwacin sel masu ba da gudummawa marasa EB. Wannan binciken yana nuna cewa gyaran gyare-gyare na maganganun LAMA3 na iya yuwuwar magance lahanin mannewar tantanin halitta ga wasu marasa lafiyar EB na iska.

Don ci gaba da binciken, masanan za su buƙaci samun damar ɗaukar sel da aka gyara daga al'ada da dasa su zuwa hanyoyin iska. Duk da haka, ba kamar na fata ba, a halin yanzu babu wata hanyar tiyata da za ta ba da damar yin hakan yayin da ake kiyaye hanyoyin iska. Don haka, ƙungiyar ta gwada gwajin ƙwayar ƙwayar cuta ta epithelial ta amfani da samfurin tiyata. Sun keɓe ƙwayoyin basal na iska kuma sun girma a cikin yanayin al'adar tantanin halitta kama da waɗanda aka yi amfani da su don marasa lafiyar EB a baya, sannan suka haɓaka na'urar bugu na 3D na musamman waɗanda aka tsara don tallafawa grafts na sel na tracheal epithelial. Binciken bayan tiyata ya nuna nasarar haɓakar ƙwayoyin halitta. Mahimmanci, wannan yana buɗe ƙofa ga yuwuwar sel autologous na tsohuwar vivo don bunƙasa bayan dasawa a cikin yanayin da ya dace da asibiti.

Sakamakon wannan binciken yana ba da bege cewa a nan gaba zai yiwu a haɗa magungunan ƙwayoyin cuta da kwayoyin halitta don ƙirƙirar sabon bayani ga marasa lafiya tare da bayyanar iska na EB. Ci gaban da aka samu wajen fahimtar tushen kwayoyin halitta na hanyar iska ta EB, haɓaka dabarun gyaran kwayoyin halitta, da samun nasarar shigar da ƙwayoyin halitta a cikin nau'in dabba mai kama da ɗan adam ta hanyar tiyata yana nuna yuwuwar hanyoyin warkewa. Matakai na gaba a cikin wannan binciken za su kasance don daidaita ƙwayoyin lentiviral don dacewa da amfani ga marasa lafiya, da kuma ƙara haɓaka inganci da sake haifuwa na dashen tantanin halitta.