Utsi pa RDEB gene therapy (2022)

Ma virus asanu atsopano a gene therapy adapangidwa ndipo akuphunziridwa pano kuti awone momwe amabwezeretsera mapuloteni a collagen omwe akusowa m'maselo kuchokera kwa odwala a RDEB.

Maselo a khungu, otchedwa keratinocytes ndi fibroblasts, akhala akukulira mu labotale ndipo akuwonetsedwa kwa nthawi yoyamba kuti adziunjike m'magulu monga momwe amawonekera pakhungu pambuyo popopera mankhwala.

Mtundu wina wa fibroblast umathandizira kuchiritsa popanda mabala ndipo izi zidasonkhanitsidwa bwino ndikukulitsidwa mu labotale kuchokera ku maselo a odwala a RDEB ndikuwumitsidwa kuti agwiritse ntchito mtsogolo.

Njira yopopera mankhwala a jini yayesedwa kuti kuyesa kwachipatala kupitirire ngati njira ina iliyonse mwa njira zisanu zatsopano zothandizira jini zimagwira ntchito bwino m'maselo.

Ochita kafukufuku adasindikiza ndemanga za kuthekera kwa ntchito yawo kumapeto kwa 2021 ndi adalembetsa kuwunika mwadongosolo mu 2022. Mu May 2022 Dr Lwin ndi Prof McGrath anavomereza ndalama kuchokera ku DEBRA UK m'nkhani yakuti Kubwezeretsa mtundu VII collagen pakhungu.

Lewofufuza zamalonda: Dr Su Lwin ndi Registrar wa Dermatology ndi Honorary Clinical Research Fellow ku St John's Institute of Dermatology, Guy's ndi St Thomas' NHS Foundation Trust, ndi King's College London. Amagwira ntchito pa kafukufuku wa EB ngati Lead Clinical Research Fellow pamayesero angapo ochita upainiya a jini ndi ma cell kuyambira 2014 pomwe adalowa nawo Prof John McGrath's Lab, kuphatikiza mayeso a EBSTEM, GENEGRAFT ndi LENTICOL-F. Akupitiriza kugwirizana ndi ogwira nawo ntchito m'mayiko komanso apadziko lonse kuti apereke kafukufuku wake popanga mankhwala othandiza komanso otheka kwa anthu omwe ali ndi EB.

Ofufuza nawo:
Prof John McGrath MD FRCP FMedSci ali ndi Mary Dunhill Chair mu Cutaneous Medicine ku King's College London ndipo ndi Mutu wa Genetic Skin Disease Unit, komanso Honorary Consultant Dermatologist ku St John's Institute of Dermatology, Guy's ndi St Thomas' NHS Foundation Trust ku London. Zokonda zake zazikulu ndi za majini ndi mankhwala obwezeretsanso komanso momwe izi zimakhudzira dermatology ndi matenda apakhungu. Akuchita nawo njira zingapo zotsatirira m'badwo wotsatira kuti athandizire kuwunika kwa ma genodermatoses komanso ndi wofufuza wamkulu pamayesero angapo oyambilira a ma cell ndi majini kwa odwala omwe ali ndi matenda akhungu obadwa nawo.

Dr Michael Antoniou ndi mtsogoleri wa Gene Expression and Therapy Group mkati mwa Dipatimenti ya Medical and Molecular Genetics ya King's College London, komwe wakhala akuchokera ku 1994. Zofuna zake zofufuza zikuphatikizapo kufufuza njira zoyendetsera majini ndikugwiritsa ntchito zomwe apezazi kuti apange mankhwala opangira majini. mankhwala. Ndi ogwira nawo ntchito m'makampani, Dr Antoniou wapanga njira yabwino kwambiri yolumikizira ma jini (ukadaulo wa UCOE®) popanga mapuloteni ochizira monga ma antibodies komanso kugwiritsa ntchito mankhwala a gene. Adapanganso mankhwala ochizira majini omwe pakali pano akuyesedwa ku Italy chifukwa cha matenda amagazi a b-thalassemia. Nthawi zambiri gulu la Dr Antoniou ndi mtsogoleri pakupanga mankhwala a gene therapy omwe amatha kugwira ntchito mochulukirachulukira komanso osasunthika motero amapereka chithandizo chanthawi yayitali. Pachifukwa ichi, zomwe a Dr Antoniou athandizira pulojekitiyi zidzakhala zofunikira kwambiri kuti tipeze zotsatira zochiritsira zokhalitsa potsatira chithandizo cha majini cha odwala a RDEB.

Othandiza:
Prof Alain Hovnanian ndi Dr Matthias Titeux, INSERM UMR 1163, Imagine Institute, Paris, France.

"Zithandizo zothandiza odwala za RDEB ndizofunikira kwambiri. Gululi likufuna kuthana ndi vutoli popanga mankhwala opopera amtundu wa RDEB opangidwa kuti azitha kuchiza kwanthawi yayitali kuphatikiza kupewa mabala "

Dr Su Lwin

Grant Mutu: Kafukufuku woyambirira wa mankhwala opopera pa majini a recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) ndi imodzi mwa mitundu yoopsa kwambiri ya EB yokhala ndi kulemedwa kwa matenda komanso kufa kwakukulu chifukwa cha cutaneous squamous cell carcinoma (cSCC). Zotsatira za masinthidwe amtundu wa COL7A1 womwe umatulutsa mtundu wa VII collagen, umabweretsa matuza ndi kufooka kwa minofu. Chisamaliro chapalliative chokha chomwe chilipo; Choncho, chithandizo chothandiza kwa odwala n’chofunika kwambiri. Gululi likuganiza zothana ndi vutoli popanga mankhwala opopera pa majini a RDEB opangidwa kuti azitha kuchiza kwanthawi yayitali, kuphatikiza kupewa zipsera.

Kutengera mayeso aposachedwa a gene therapy, Lenticol-F, dongosololi ndikuwonjezera ma cell akhungu a wodwala a RDEB ndi makope ogwira ntchito a jini ya COL7A1. Kuti akwaniritse izi, amalingalira kugwiritsa ntchito mtundu wa kachilombo wolumala wotchedwa lentivirus kuti apereke jini mu keratinocytes ndi fibroblasts kenako kuwaza pakhungu lomwe lakhudzidwa mothandizidwa ndi SkinGun™ yopangidwa ndi kampani ya biotech. RenovaCare.

Poyambirira, polojekitiyi idzayesa kupanga umboni wa lingaliro ndikuwunika ngati maselo opopera amapanga khungu logwira ntchito pogwiritsa ntchito zitsanzo za zinyama. Cholinga chawo ndikuwunika momwe ma virus awa amaperekera jini yogwira ntchito m'maselo a odwala ndikuwonetsetsa ngati chithandizo chake chikhalitsa.

Kudalira kugwiritsa ntchito utsi wa cell kuti apereke ma jini amtundu wa VII collagen kungathetse kufunikira kwa njira zowononga komanso kupereka chithandizo chothandizira odwala. Kuphatikiza apo, ma cell owonjezera a jini amatha kukula mwachangu ndikusungidwa pamalo otentha mpaka wodwalayo atakonzeka kuwalandira, zomwe zingapangitse kuti chithandizo cha jini chitheke.

Chithunzichi chikuwonetsa njira yopopera mankhwala pa jini/maselo a RDEB.

Ndalamazi zidzalola ochita kafukufuku kuti apeze deta yofunikira ya mankhwala opopera pa jini yofunikira pa ntchito zaumunthu zomwe zingatheke mosavuta kuti zigwiritsidwe ntchito kuchipatala, motero zimapindulitsa anthu ambiri omwe ali ndi RDEB.

Chithandizo cha jini chopopera pa recessive dystrophic epidermolysis bullosa: Maphunziro achipatala a lentiviral-mediated COL7A1- supplemented epidermal stem cell ndi CD39+CD26- fibroblast spray-on therapy.

Ntchito yofufuzayi imayang'ana pa recessive dystrophic epidermolysis bullosa (RDEB), mtundu wovuta kwambiri wa EB. RDEB imayamba chifukwa cha zolakwika Chidwi jini yomwe imabweretsa kusapezeka kapena kusagwira bwino ntchito kwamtundu wa VII collagen (C7). C7 imapanga zingwe zonga mbedza zotchedwa anchoring fibrils (AFs) zomwe zimasunga kumtunda kwa epidermis ndi m'munsi mwa dermis. Mu RDEB, kuchepa kapena kusagwira ntchito kwa C7 ndi AFs zogwira dermis ndi epidermis kumabweretsa matuza ndi kukokoloka ndi mabala osatha. Pofunafuna chithandizo chamankhwala cha RDEB, tidaganiza zopanga zoyeserera zotsata ma lab m'ma laboratories ku King's College London ndi ku INSERM ku Paris, mothandizana ndi mnzathu wamakampani RenovaCare Inc. popanga mankhwala opopera pa majini kwa anthu omwe ali ndi RDEB, yomwe ndi projekiti ya Spraycol.

Mwachidule, pali zinthu zitatu zapadera za pulojekitiyi: ukadaulo wothandiza kwambiri komanso wokhalitsa kwanthawi yayitali, wokomera mtima, wosasokoneza wopopera mankhwala pogwiritsa ntchito SkinGun™ yochokera ku kampani ya biotech RenovaCare Inc. njira yofulumira yachipatala-yomasulira.

Ngakhale pali zovuta zomwe sizinachitikepo zakuchedwa kwa projekiti, zoletsa kuyenda komanso kutsekedwa kwa malire chifukwa cha mliri wapadziko lonse lapansi, komanso kumwalira kwa membala wa ogwira nawo ntchito pamakampani, izi zachitika:

1. Tapanga ndi kuphatikizira bwino zida zisanu zatsopano zopangira majini pogwiritsa ntchito mtundu wolumala wa kachilomboka, wopangidwa kuti ugwire bwino ntchito popereka jini ya COL7A1 ku maselo odwala a RDEB. Izi zikutsimikiziridwa pakali pano chifukwa cha mphamvu zawo komanso mphamvu zobwezeretsa puloteni yosowa C7 m'maselo odwala.
2. Gawo lofunika kwambiri la polojekitiyi ndikuwonetsa kuti maselo ochokera kumtunda ndi kumunsi kwa khungu - keratinocytes ndi fibroblasts, atapopera mankhwala, amatha kusonkhana mofanana ndi khungu la munthu. Kuti tichite izi, tinayenera kupanga keratinocytes ndi fibroblasts zolembedwa ndi mitundu iwiri yosiyana - yofiira ndi yobiriwira, kuti tithe kuziwona ndikuwona khalidwe lawo pansi pa microscope. Maselo olembedwawa, pamodzi ndi ma cell omwe sanalembedwe adapangidwa ndipo adapopera bwino kuti awone ngati khungu lamitundu iwiri limapangidwa pambuyo popopera mankhwala. Kuchokera pazoyesererazi, tawonetsa umboni woyambirira wochiritsa mabala ndi kupopera mbewu mankhwalawa pama cell a khungu la munthu komanso ma cell odwala a RDEB osinthidwa ndi majini.
3. Tawonetsanso kuti kuchuluka kwa maselo a RDEB fibroblast, omwe ndi ofunikira kwambiri kuti achepetse zipsera pamene kuchira kwa bala kumachitika, adasiyanitsidwa bwino ndi maselo odwala ndipo akuwoneka wathanzi. Tawonetsanso kuti njira yodzipatula yomwe imagwiritsidwa ntchito kukulitsa kuchulukana kumeneku sikulepheretsa ma cell kukula zomwe zimatipangitsa kukulitsa ma cell ambiri ndikuundana kuti agwiritse ntchito mtsogolo. Kuchuluka kwa ma fibroblasts uku ndikosangalatsa kwambiri chifukwa ali ndi mawonekedwe apadera pakuchiritsa mabala popanda kuyambitsa zipsera.

Kudzera mu pulojekitiyi, tapeza mwayi wapadera womwe ungathandize njira yofulumira yomasulira mankhwala opopera pa jini pogwira ntchito limodzi ndi anzathu omwe akhalapo kwanthawi yayitali ochokera ku INSERM, Paris ndi CIEMAT, Madrid poyesa mankhwala awo omwe ali kale amasiye. amanga.

Maphunziro ambiri ofunika anaphunziridwa m’phunziroli.

Choyamba, tidaphunzira kuti ma cell akhungu opopera (fibroblasts ndi keratinocytes) ali ndi "chidziwitso" cham'mene angazigwirizanitse atapopera pakhungu lovulala (kafukufuku wathu wapano wawonetsa izi). M'mawu ena, maselo a pansi wosanjikiza khungu - fibroblasts, ndi amene ali pamwamba wosanjikiza - keratinocytes, agwirizane okha mu dongosolo ngakhale atakula mu labotale mbale ndi kukumana utsi-pa ndondomeko kudzera makina makina. Kudziwa kwathu, ndife gulu loyamba kunena kuti maselo opopera pakhungu amatha kubwezeretsa khungu lovulala kudzera m'mibadwo yamapangidwe akhungu oyamba (epithelial stratification).

Chachiwiri, tidaphunziranso kuti tinthu tating'onoting'ono tidabweretsa zovuta zosiyanasiyana kuyesa ma cell omwe amapopera chifukwa cha malo ang'onoang'ono a bala okhala ndi ma cell 'oterera' omwe amatayika akamapaka. Maphunziro ofunikirawa atikonzekeretsa ndi chidziwitso komanso chidziwitso chamtengo wapatali kuti tithe kupanga zoyeserera zomwe zingatifikitse kufupi ndi kuyesa mwa anthu. Mwachitsanzo, mgwirizano wathu wanthawi yayitali ndi Renovacare (omwe ali ndi makina opopera) komanso othandizira maphunziro athu ku Paris ndi Madrid, zitithandiza, ngati gawo lotsatira, kuyesa jini ndi selo. mankhwala mu zitsanzo zazikulu ndi anthu, motero.

Tikuyembekeza kupititsa patsogolo kupita patsogolo kwathu pakumasulira kwachipatala kwa spray-on gene/cell therapy ya EB. (Kuchokera lipoti lomaliza Januware 2023.)