Shirka Tallaalka iyo Caafimaadka, khubaradu waxay ku baaqeen "qof walba waa inuu fiiro gaar ah u yeeshaa tallaallada mRNA, kuwaas oo bini'aadamka siiya fikir aan xadidnayn."Haddaba waa maxay dhabta ah tallaalka mRNA?Sidee lagu helay iyo waa maxay qiimaha codsigeeda?Ma iska caabin kartaa COVID-19 ka socda adduunka oo dhan?Dalkaygu si guul leh ma u sameeyay tallaalka mRNA?Maanta, aynu wax ka barano tagtada iyo hadda tallaalada mRNA.

01
Waa maxay mRNA ku jira tallaalada mRNA?

mRNA (Rasuul RNA), yacni, messenger RNA, waa nooc ka mid ah RNA hal xadhig leh oo laga soo guuriyay xadhig DNA ah qaab template ah oo xanbaarsan macluumaadka hidde-socod ee hagi kara isku-xidhka borotiinka.Erayada laymanka, mRNA waxa ay ku celisaa xogta hidaha ee hal xadhig oo DNA-da laba-geesoodka ah ee ku jira xudunta, ka dibna waxay ka tagtaa nukleus si ay u soo saarto borotiinno ku jira cytoplasm.Sitobalaasamka, ribosomes waxay ku dhaqaaqaan mRNA, akhriyaan isku xigxiga salkeeda, waxayna u turjumaan amino acid u dhigma, ugu dambeyntii waxay sameeyaan borotiin (Jaantus 1).

Jaantuska 1 habka shaqada mRNA

02
Waa maxay tallaalka mRNA maxaase ka dhigaya mid gaar ah?

Tallaalada mRNA waxay soo bandhigaan mRNA iyagoo ku dhejinaya antigens-ka cudur-gaar ah jirka, waxayna adeegsadaan habka isku-darka borotiinka ee unugga martida loo yahay si ay u soo saaraan antigens, taas oo kicinaysa jawaab celin difaac.Caadi ahaan, taxanaha mRNA ee antigens gaar ah ayaa loo dhisi karaa iyadoo loo eegayo cudurro kala duwan, baakadeysan oo loo raro unugyo by novel lipid nanocarrier particles, ka dibna taxanaha mRNA ee ribosomes bini'aadamka ayaa loo isticmaalaa si loo tarjumo taxanaha mRNA si loo soo saaro borotiinnada antigen-ka, kuwaas oo loo aqoonsan yahay nidaamka difaaca jirka ka dib dheecaanka si loo gaaro doorka difaaca.

Jaantuska 2. In vivo saamaynta tallaalka mRNA

Haddaba, maxaa u gaar ah nooca tallaalka mRNA marka la barbar dhigo tallaalada dhaqameed?Tallaalka mRNA waa tallaalada jiilka saddexaad ee ugu goynta badan, waxaana loo baahan yahay cilmi-baaris dheeraad ah si kor loogu qaado xasilloonidooda, loo habeeyo difaacooda, iyo horumarinta tignoolajiyada cusub ee gaarsiinta.

Jiilkii ugu horeeyay ee tallaal dhaqameedka waxaa ka mid ah tallaalada aan firfircoonayn iyo tallaallada nool ee la dhimay, kuwaas oo ah kuwa ugu isticmaalka badan.Tallaalada aan firfircoonayn waxay tixraacaan marka ugu horreysa ee fayrasyada ama bakteeriyada lagu dhaqo, ka dibna lagu daayo kulayl ama kiimikooyin (sida caadiga ah formalin);Tallaalada nool ee la dhimay waxay tixraacaan cudur-keenayaasha beddela oo daciifiya suntooda daawaynta kala duwan ka dib.laakiin wali way sii haysataa difaaceeda.In lagu tallaalo jidhka ma keenayso in cudurku dhaco, laakiin cudur-sidaha waxa uu ku kori karaa oo ku tarmi karaa jidhka, waxa uu kicin karaa jawaab celinta difaaca jidhka, waxaanu door ka qaataa sidii uu u heli lahaa difaac muddo dheer ama cimri dheer ah.

Jiilka labaad ee tallaalada cusub waxaa ka mid ah tallaalada subunit iyo tallaalada borotiinka ee dib-u-habaynta.Tallaalka Subunit waa tallaal qayb ka mid ah tallaalka oo laga sameeyay qaybaha difaaca ee ugu muhiimsan ee bakteeriyada cudur-sidaha, taas oo ah, iyada oo loo marayo kala-baxa kiimikaad ama proteolysis la kantaroolo, qaab dhismeedka borotiinka gaarka ah ee bakteeriyada iyo fayrasyada ayaa la soo saaraa oo la baaraa.Tallaallada laga sameeyay jajabyada firfircoon ee difaaca jirka;Tallaalada borotiinka ee dib-u-dhaqaajinta ah waa borotiinada dib-u-celinta antigen-ka ee laga soo saaro hababka muujinta unugyada kala duwan.

Jiilka saddexaad ee tallaallada jeexjeexan waxaa ka mid ah tallaallada DNA-da iyo tallaallada mRNA.Waa in si toos ah loo soo bandhigo jajabka hidda-wadaha fayraska (DNA ama RNA) oo ku dhejinaya borotiinka antigenic gaar ah unugyada somatic ee xayawaanka (muritaanka tallaalka ee jidhka bini'aadamka), oo soo saara borotiinka antigenic iyada oo loo marayo nidaamka borotiinka ee unugyada martida loo yahay, iyada oo u horseedaysa martida si ay u soo saarto difaac jawaabta borotiinka antigenic si loo gaaro ujeedada ka hortagga iyo daaweynta cudurka.Farqiga u dhexeeya labadooda ayaa ah in DNA marka hore lagu qoro mRNA ka dibna borotiinka la farsameeyo, halka mRNA si toos ah loo farsameeyo.

03
Taariikhda daahfurka iyo qiimaha codsiga ee tallaalka mRNA

Markay timaaddo tallaallada mRNA, waa inaan xusnaa saynis yahan dumar ah oo aad u wanaagsan, Kati Kariko, taasoo aasaas cilmi baaris adag u dhigtay imaanshaha tallaalada mRNA.Waxay ka buuxday xiisaha cilmi-baarista ee mRNA inta ay wax baranaysay.In ka badan 40 sano oo ay ku jirtay xirfadeeda cilmi-baarista sayniska, waxay la kulantay dib-u-dhacyo soo noqnoqda, ma dalban maalgelin cilmi-baaris cilmi-baaris ah, mana aysan haysan boos cilmi-baaris cilmiyeed oo deggan, laakiin had iyo jeer waxay ku adkaysanaysaa cilmi-baarista mRNA.

Kati Karito

Waxaa jira saddex nood oo muhiim ah soo ifbaxa tallaallada mRNA.

Talaabadii ugu horeysay, waxay ku guulaysatay inay soo saarto molecule mRNA-ga ee la rabay iyada oo loo marayo dhaqanka unugyada, laakiin waxay la kulantay dhibaato ah samaynta mRNA-ga ee jirka: ka dib markii ay ku duri karto mRNA-ga jiirka, waxaa liqi doona habka difaaca ee jiirka.Kadib waxay la kulantay Weissman.Waxay isticmaaleen molecule ku jira tRNA oo loo yaqaan pseudouridine si ay mRNA uga dhigaan jawaabta difaaca.[2].
Talaabada labaad, agagaarka 2000, Prof. Pieter Cullis wuxuu bartay lipid nanotechnology LNPs ee vivo gaarsiinta siRNA ee codsiyada aamusinta hidda-socodka [3] [4].Ururka Weissman Kariko et al.Waxaa la ogaaday in LNP ay tahay side ku habboon mRNA gudaha vivo, waxaana laga yaabaa inay noqoto aalad qiimo leh oo lagu soo gudbiyo mRNA codeynta borotiinnada daweynta, ka dibna lagu xaqiijiyay ka hortagga fayraska Zika, HIV iyo burooyinka [5] [6] [7] [8].

Talaabada saddexaad, 2010 iyo 2013, Moderna iyo BioNTech waxay si isdaba joog ah u heleen shatiyada patent-ka ee la xidhiidha isku-dhafka mRNA ee Jaamacadda Pennsylvania si loo horumariyo.Katalin wuxuu sidoo kale noqday madaxweyne ku xigeenka sare ee BioNTech 2013 si loo sii horumariyo tallaalada mRNA.

Maanta, tallaallada mRNA waxaa loo isticmaali karaa cudurrada faafa, burooyinka, iyo neefta.Xaaladda COVID-19 ee ka kacsan adduunka oo dhan, tallaallada mRNA waxa laga yaabaa inay door ka ciyaaraan sidii waardiye ahaan.

04
Rajada codsiga ee tallaalka mRNA ee COVID-19

Iyada oo faafitaanka caalamiga ah ee COVID-19, dalalku waxay si adag uga shaqeynayaan sidii ay u soo saari lahaayeen tallaal looga hortagayo faafitaanka.Sida nooc cusub oo tallaal ah, tallaalka mRNA wuxuu door hormuud ah ka ciyaaray soo ifbaxa cudurka cusub ee taajka.Joornaalo badan oo sare ayaa soo sheegay doorka mRNA ee SARS-CoV-2 coronavirus-ka cusub (Jaantuska 3).

Jaantuska 3 Ka warbixin tallaalada mRNA si looga hortago coronavirus cusub (oo ka yimid NCBI)

Ugu horreyntii, saynisyahano badan ayaa ka warbixiyay cilmi-baarista tallaalka mRNA (SARS-CoV-2 mRNA) ee ka dhanka ah coronavirus-ka cusub ee jiirarka.Tusaale ahaan: tallaalka mRNA (mRNA-LNP) ee lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP), duritaanka hal-dose waxay keenaysaa jawaabaha unugga nooca 1 CD4+ T iyo CD8+ T, balaasmaha dheer iyo jawaabaha unugyada xusuusta B, iyo adkaysi iyo joogtaynta dhexdhexaadinta jawaabta antibody.Tani waxay tusinaysaa in tallaalka mRNA-LNP uu yahay musharrax rajo leh oo ka dhan ah COVID-19[9][10].

Marka labaad, saynisyahannada qaar ayaa isbarbar dhigay saamaynta SARS-CoV-2 mRNA iyo tallaallada dhaqameed.Marka la barbardhigo tallaalada borotiinka ee dib-u-soo-celinta: Tallaallada mRNA waxay aad uga sarreeyaan tallaalada borotiinka ee jawaabta xarunta germinal, firfircoonida Tfh, dhexdhexaadinta wax soo saarka antibody, unugyada xusuusta gaarka ah ee B, iyo unugyada plasma ee muddada dheer noolaa [11].

Kadib, markii murashaxiinta tallaalka SARS-CoV-2 mRNA ay galeen tijaabooyin caafimaad, walaac ayaa laga soo qaaday muddada gaaban ee ilaalinta tallaalka.Saynis yahanadu waxay soo saareen qaab lipid-ku-xidhan oo ah tallaalka mRNA ee nucleoside-la beddelay oo loo yaqaan mRNA-RBD.Hal irbad ayaa dhalin karta unugyada difaaca jirka oo xoog leh iyo jawaabaha gacanta, waxayna ku dhawaad ​​si buuxda u ilaalin kartaa jiirarka moodada ah ee qaba 2019-nCoV, oo leh heerar sare oo difaaca jirka ah oo la ilaaliyo ugu yaraan 6.5 bilood.Xogtaasi waxay soo jeedinaysaa in hal qiyaas oo mRNA-RBD ah ay bixiso difaac waqti dheer ah oo ka dhan ah loolanka SARS-CoV-2 [12].
Waxa kale oo jira saynisyahano ka shaqaynaya sidii ay u soo saari lahaayeen tallaalo cusub oo badbaado leh oo waxtar leh oo ka dhan ah COVID-19, sida tallaalka BNT162b.Macaques-ka laga ilaaliyo SARS-CoV-2, waxay mareenka neef-mareenka hoose ka ilaaliyeen fayraska RNA, waxay soo saareen unugyada difaaca jirka oo aad u xoog badan, mana muujin wax calaamado ah oo kor u qaadaya cudurka.Laba musharrax ayaa hadda ku socda qiimeynta marxaladda I ee tijaabooyinka, iyo qiimeynta tijaabooyinka caalamiga ah ee II/III ayaa sidoo kale socda, codsiguna wuxuu ku dhow yahay geeska [13].

05
Heerka tallaalka mRNA ee adduunka

Waqtigan xaadirka ah, BioNTech, Moderna iyo CureVac waxaa loo yaqaanaa saddexda hoggaamiye ee daaweynta mRNA ee ugu sarreeya adduunka.Waxaa ka mid ah, BioNTech iyo Moderna ayaa safka hore kaga jira cilmi baarista iyo horumarinta tallaalka taajka cusub.Moderna waxa ay diiradda saareysay cilmi baarista iyo horumarinta daawooyinka iyo tallaalada mRNA ee la xiriira.Tallaalka tijaabada ah ee wajiga III ee COVID-19 mRNA-1273 waa mashruuca ugu kobaca badan ee shirkadda.BioNTech sidoo kale waa hormoodka caalamiga ah ee dawada mRNA iyo tallaalka cilmi baarista iyo horumarinta shirkadda, oo leh wadar ahaan 19 daawooyin / tallaalo mRNA ah, 7 ka mid ah ayaa soo galay marxaladda caafimaad.CureVac waxa ay diiradda saareysay cilmi baarista iyo horumarinta dawooyinka/talaalada mRNA, waana shirkaddii ugu horreysay ee adduunka si ay u dhisto khadka wax soo saarka RNA ee GMP-raaca, iyada oo diiradda saareysa burooyinka, cudurrada faafa iyo cudurrada dhifka ah.

Alaabta la xidhiidha:Horjoogaha RNase
Erayada muhiimka ah: tallaalka miRNA, Go'doominta RNA, soo saarista RNA, Inhibitor RNase

Tixraac:1.K Karikó, Buckstein M, Ni H, iyo al.Cabudhinta Aqoonsiga RNA ee Soo Dhaweeyayaasha Toll-sida: Saamaynta Wax ka beddelka Nucleoside iyo Asalkii Kobcinta ee RNA[J].Xasaanadda, 2005, 23 (2): 165-175.
2. K Karikó, Muramatsu H, Welsh FA, iyo al.Ku daridda Pseudouridine ee mRNA waxay dhalisaa faylal aan difaac lahayn oo sarreeya iyadoo la kordhinayo awoodda tarjumaada iyo xasilloonida nafleyda[J].Daaweynta Molecular, 2008.3.Chonn A, Cullis PR.Horumarkii dhawaa ee tignoolajiyada liposomeka iyo codsiyadooda gudbinta hidda-wadaha [J].Dib u eegisyada Bixinta Dawooyinka Sare, 1998, 30 (1-3): 73.4.Kulkarni JA, Witzigmann D, Chen S, iyo al.Farsamada Nanoparticle ee Dufanka leh ee Turjumaadda Kiliinikada ee SiRNA Therapeutics[J].Xisaabaadka Cilmi-baarista Kiimikada, 2019, 52(9.5.Kariko, Katalin, Madden, iyo al.Kinetics-ka muujinta mRNA-ga nucleoside-la beddelay ee lagu keenay nanoparticles lipid jiirarka iyada oo loo marayo waddooyin kala duwan[J].Joornaalka Siidaynta La Xakameeyay Joornaalka Rasmiga ah ee Bulshada Siidaynta La Xakameeyay, 2015.6.Ka ilaalinta fayraska Zika ee hal qiyaas yar oo nucleoside ah oo wax laga beddelay tallaalka mRNA[J].Dabeecadda, 2017, 543 (7644): 248-251.7.Pardi N, Secreto AJ, Shan X, iyo al.Maamulka mRNA-ga nucleoside-la beddelay oo si weyn u dhexdhexaadinaya antibody-ka ayaa ka ilaalinaysa jiirarka bani'aadamnimada ee loolanka HIV-1 [J].Isgaarsiinta Dabeecadda, 2017, 8: 14630.8.Stadler CR, B?Hr-Mahmud H, Celik L, iyo al.Ciribtirka burooyinka waaweyn ee jiirarka iyada oo la adeegsanayo unugyada difaacayaasha bispecific ee mRNA-ku dhejiyay[J].Daawooyinka Dabiiciga ah, 2017.9.NN Zhang, Li XF, Deng YQ, iyo al.Tallaalka mRNA ka-hortagga COVID-19[J].Unug, 2020.10.D Laczkó, Hogan MJ, Toulmin SA, iyo al.Tallaalka Keliya ee Nucleoside-la Bedelay Tallaalka mRNA wuxuu saarayaa jawaabaha difaaca jirka ee xoogga badan ee ka dhanka ah SARS-CoV-2 ee jiirka - ScienceDirect[J].2020.11.Lederer K, Castao D, Atria DG, iyo al.Tallaalka SARS-CoV-2 mRNA Kobciyay Awoodaha Antigen-Specific Center Germinal Jawaabaha ee la xidhiidha Dhexdhexaadinta Jiilka Kahortagga Jirka[J].Xasaanadda, 2020, 53 (6): 1281-1295.e5.12.Huang Q, Ji K, Tian S, iyo al.Tallaalka mRNA-ga hal-door ah wuxuu bixiyaa difaac-dheer-dheer jiirarka hACE2 transgenic ee SARS-CoV-2[J].Isgaarsiinta Dabeecadda.13.Vogel AB, Kanevsky I, Ye C, iyo al.Tallaalka difaaca jirka ee BNT162b ayaa ka ilaaliya rhesus macaques SARS-CoV-2[J].Dabeecadda, 2021: 1-10.