Mu nama y’inkingo n’ubuzima, impuguke zasabye "abantu bose bagomba kwitondera inkingo za mRNA, ziha abantu ibitekerezo bitagira imipaka."None urukingo rwa mRNA ni uruhe?Yavumbuwe gute kandi agaciro kayo ni iki?Irashobora kurwanya COVID-19 ikaze kwisi yose?Igihugu cyanjye cyatsinze urukingo rwa mRNA?Uyu munsi, reka twige kubyashize nubu byinkingo za mRNA.

01
Niki mRNA mu rukingo rwa mRNA?

mRNA (Intumwa RNA), ni ukuvuga intumwa RNA, ni ubwoko bwa RNA imwe ihindurwamo umurongo wa ADN nk'icyitegererezo kandi itwara amakuru akomoka ku ngirabuzimafatizo ashobora kuyobora intungamubiri za poroteyine.Mu magambo y’abalayiki, mRNA yigana amakuru yimiterere yumurongo umwe wa ADN ikubye kabiri muri nucleus, hanyuma igasiga nucleus ikabyara proteyine muri cytoplazme.Muri cytoplazme, ribosomes igenda yerekeza kuri mRNA, soma urutonde rwayo, hanyuma uyihindure muri aside amine ihuye nayo, amaherezo ikora poroteyine (Ishusho 1).

Igishushanyo 1 mRNA inzira yo gukora

02
Urukingo rwa mRNA ni iki kandi ni iki rutuma rwihariye?

Urukingo rwa mRNA rwinjiza mRNA ikubiyemo antigene yihariye y’indwara mu mubiri, kandi igakoresha uburyo bwa poroteyine yo mu bwoko bwa poroteyine yakira kugira ngo ikore antigene, bityo itume ubudahangarwa bw'umubiri.Ubusanzwe, mRNA ikurikirana ya antigene yihariye irashobora kubakwa ukurikije indwara zitandukanye, igapakirwa ikajyanwa mu ngirabuzimafatizo hakoreshejwe uduce duto twa lipide nanocarrier, hanyuma mRNA ikurikirana ya ribosomes yumuntu ikoreshwa muguhindura urutonde rwa mRNA kugirango ikore poroteyine za antigen zanduye, zizwi na sisitemu ya autoimmune nyuma yo gusohora kugirango itange igisubizo cyumudugudu (Ishusho 2).

Igicapo 2. Muri vivo ingaruka zurukingo rwa mRNA

None, ni iki kidasanzwe kuri ubu bwoko bw'urukingo rwa mRNA ugereranije n'inkingo gakondo?Urukingo rwa mRNA ninkingo zambere zo mu gisekuru cya gatatu, kandi hakenewe ubundi bushakashatsi kugira ngo umutekano wabo urusheho gukomera, kugenzura ubudahangarwa bwabo, no guteza imbere ikoranabuhanga rishya ryo gutanga.

Igisekuru cya mbere cyinkingo gakondo zirimo cyane cyane inkingo zidakozwe hamwe ninkingo nzima, nizo zikoreshwa cyane.Inkingo zidakora zivuga mbere na mbere ziterwa na virusi cyangwa bagiteri, hanyuma zikayitangiza ubushyuhe cyangwa imiti (ubusanzwe formalin);inkingo nzima zivuga indwara ziterwa na virusi zihindura kandi zigabanya uburozi bwazo nyuma yubuvuzi butandukanye.ariko aracyafite ubudahangarwa bwayo.Kwinjiza mu mubiri ntibizatera indwara, ariko virusi irashobora gukura no kugwira mu mubiri, bigatera ubudahangarwa bw'umubiri, kandi ikagira uruhare mu kurindwa igihe kirekire cyangwa ubuzima.

Igisekuru cya kabiri cyinkingo nshya zirimo urukingo rwa subunit ninkingo za proteine ​​recombinant.Urukingo rwa Subunit ni urukingo rwa subunit rukingiwe rugizwe n’ibice nyamukuru birinda immunogen bigize bagiteri zitera indwara, ni ukuvuga binyuze mu kubora imiti cyangwa proteolysis igenzurwa, imiterere yihariye ya poroteyine ya bagiteri na virusi ikuramo kandi ikagenzurwa.Inkingo zakozwe mu bice bikingira indwara;inkingo za poroteyine za recombinant ni poroteyine za antigen recombinant zikorwa muri sisitemu zitandukanye zo kwerekana selile.

Igisekuru cya gatatu cyinkingo zigezweho zirimo inkingo za ADN ninkingo za mRNA.Ni ukumenyekanisha mu buryo butaziguye agace ka virusi (ADN cyangwa RNA) gakubiyemo poroteyine zimwe na zimwe za antigenic mu ngirabuzimafatizo z’inyamanswa (gutera urukingo mu mubiri w’umuntu), no gukora poroteyine ya antigenic binyuze muri sisitemu ya sintezamubiri ya poroteyine yo mu ngirabuzimafatizo, kugira ngo nyirubwite atange ubudahangarwa bw'umubiri wa poroteyine kugira ngo ugere ku ntego yo gukumira no kuvura indwara.Itandukaniro riri hagati yibi byombi nuko ADN yabanje kwandikwa muri mRNA hanyuma proteine ​​ikomatanya, mugihe mRNA ihuriweho.

03
Amateka yubuvumbuzi nagaciro kerekana urukingo rwa mRNA

Ku bijyanye n'inkingo za mRNA, tugomba kuvuga umuhanga w’umugore w’indashyikirwa, Kati Kariko, washyizeho urufatiro rukomeye rw’ubushakashatsi mu bya siyansi kugira ngo habeho inkingo za mRNA.Yari yuzuye ubushakashatsi muri mRNA mugihe yigaga.Mu myaka irenga 40 amaze akora ubushakashatsi mu bya siyansi, yagiye asubira inyuma inshuro nyinshi, ntiyasaba amafaranga y’ubushakashatsi bwa siyansi, kandi ntabwo yari afite umwanya uhamye w’ubushakashatsi, ariko yamye ashimangira ubushakashatsi bwa mRNA.

Kati Karito

Hariho ibintu bitatu by'ingenzi mugihe haje inkingo za mRNA.

Mu ntambwe yambere, yashoboye gukora molekile ya mRNA yifuzwa binyuze mumico y'utugari, ariko yahuye nikibazo cyo gukora imikorere ya mRNA mumubiri: nyuma yo gutera mRNA mumbeba, byari kumirwa na sisitemu yumubiri.Hanyuma yahuye na Weissman.Bakoresheje molekile muri tRNA yitwa pseudouridine kugirango mRNA yirinde ubudahangarwa bw'umubiri.] [2].
Mu ntambwe ya kabiri, ahagana mu 2000, Prof. Pieter Cullis yize lipide nanotehnologiya LNPs mu gutanga vivo ya siRNA yo gucecekesha gene [3] [4].Ishirahamwe Weissman Kariko n'abandi.yasanze LNP itwara mRNA ikwiye muri vivo, kandi ishobora kuba igikoresho cyingenzi cyo gutanga mRNA ikubiyemo poroteyine zo kuvura, hanyuma bikagenzurwa mu gukumira virusi ya Zika, virusi itera sida ndetse n’ibibyimba [5]] [6] [7] [8].

Mu ntambwe ya gatatu, muri 2010 na 2013, Moderna na BioNTech bakurikiranye babonye impushya z'ipatanti zijyanye na synthesis ya mRNA yo muri kaminuza ya Pennsylvania kugirango barusheho gutera imbere.Katalin kandi yabaye visi perezida mukuru wa BioNTech mu 2013 kugirango arusheho guteza imbere inkingo za mRNA.

Muri iki gihe, inkingo za mRNA zirashobora gukoreshwa mu ndwara zandura, ibibyimba, na asima.Ku bijyanye na COVID-19 ikaze ku isi, inkingo za mRNA zishobora kugira uruhare nka vanguard.

04
Icyifuzo cyo gusaba urukingo rwa mRNA muri COVID-19

Hamwe n'icyorezo cya COVID-19 ku isi, ibihugu birimo gukora cyane kugira ngo hategurwe urukingo rwo guhashya iki cyorezo.Nkubwoko bushya bwurukingo, urukingo rwa mRNA rwagize uruhare runini mugutangira icyorezo gishya.Ibinyamakuru byinshi byo hejuru byagaragaje uruhare rwa mRNA muri SARS-CoV-2 coronavirus nshya (Ishusho 3).

Igishushanyo cya 3 Raporo ku nkingo za mRNA kugirango wirinde coronavirus nshya (kuva NCBI)

Mbere na mbere, abahanga benshi batangaje ubushakashatsi ku rukingo rwa mRNA (SARS-CoV-2 mRNA) kurwanya coronavirus nshya mu mbeba.Kurugero: lipid nanoparticle-enapsulated-nucleoside-yahinduwe urukingo rwa mRNA (mRNA-LNP), inshinge imwe imwe itera ubwoko bukomeye bwa CD4 + T na CD8 + T, ibisubizo bimaze igihe kirekire hamwe na selile B yibisubizo bya selile, hamwe na antibody ikomeye kandi ihamye.Ibi byerekana ko urukingo rwa mRNA-LNP ari umukandida utanga ikizere cyo kurwanya COVID-19 [9].

Icya kabiri, abahanga bamwe bagereranije ingaruka za SARS-CoV-2 mRNA ninkingo gakondo.Ugereranije n'inkingo za poroteyine za recombinant: urukingo rwa mRNA ruruta kure urukingo rwa poroteyine mu gisubizo cya germinal center, gukora Tfh, kutabuza umusaruro wa antibody, selile B yibuka, hamwe na plasma ndende.

Noneho, mugihe abakandida b'inkingo za SARS-CoV-2 mRNA binjiye mu bigeragezo by’amavuriro, hagaragaye impungenge z’igihe gito cyo gukingira inkingo.Abahanga mu bya siyansi bakoze uburyo bwa lipide ikubiyemo urukingo rwa nucleoside rwahinduwe urukingo rwa mRNA rwitwa mRNA-RBD.Urushinge rumwe rushobora kubyara antibodiyite zikomeye hamwe nibisubizo bya selile, kandi birashobora kurinda rwose imbeba ntangarugero zanduye 2019-nCoV, hamwe na antibodiyite nyinshi zangiza byibuze amezi 6.5.Aya makuru yerekana ko igipimo kimwe cya mRNA-RBD gitanga uburinzi burambye kwirinda SARS-CoV-2 [12].
Hariho kandi abahanga bakora kugirango bategure inkingo nshya zifite umutekano kandi zifatika zirwanya COVID-19, nkurukingo rwa BNT162b.Makaque yarinze SARS-CoV-2, yarinze inzira zubuhumekero zo hepfo virusi RNA, ikora antibodi zikomeye cyane, kandi nta kimenyetso cyerekana ko indwara ziyongera.Muri iki gihe abakandida babiri barimo gusuzumwa mu cyiciro cya I, kandi isuzuma mu cyiciro cya II / III ku isi naryo rirakomeje, kandi gusaba ni hafi [13].

05
Imiterere y'urukingo rwa mRNA kwisi

Kugeza ubu, BioNTech, Moderna na CureVac bazwi nkabayobozi batatu ba mbere ku isi bavura mRNA.Muri byo, BioNTech na Moderna biri ku isonga mu bushakashatsi no guteza imbere urukingo rushya rw'ikamba.Moderna yibanze ku bushakashatsi no guteza imbere imiti ninkingo zijyanye na mRNA.Urukingo rwa COVID-19 icyiciro cya III mRNA-1273 niwo mushinga wihuta cyane muri sosiyete.BioNTech kandi n’isosiyete ikora ubushakashatsi ku iterambere n’inkingo za mRNA ku isi, hamwe n’imiti 19 ya mRNA / inkingo, 7 muri zo zinjiye mu rwego rw’amavuriro.CureVac yibanze ku bushakashatsi no guteza imbere imiti ya mRNA / inkingo, kandi ni yo sosiyete ya mbere ku isi yashyizeho umurongo wa RNA wubahiriza GMP, wibanda ku bibyimba, indwara zandura n'indwara zidasanzwe.

Ibicuruzwa bifitanye isano:RNase Inhibitor
Amagambo shingiro: urukingo rwa miRNA, Kwigunga kwa RNA, gukuramo RNA, Inhibitor ya RNase

Reba: 1.K Karikó, Buckstein M, Ni H, n'abandi.Kurwanya RNA Kumenyekana na Toll-imeze nk'iyakira: Ingaruka zo Guhindura Nucleoside n'inkomoko y'ubwihindurize ya RNA [J].Ubudahangarwa, 2005, 23 (2): 165-175.
2. K Karikó, Muramatsu H, Welsh FA, n'abandi.Kwinjiza Pseudouridine muri mRNA Yitanga Vector Isumba Nonimmunogenic Vector Yongerewe Ubushobozi bwo Guhindura no Guhindura Ibinyabuzima [J].Ubuvuzi bwa molekile, 2008.3.Chonn A, Cullis PR.Iterambere rya vuba muri tekinoroji ya liposome hamwe nuburyo bukoreshwa mugutanga gene sisitemu [J].Isuzuma ryo Gutanga Ibiyobyabwenge Byambere, 1998, 30 (1-3): 73.4.Kulkarni JA, Witzigmann D, Chen S, n'abandi.Lipid Nanoparticle Ikoranabuhanga rya Clinical Translation ya siRNA ivura [J].Konti yubushakashatsi bwimiti, 2019, 52 (9) .5.Kariko, Katalin, Madden, n'abandi.Kugaragaza kinetike ya nucleoside yahinduwe mRNA itangwa muri lipide nanoparticles ku mbeba n'inzira zitandukanye [J].Ikinyamakuru cyo kugenzura isohoka Ikinyamakuru cyemewe cyumuryango ugenzurwa kurekura, 2015.6.Kurinda virusi ya Zika hamwe ninkingo imwe ya nucleoside yahinduwe urukingo rwa mRNA [J].Kamere, 2017, 543 (7644): 248-251.7.Pardi N, Secreto AJ, Shan X, n'abandi.Ubuyobozi bwa nucleoside yahinduwe mRNA ikubiyemo antibody itabuza cyane kurinda imbeba zabantu zanduye virusi ya VIH-1 [J].Itumanaho rya Kamere, 2017, 8: 14630.8.Stadler CR, B? Hr-Mahmud H, Celik L, n'abandi.Kurandura ibibyimba binini mu mbeba na antibodiyite ya bispecifica ya mRNA.Ubuvuzi bwa Kamere, 2017.9.NN Zhang, Li XF, Deng YQ, n'abandi.Urukingo rwa mRNA rushobora kurwanya COVID-19 [J].Akagari, 2020.10.D Laczkó, Hogan MJ, Toulmin SA, n'abandi.Inkingo imwe hamwe na Nucleoside Yahinduwe Urukingo rwa mRNA Ikingira Immune Ikomeye ya Cellular na Humoral Ibisubizo kuri SARS-CoV-2 mu mbeba - ScienceDirect [J].2020.11.Lederer K, Castao D, Umuyobozi wa Atriya, n'abandi.Inkingo za SARS-CoV-2 mRNA Inkingo Zitera imbaraga Antigen-yihariye ya Germinal Centre Igisubizo gifitanye isano no kutabogama kwa Antibody [J].Ubudahangarwa, 2020, 53 (6): 1281-1295.e5.12.Huang Q, Ji K, Tian S, n'abandi.Urukingo rumwe rukumbi rwa mRNA rutanga uburinzi burambye bwimbeba za HACE2 transgenic ziva muri SARS-CoV-2 [J].Itumanaho rya Kamere.13.Vogel AB, Kanevsky I, Ye C, n'abandi.Urukingo rwa Immunogenic BNT162b rurinda rhesus macaque SARS-CoV-2 [J].Kamere, 2021: 1-10.