Kubwezeretsanso mankhwala oletsa mabala mu RDEB (2023)

Ofufuza adapeza kuti mankhwala awiri (givinostat ndi valproic acid) adathandizira kupanga maselo akhungu a RDEB omwe amakula mu labotale kukhala athanzi. Valproic acid inathanso kuchepetsa zizindikiro za RDEB zomwe zimakhudza maso, tsitsi ndi khungu. Valproic acid amavomerezedwa ndikugwiritsidwa ntchito kwambiri pazinthu zina. Ntchitoyi imapereka umboni wotsimikizira kuti ikukonzedwanso kuti ichedwetse kuyambika ndi kupitilira kwa zizindikiro mwa anthu okhala ndi RDEB.

Ofufuza adasindikiza ndemanga ya ntchito yawo pakhungu la fibrosis mu 2021.

Dr Daniele Castiglia ndi katswiri wa ma geneticist komanso Mtsogoleri wa laboratory of molecular and cell biology ku Istituto Dermopatico dell'Immacolata, IDI-IRCCS ku Rome. Ali ndi zaka zopitilira 20 akugwira ntchito m'munda wa EB ndi ma genodermatoses ena omwe amapeza maluso apadera okhudzana ndi ma cell ndi kulumikizana kwa genotype-phenotype. Zochita zake zofufuzira zimayang'ana kwambiri njira zama cell ndi mamolekyu azovuta za EB kuti awulule zolinga zatsopano za njira zochiritsira zosinthira matenda.

"Lingaliro lathu likufuna kuyesa kuchiritsa kwamankhwala awiri a epigenetic, omwe amagwiritsidwa ntchito kale pamatenda ena a fibrotic."

– Dr Daniele Castiglia

Grant Title: Anti-fibrotic therapeutic potential of histone deacetylase inhibitors (HDACi) for recessive dystrophic epidermolysis bullosa.

Zowona zikuwonetsa kuti kulakwitsa kwa majini komwe kumayambitsa kusowa kwa kolajeni VII sizomwe zimayambitsa matenda mu recessive dystrophic epidermolysis bullosa (RDEB). Majini ena, otchedwa 'modifier genes', (majini omwe amakhudza kapena kusintha mawonekedwe a jini ina), amathanso kusintha kapena kukulitsa matenda kutengera zochita zawo. Ma jini osintha awa ndi zotsatira zake zitha kuyang'aniridwa mwachirengedwe (kuyesera ndikupeza chithandizo) kuti muchepetse zizindikiro komanso kusintha momwe matendawa akuyendera. Izi zitha kuchitika kuphatikiza kulunjika ku cholakwika choyambirira cha chibadwa.

Kusintha kwachibadwa kapena "epigenetic" ndizomwe zimasintha kuyambika kwa majini popanda kusintha DNA yathu kapena ma genetic. Akhoza kukhala ndi udindo pa kusiyana kwa majini osintha.

Chodetsa nkhaŵa chachikulu mu RDEB ndi kukhalapo kwa kutupa ndi kupita patsogolo kwa fibrosis ya khungu ndi mucosae (m'kamwa, kum'mero, ndi zina zotero) zomwe zimabweretsa mavuto aakulu, monga mitten deformities (kuphatikizana kwa zala), zolimba (kuchepa kwa mmero) ndi EB yogwirizana ndi khansa. Zogwirizana kwambiri ndi izi, puloteni yotchedwa TGF-β yomwe imayambitsa mayankho ambiri a maselo, imayambitsa zizindikiro za maselo zomwe zimayambitsa RDEB skin fibrosis kuyambira ndi kupita patsogolo.

Zotsatira zoyesera zikuwonetsa kuti kusintha kwa epigenetic kungakhudze kukula kwa matenda a RDEB mwa kulimbikitsa maselo kupita ku fibrosis khungu likavulala ndipo izi zitha kukhala chandamale cha chithandizo. Gululi lapeza kuti mankhwala ang'onoang'ono omwe amayang'ana mtundu umodzi wa kusintha kwa epigenetic wotchedwa histone acetylation (mamolekyu omwe amakhudza momwe DNA imapangidwira m'malo mwa chibadwa chake) akhoza kuchepetsa RDEB fibrosis ndi ntchito ya TGF-β.

Lingaliroli likufuna kuyesa kuchiritsa kapena chithandizo chamankhwala awiri a "epigenetic", omwe amagwiritsidwa ntchito kale m'matenda ena a fibrotic, pochepetsa komanso kuchedwetsa zovuta zokhudzana ndi matenda mu labotale ya RDEB.

DNA (chingwe chofiira) chimakutidwa ndi histones (mikanda yabuluu). DNA yophatikizika imalumikizana ndi majini osagwira ntchito pomwe kusintha kwa histone, kotchedwa acetylation (Ac) kumapangitsa DNA kukhala yocheperako, zomwe nthawi zambiri zimakonda kuyambitsa ma jini. Mwa kuletsa histone deacetylases (HDACs), mankhwala epigenetic, monga givinostat ndi valproic acid, amakonda kuwonjezeka kwa histone acetylation, motero amalimbikitsa jini. Majini osintha okhala ndi anti-fibrotic amatha kutsegulidwa.

Gululo lifufuza kuthekera kwa "ma epidrugs" awa kuti asinthe mawonekedwe a jini kuti athe kuthana ndi ma fibrosis pakhungu la RDEB. Mankhwala awiri omwe adzayesedwe mu kafukufukuyu ndi givinostat, histone deacetylation inhibitor (HDACi) yomwe ili m'mayesero achipatala pazochitika zingapo, ndi mankhwala ovomerezeka otchedwa valproic acid omwe ali ndi chilolezo cha matenda ena, onse omwe amadziwika. kukhala ndi zotsatira za antifibrotic zomwe zawonetsedwa mu kafukufuku wam'mbuyomu. Zotsatira za kafukufukuyu mwachiyembekezo zidzatsogolera ku mayesero ena azachipatala mwina kubweza kapena kugwiritsanso ntchito mankhwala kuti athe kuthana ndi RDEB fibrosis ndi mavuto okhudzana nawo.

Zowona zambiri zimatsimikizira kuti kuchuluka kwa collagen VII sizomwe zimayambitsa matenda a recessive dystrophic epidermolysis bullosa (RDEB) odwala; majini ena, otchedwa modifier genes, amatha kusintha kapena kukulitsa mawonetseredwe a matenda kutengera ngati ali ndi mphamvu zambiri kapena zochepa. Chifukwa chake, ma jini osintha ndi zotsatira zake zitha kulunjika mwachirengedwe kuti muchepetse zizindikiro ndikuwongolera matenda.

Chodetsa nkhaŵa chachikulu mu RDEB ndi kukhalapo kwa kutupa ndi kupita patsogolo kwa fibrosis (induration) ya khungu ndi mucosae (m'kamwa, m'mitsempha, ndi zina zotero) zomwe zimayambitsa maonekedwe a matenda aakulu, monga mitten deformities, strictures ndi khansa. TGF-β, puloteni yomwe imayambitsa mayankho ambiri a maselo, imayambitsa zizindikiro za maselo zomwe zimayambitsa RDEB skin fibrosis kuyamba ndi kupita patsogolo.

Zosintha zosinthika zomwe zimathandizira kuyambitsa kwa majini osasintha ma DNA athu amadziwika ngati kusintha kwa epigenetic. Atha kukhala ndi udindo pakusiyana kwa majini osintha komanso mawonekedwe azachipatala mwa anthu a RDEB.

Tinapeza kuti mankhwala ang'onoang'ono omwe amayang'ana kusintha kwakukulu kwa epigenetic, histone acetylation, akhoza kuchepetsa RDEB fibroblast fibrosis ndi ntchito ya TGF-β.

Cholinga chathu ndi kuyesa mphamvu zochiritsira za mankhwala awiri a epigenetic, omwe amagwiritsidwa ntchito kale m'magulu azachipatala mu zovuta zina za fibrotic, pochepetsa komanso kuchedwetsa mawonetseredwe a matenda a mtundu wa RDEB. Tidapeza kuti imodzi mwamankhwala awiriwa imatha kuthana ndi vuto la khungu komanso kupita patsogolo kwa matenda pochepetsa mawonetseredwe owopsa monga kutayika kwa manambala ndi mabala a cornea. Kafukufuku akupitilira kufufuza zotsatira za mamolekyu ndi ma cellular pakugwiritsa ntchito mankhwala osokoneza bongo. (Kuchokera ku lipoti la 2022).

Zowona zambiri zimatsimikizira kuti kuchuluka kwa collagen VII sizomwe zimayambitsa matenda a recessive dystrophic epidermolysis bullosa (RDEB) odwala; majini ena, otchedwa "modifier genes", akhoza kusintha kapena kuonjezera mawonetseredwe a matenda kutengera ngati akugwira ntchito mochuluka kapena mocheperapo. Chifukwa chake, ma jini osintha ndi kuwongolera kwawo ndi zochitika zawo zitha kukhala zolunjika pakuchepetsa zizindikiro ndikuwongolera matenda. Mwachitsanzo, kusintha kwa mawonekedwe a jini a decorin ndi TGF-β, mamolekyu awiri omwe amapezeka pakhungu laling'ono, adanenedwa mu RDEB monga momwe amachitira ndi kuopsa kwa matenda, ndipo maphunziro awiri asonyeza kuti kupereka decorin pakhungu lokhudzidwa ndi RDEB kumathandizira matenda a phenotype. polimbana ndi ntchito ya TGF-β, yowonjezereka yomwe imayambitsa zizindikiro za maselo omwe amachititsa kuti khungu liyambe kuphulika ndi kupita patsogolo. Zowonadi, chodetsa nkhaŵa chachikulu mu RDEB ndi kukhalapo kwa kutupa ndi kupita patsogolo kwa fibrosis (induration) ya khungu ndi mucosae (m'kamwa, m'mitsempha) zomwe zimayambitsa mawonetseredwe a matenda oopsa, monga kupunduka kwa mitten, kuuma ndi khansa.

Kusintha kosinthika komwe kumasintha machitidwe a majini osasintha ma DNA omwe amadziwika kuti kusintha kwa epigenetic. Atha kukhala ndi udindo pakusiyana kwa majini osintha komanso mawonekedwe azachipatala mwa anthu a RDEB. Zotsatira za ntchito yathu zikuwonetsa kuti kusintha kwakukulu kwa epigenetic, komwe kumatchedwa histone acetylation, kumasinthidwa pakhungu la RDEB. Kupatula apo, tinazindikira "mankhwala a epigenetic" awiri (givinostat ndi valproic acid) omwe amayang'ana histone acetylation ndipo adapeza kuti onse amatha kuthana ndi khalidwe la profibrotic la cultured fibroblasts kuchokera kwa anthu a RDEB, kuphatikizapo kuchepetsa ntchito ya TGF-β.

Cholinga chathu chinali kuyesa kuthekera kwa mankhwalawa awiriwa, omwe adayesedwa kale m'matenda ena a fibrotic pamlingo wa preclinical, pochepetsa komanso kuchedwetsa mawonetseredwe a matenda a RDEB mumtundu wa mbewa wa RDEB. Tidapeza kuti valproic acid imatha kulimbana ndi fibrosis yapakhungu ndikuchepetsa bwino zovuta za matenda, monga kutayika kwa manambala ndi mabala a cornea. Mankhwalawa amagwira ntchito polimbana ndi zotsatira zodalira TGF-β, (matrix osadziwika bwino, kuwonjezeka kwa maselo, kuyambitsa njira zowonetsera profibrotic ndi protumorigenic). Monga valproic acid imavomerezedwa ndikugwiritsidwa ntchito kwambiri m'zachipatala kwa anthu omwe alibe khungu, ikhoza kubwezeretsedwanso pofuna kuthana ndi kuyambika ndi kupitirira kwa fibrosis mwa anthu a RDEB. (Kuchokera ku lipoti lomaliza la 2023.)