Sebokeng sa Vaccine le Bophelo bo Botle, litsebi li ile tsa kopa "e mong le e mong o lokela ho ela hloko liente tsa mRNA, tse fang batho monahano o se nang moeli."Joale ha e le hantle ente ea mRNA ke eng?E ile ea sibolloa joang le hore na tšebeliso ea eona ke ea bohlokoa hakae?A na e ka hanela seoa sa COVID-19 lefatšeng ka bophara?Na naha ea heso e atlehile ho etsa ente ea mRNA?Kajeno, ha re ithuteng ka liente tsa mRNA tse fetileng le tsa hajoale.

01
MRNA ke eng ka har'a liente tsa mRNA?

mRNA (Messenger RNA), ke hore, lenģosa RNA, ke mofuta oa RNA e nang le thipa e le 'ngoe e ngotsoeng ho tloha moleng oa DNA e le template 'me e na le boitsebiso ba lefutso bo ka tataisang motsoako oa protheine.Ho ea ka mantsoe a layman, mRNA e pheta tlhaiso-leseling ea lefutso ea DNA e nang le likhoele tse peli khubung, ebe e siea khubu ho hlahisa liprotheine ho cytoplasm.Ka cytoplasm, li-ribosome li tsamaea haufi le mRNA, li bala tatellano ea eona ea motheo, 'me li e fetolela ho amino acid e lumellanang le eona, qetellong e etsa protheine (Setšoantšo sa 1).

Setšoantšo sa 1 mRNA tshebetso ea ho sebetsa

02
Ente ea mRNA ke eng, 'me ke eng e etsang hore e be e ikhethang?

Liente tsa mRNA li kenya li-antigen tse khethehileng tsa lefu la mRNA 'meleng,' me li sebelisa mokhoa oa ho kopanya protheine ea sele e amohelang ho hlahisa li-antigen, ka hona ho tsosa karabelo ea 'mele ea ho itšireletsa mafung.Hangata, tatellano ea mRNA ea li-antigen tse khethehileng e ka hahoa ho ea ka mafu a fapaneng, a kenngoa le ho isoa liseleng ka likaroloana tse ncha tsa lipid nanocarrier, 'me ka mor'a moo tatellano ea mRNA ea li-ribosomes tsa batho e sebelisoa ho fetolela tatellano ea mRNA ho hlahisa liprotheine tsa antigen tsa lefu, tse amoheloang ke tsamaiso ea 'mele ea ho itšireletsa mafung e le ho thibela ho itšireletsa mafung ka mor'a hore ho finyelloe karolo ea 2.

Setšoantšo sa 2. In vivo effect ea ente ea mRNA

Joale, ke eng e ikhethang ka mofuta ona oa ente ea mRNA ha e bapisoa le liente tsa setso?Liente tsa mRNA ke liente tse tsoetseng pele haholo tsa moloko oa boraro, 'me lipatlisiso tse ling lia hlokahala ho matlafatsa botsitso ba tsona, ho laola matla a bona a ho itšireletsa mafung, le ho nts'etsapele mahlale a macha a phano.

Moloko oa pele oa liente tsa setso haholo-holo li kenyelletsa liente tse sa sebetseng le liente tse phelang tse fokolitsoeng, e leng tsona tse sebelisoang haholo.Liente tse sa sebetseng li bua ka livaerase kapa libaktheria tsa pele, ebe li li kenya ka mocheso kapa lik'hemik'hale (hangata formalin);live attenuated ente li bua ka likokoana-hloko tse fetolang le ho fokolisa chefo ea tsona ka mor'a liphekolo tse fapaneng.empa e ntse e boloka immunogenicity ea eona.Ho e kenya ka har'a 'mele ho ke ke ha baka ketsahalo ea lefu, empa kokoana-hloko e ka hōla le ho ikatisa' meleng, ea tsosa karabelo ea 'mele ea ho itšireletsa mafung,' me ea phetha karolo ea ho fumana tšireletso ea nako e telele kapa ea bophelo bohle.

Moloko oa bobeli oa liente tse ncha li kenyelletsa liente tsa subunit le liente tse kopanyang tsa protheine.Subunit vaccine ke ente ea subunit e entsoeng ka likarolo tse ka sehloohong tse sireletsang immunogen ea baktheria ea pathogenic, ke hore, ka ho bola ha lik'hemik'hale kapa proteolysis e laoloang, sebopeho se khethehileng sa protheine ea baktheria le livaerase se ntšoa ebe se hlahlojoa.Liente tse entsoeng ka likaroloana tse sebetsang tsa immunological;liente tse recombinant protheine ke li-antigen recombinant protheine tse hlahisoang lits'ebetsong tse fapaneng tsa polelo ea lisele.

Moloko oa boraro oa liente tsa morao-rao li kenyelletsa liente tsa DNA le liente tsa mRNA.Ke ho hlahisa ka kotloloho sekhechana sa liphatsa tsa lefutso (DNA kapa RNA) e kenyang protheine e itseng ea antigen ka har'a lisele tsa somatic (ente ea ente 'meleng oa motho), le ho hlahisa protheine ea antigenic ka protheine synthesis system ea sele e amohelang, ho etsa hore moeti a hlahise boits'ireletso ba protheine ea antigenic e le ho fihlela sepheo sa ho thibela le ho phekola mafu.Phapang pakeng tsa tse peli ke hore DNA e qala ho ngoloa ho mRNA ebe protheine e etsoa, ​​​​ha mRNA e etsoa ka ho toba.

03
Nalane ea sibollo le boleng ba ts'ebeliso ea ente ea mRNA

Ha re bua ka liente tsa mRNA, re tlameha ho bua ka rasaense ea hlahelletseng oa basali, Kati Kariko, ea thehileng motheo o tiileng oa lipatlisiso tsa mahlale bakeng sa ho fihla ha liente tsa mRNA.O ne a tletse thahasello ea lipatlisiso ho mRNA ha a ntse a ithuta.Lilemong tse fetang 40 tsa mosebetsi oa hae oa ho etsa lipatlisiso tsa mahlale, o ile a tobana le litšitiso khafetsa, ha a ka a etsa kopo ea lichelete tsa lipatlisiso tsa mahlale, a bile a se na boemo bo tsitsitseng ba lipatlisiso tsa mahlale, empa esale a tsitlallela ho etsa lipatlisiso tsa mRNA.

Kati Karito

Ho na le li-node tse tharo tsa bohlokoa ts'ebetsong ea liente tsa mRNA.

Mohato oa pele, o atlehile ho hlahisa molek'hule ea mRNA eo a e batlang ka setso sa lisele, empa o ile a kopana le bothata ba ho etsa hore mRNA e sebetse 'meleng: ka mor'a ho kenya mRNA ka har'a mouse, e ne e tla metsoa ke sesole sa mouse.Eaba o kopana le Weissman.Ba sebelisitse molek'hule ho tRNA e bitsoang pseudouridine ho etsa hore mRNA e qobe karabelo ea 'mele ea ho itšireletsa mafung.[2].
Mohatong oa bobeli, hoo e ka bang ka 2000, Prof. Pieter Cullis o ile a ithuta lipid nanotechnology LNPs bakeng sa ho fana ka siRNA bakeng sa lisebelisoa tsa ho khutsisa liphatsa tsa lefutso [3][4].Mokhatlo oa Weissman Kariko et al.e fumane hore LNP ke sejari se loketseng sa mRNA ka har'a vivo, 'me e ka' na ea e-ba sesebelisoa sa bohlokoa sa ho fana ka liprotheine tsa phekolo tsa mRNA, 'me ka mor'a moo tsa netefatsoa ho thibela kokoana ea Zika, HIV le lihlahala [5] [6][7][8].

Mohato oa boraro, ka 2010 le 2013, Moderna le BioNTech ba ile ba fumana mangolo a tumello ea molao a amanang le mRNA synthesis ho tsoa Univesithing ea Pennsylvania bakeng sa nts'etsopele e tsoelang pele.Katalin hape e bile motlatsi oa mopresidente oa BioNTech ka 2013 ho nts'etsapele liente tsa mRNA.

Kajeno, liente tsa mRNA li ka sebelisoa ho mafu a tšoaetsanoang, lihlahala le asthma.Tabeng ea COVID-19 e ntseng e tsoela pele lefatšeng ka bophara, liente tsa mRNA li ka bapala karolo ea pele.

04
Tebello ea ts'ebeliso ea ente ea mRNA ho COVID-19

Ka seoa sa lefats'e sa COVID-19, linaha li sebetsa ka thata ho etsa ente ho thibela seoa sena.Joalo ka mofuta o mocha oa ente, ente ea mRNA e nkile karolo e ka sehloohong ho qaleng ha seoa se secha sa moqhaka.Likoranta tse ngata tse holimo li tlalehile karolo ea mRNA ho SARS-CoV-2 coronavirus e ncha (Setšoantšo sa 3).

Setšoantšo sa 3 Tlaleho ka liente tsa mRNA ho thibela coronavirus e ncha (ho tloha ho NCBI)

Pele ho tsohle, bo-rasaense ba bangata ba tlalehile lipatlisiso tsa ente ea mRNA (SARS-CoV-2 mRNA) khahlano le coronavirus e ncha ho litoeba.Ka mohlala: ente ea lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP), ente ea tekanyo e le 'ngoe e etsa hore ho be le likarabo tsa lisele tsa CD4 + T le CD8 + T tsa mofuta o matla, plasma ea nako e telele le likarabo tsa memori ea B, le likarabo tse matla le tse tsitsitseng tsa antibody tse fokolang.Sena se supa hore ente ea mRNA-LNP ke motho ea tšepisang khahlanong le COVID-19[9][10].

Taba ea bobeli, bo-ramahlale ba bang ba ile ba bapisa litlamorao tsa SARS-CoV-2 mRNA le liente tsa setso.Ha ho bapisoa le liente tsa protheine tse nchafalitsoeng: liente tsa mRNA li phahame haholo ho feta liente tsa protheine ka karabo ea setsi sa likokoana-hloko, ts'ebetso ea Tfh, tlhahiso ea antibody e fokolang, lisele tse khethehileng tsa mohopolo oa B, le lisele tsa plasma tsa nako e telele [11].

Joale, ha bakuli ba ente ea SARS-CoV-2 mRNA ba kena litekong tsa bongaka, ho ile ha hlaha matšoenyeho mabapi le nako e khuts'oane ea ts'ireletso ea ente.Bo-rasaense ba thehile mofuta o kentsoeng ka lipid oa ente e fetotsoeng ea mRNA e nang le nucleoside e bitsoang mRNA-RBD.Ente e le 'ngoe e ka hlahisa li-antibodies tse matla le likarabo tsa liselefouno,' me e ka batla e sireletsa ka botlalo litoeba tsa mohlala tse tšoaelitsoeng ke 2019-nCoV, ka litekanyetso tse phahameng tsa li-antibodies tse bolokiloeng bonyane likhoeli tse 6.5.Lintlha tsena li fana ka maikutlo a hore tekanyetso e le 'ngoe ea mRNA-RBD e fana ka tšireletso ea nako e telele khahlano le phephetso ea SARS-CoV-2 [12].
Ho boetse ho na le bo-ramahlale ba sebetsang ho etsa liente tse ncha tse sireletsehileng le tse sebetsang khahlano le COVID-19, joalo ka ente ea BNT162b.Li-macaque tse sirelelitsoeng ho tsoa ho SARS-CoV-2, li sirelelitse pampitšana e tlase ea phefumoloho ho RNA ea vaerase, tsa hlahisa li-antibodies tse matla haholo, 'me li sa bonts'e matšoao a ntlafatso ea mafu.Bakhethoa ba babeli hajoale ba ntse ba hlahlojoa litekong tsa mohato oa I, 'me tlhahlobo ea liteko tsa lefats'e ea II/III le eona e ntse e tsoela pele, mme ts'ebeliso e haufi le sekhutlo [13].

05
Boemo ba ente ea mRNA lefatšeng

Hajoale, BioNTech, Moderna le CureVac li tsejoa e le baetapele ba bararo ba phahameng ka ho fetesisa ba phekolo ea mRNA.Har'a bona, BioNTech le Moderna li ka pele ho lipatlisiso le nts'etsopele ea ente e ncha ea moqhaka.Moderna esale a tsepamisitse maikutlo ho lipatlisiso le nts'etsopele ea lithethefatsi le liente tse amanang le mRNA.Ente ea teko ea COVID-19 phase III mRNA-1273 ke projeke e holang ka potlako ea k'hamphani.BioNTech hape ke k'hamphani e etelletseng pele lefatšeng ka bophara ea lithethefatsi le lipatlisiso tsa ente ea mRNA, e nang le kakaretso ea litlhare/liente tsa mRNA tse 19, tse 7 tsa tsona li kene setsing sa bongaka.CureVac esale e shebane le lipatlisiso le nts'etsopele ea litlhare/ente tsa mRNA, 'me ke k'hamphani ea pele lefatšeng ho theha mohala oa tlhahiso ea RNA o lumellanang le GMP, o shebane le lihlahala, mafu a tšoaetsanoang le mafu a sa tloaelehang.

Lihlahisoa tse amanang:RNase Inhibitor
Mantsoe a bohlokoa: ente ea miRNA, RNA Isolation, RNA extraction, RNase Inhibitor

Litšupiso:1.K Karikó, Buckstein M , Ni H , et al.Khatello ea Kamohelo ea RNA ka Li-Receptors tse kang Toll: The Impact of Nucleoside Modification le Evolutionary Origin of RNA[J].Immunity, 2005, 23(2):165-175.
2. K Karikó, Muramatsu H , Welsh FA , et al.Ho Kenyelletsoa ha Pseudouridine ka ho mRNA ho Hlahisa Vector e Phahameng e sa Feleng Thibelo ea ho Fetolela le Botsitso ba Likokoana-hloko[J].Phekolo ea Limolek'hule, 2008.3.Chonn A , Cullis PR .Likhatelopele tsa morao-rao tsa liposome technologies le likopo tsa tsona tsa tsamaiso ea liphatsa tsa lefutso[J].Litlhahlobo tse tsoetseng pele tsa ho fana ka lithethefatsi, 1998, 30 (1-3): 73.4.Kulkarni JA , Witzigmann D , Chen S , et al.Lipid Nanoparticle Technology for Clinical Translation of siRNA Therapeutics[J].Litlaleho tsa Patlisiso ea Lik'hemik'hale, 2019, 52(9).5.Kariko, Katalin, Madden, et al.Expression kinetics ea nucleoside-modified mRNA e tlisoang ka lipid nanoparticles ho litoeba ka litsela tse fapaneng[J].Journal of Controlled Release Journal of Official of the Controlled Release Society, 2015.6.Tšireletso ea kokoana-hloko ea Zika ka ente e le 'ngoe ea lethal dose e le 'ngoe ea nucleoside-modified mRNA[J].Tlhaho, 2017, 543 (7644): 248-251.7.Pardi N , Secreto AJ , Shan X , et al.Tsamaiso ea "nucleoside-modified mRNA encoding" e sireletsang litoeba khahlanong le phephetso ea HIV-1[J].Tlhaho ea puisano, 2017, 8: 14630.8.Stadler CR , B?Hr-Mahmud H , Celik L , et al.Ho felisoa ha lihlahala tse kholo ho litoeba ka li-antibodies tsa bispecific tse kentsoeng ke mRNA[J].Meriana ea Tlhaho, 2017.9.NN Zhang, Li XF , Deng YQ , et al.Ente e Thermostable mRNA khahlano le COVID-19[J].Cell, 2020.10.D Laczkó, Hogan MJ , Toulmin SA , et al.Ente e le 'Ngoe e nang le Liente tsa Nucleoside-Modified mRNA e Fumaneha Likarabo tse Matla tsa Lisele le Humoral Immune khahlano le SARS-CoV-2 ho Litoeba - ScienceDirect[J].2020.11.Lederer K , Castao D , Atria DG , et al.SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Likarabo Tse Amanang le Moloko oa Likokoana-hloko tse Neutralizing[J].Ho itšireletsa mafung, 2020, 53 (6): 1281-1295.e5.12.Huang Q , Ji K , Tian S , et al.Ente ea tekanyo e le 'ngoe ea mRNA e fana ka tšireletso ea nako e telele bakeng sa litoeba tsa haACE2 tse fetohang ho tsoa ho SARS-CoV-2[J].Puisano ea Tlhaho.13.Vogel AB , Kanevsky I , Ye C , et al.Liente tsa Immunogenic BNT162b li sireletsa rhesus macaques ho tsoa ho SARS-CoV-2[J].Tlhaho, 2021:1-10.