KwiNkomfa yeSitofu kunye nezeMpilo, iingcali zabiza "wonke umntu kufuneka anikele ingqalelo kugonyo lwe-mRNA, olunika abantu ukucinga okungenamkhawulo."Ke yintoni kanye kanye isitofu sokugonya se-mRNA?Yafunyaniswa njani kwaye lithini ixabiso lesicelo sayo?Ngaba inokuxhathisa ukugquba kwe-COVID-19 kwihlabathi liphela?Ngaba ilizwe lam liphuhlise ngempumelelo isitofu sokugonya se-mRNA?Namhlanje, makhe sifunde malunga nexesha elidlulileyo nelikhoyo lokugonya i-mRNA.

01
Yintoni i-mRNA kwizitofu zokugonya ze-mRNA?

I-mRNA (uMthunywa u-RNA), oko kukuthi, i-RNA yesithunywa, luhlobo lwe-RNA ene-single-stranded ebhalwe kwi-strand ye-DNA njenge-template kwaye ithwala ulwazi lwezofuzo olunokukhokela i-protein synthesis.Ngokwemigaqo ye-layman, i-mRNA iphinda iphinde iphinde iphinde iphinde iphinde iphinde iphinde iphinde iphinde iphinde iphinde ilandele ulwazi lwemfuza ye-DNA ephindwe kabini kwi-nucleus, emva koko ishiya i-nucleus ivelisa iiprotheni kwi-cytoplasm.Kwi-cytoplasm, i-ribosomes ihamba kunye ne-mRNA, ifunde ukulandelelana kwesiseko sayo, kwaye iguqulele kwi-amino acid ehambelana nayo, ekugqibeleni yenza iprotheni (Umfanekiso 1).

Umzobo we-1 mRNA inkqubo yokusebenza

02
Yintoni isitofu sokugonya se-mRNA kwaye yintoni esenza sibe sodwa?

Izitofu zokugonya ze-mRNA zazisa i-mRNA yokufaka i-antigens yesifo esithile emzimbeni, kwaye isebenzise indlela yokwenziwa kweprotheyini yeseli ukuvelisa ii-antigens, ngaloo ndlela ibangela impendulo yokuzikhusela komzimba.Ngokuqhelekileyo, ulandelelwano lwe-mRNA ye-antigens ethile inokwakhiwa ngokwezifo ezahlukeneyo, zipakishwe kwaye zihanjiswe kwiiseli nge-novel lipid nanocarrier particles, kwaye ke ukulandelelana kwe-mRNA ye-ribosomes yabantu isetyenziselwa ukuguqulela ulandelelwano lwe-mRNA ukuvelisa iiprotheyini ze-antigen zesifo, eziqatshelwe yi-immune system yokukhusela i-autoimmune system ukuze kuthintelwe i-immune system kwi-secretion ye-2.

Umzobo 2. Isiphumo se-vivo sesitofu sokugonya se-mRNA

Ke, yintoni ekhethekileyo ngolu hlobo lwesitofu sokugonya se-mRNA xa kuthelekiswa nogonyo lwemveli?Izitofu zokugonya ze-mRNA zezona zitofu zokugonya zesizukulwana sesithathu, kwaye uphando olongezelelweyo luyafuneka ukomeleza uzinzo, ukulawula ukugonya kwabo, kunye nokuphuhlisa itekhnoloji entsha yonikezelo.

Isizukulwana sokuqala sezitofu zokugonya zesintu ikakhulu ziquka izitofu ezingasebenziyo kunye nezitofu zokugonya ezihlala zinciphile, ezingawona asetyenziswa kakhulu.Izitofu zokugonya ezingasebenziyo zibhekisa ekukhuliseni iintsholongwane okanye iibhaktheriya zokuqala, kwaye emva koko zingasebenzi ngobushushu okanye iikhemikhali (ngokuqhelekileyo i-formalin);izitofu zokugonya ezihlala zinciphile zibhekisa kwiintsholongwane eziguqula kwaye zenze buthathaka ubutyhefu bazo emva konyango olwahlukeneyo.kodwa igcina i-immunogenicity yayo.Ukuyifakela emzimbeni akuyi kubangela ukwenzeka kwesifo, kodwa i-pathogen inokukhula kwaye iphindaphindeke emzimbeni, ibangele ukuphendula komzimba, kwaye idlale indima ekufumaneni ukhuseleko lwexesha elide okanye ubomi obude.

Isizukulwana sesibini sezitofu zokugonya ezitsha ziquka izitofu zokugonya ezingaphantsi kweyunithi kunye nezitofu zokugonya eziphinda ziphindwe kabini.Isitofu sokugonya i-Subunit isitofu sokugonya esenziwe ngamacandelo aphambili akhuselayo e-immunogen yebhaktiriya ye-pathogenic, oko kukuthi, ngokubola kweekhemikhali okanye iproteolysis elawulwayo, iprotein ekhethekileyo yebhaktheriya kunye neentsholongwane zikhutshwa kwaye zihlolwe ngaphandle.Izitofu zokugonya ezenziwe ngamaqhekeza e-immunologically asebenzayo;izitofu zokugonya eziphinda ziphinde zakhiwe ziiproteni ze-antigen eziveliswa kwiinkqubo ezahlukeneyo zokubonisa iiseli.

Isizukulwana sesithathu sezitofu zokugonya zibandakanya izitofu ze-DNA kunye nogonyo lwe-mRNA.Kukwazisa ngokuthe ngqo iqhekeza lemfuza yentsholongwane (i-DNA okanye i-RNA) efaka i-protein ethile ye-antigenic kwiiseli ze-somatic yezilwanyana (inaliti yokugonya emzimbeni womntu), kwaye ivelise iprotein ye-antigenic ngenkqubo ye-protein synthesis ye-cell host, ikhuthaza umkhosi ukuba uvelise ukugonywa kwi-protein ye-antigenic ukuze ufezekise injongo yokuthintela kunye nonyango lwezifo.Umahluko phakathi kwezi zimbini kukuba i-DNA iqala ukubhalwa kwi-mRNA kwaye emva koko iprotheni yenziwe, ngelixa i-mRNA yenziwe ngokuthe ngqo.

03
Imbali yokufunyanwa kunye nexabiso lesicelo sesitofu sokugonya se-mRNA

Xa kuziwa kwizitofu zokugonya ze-mRNA, kufuneka sikhankanye isazinzulu sasetyhini esigqwesileyo, uKati Kariko, obeke isiseko esiluqilima sophando lwezenzululwazi malunga nokuvela kogonyo lwe-mRNA.Wayegcwele umdla wophando kwi-mRNA ngelixa wayefunda.Ngaphezulu kweminyaka engama-40 yomsebenzi wakhe wophando lwezenzululwazi, wabandezeleka ngokuphindaphindiweyo, akazange afake isicelo semali yophando lwezenzululwazi, kwaye akazange abe nesikhundla esizinzileyo sophando lwezenzululwazi, kodwa ebesoloko egxininisa kuphando lwe-mRNA.

UKati Karito

Kukho iindawo ezintathu ezibalulekileyo ekufikeni kogonyo lwe-mRNA.

Kwinqanaba lokuqala, uphumelele ukuvelisa imolekyuli ye-mRNA efunekayo ngenkcubeko yeeseli, kodwa wadibana nengxaki ekwenzeni i-mRNA isebenze emzimbeni: emva kokutofa i-mRNA kwimpuku, iya kuginywa sisistim somzimba sempuku.Emva koko wadibana no-Weissman.Basebenzise imolekyuli ekwi-tRNA ebizwa ngokuba yipseudouridine ukwenza i-mRNA ibaleke impendulo yokhuselo lomzimba.[2].
Kwinqanaba lesibini, malunga no-2000, uProf. Pieter Cullis wafunda i-lipid nanotechnology LNPs ukwenzela ukuhanjiswa kwe-siRNA kwi-vivo yokusetyenziswa kofuzo lokuthulisa [3][4].Umbutho we-Weissman uKariko et al.ifumanise ukuba i-LNP ngumphathi ofanelekileyo we-mRNA kwi-vivo, kwaye inokuba sisixhobo esixabisekileyo sokuhambisa i-mRNA yeeprotheyini zonyango zonyango, kwaye emva koko ingqinwe kuthintelo lwe-Zika virus, HIV kunye namathumba [5] [6][7][8].

Kwinqanaba lesithathu, ngo-2010 nango-2013, iModerna kunye neBioNTech zafumana iilayisensi zepatent ngokulandelelanayo ezinxulumene ne-mRNA synthesis kwiDyunivesithi yasePennsylvania ukuze kuphuhliswe ngakumbi.UKatalin uphinde waba ngusekela mongameli ophezulu we-BioNTech ngo-2013 ukuqhubela phambili ukuphuhlisa amayeza okugonya i-mRNA.

Namhlanje, ugonyo lwe-mRNA lunokusetyenziswa kwizifo ezosulelayo, amathumba, kunye nesifuba.Kwimeko ye-COVID-19 egquba kwihlabathi liphela, izitofu zokugonya ze-mRNA zinokudlala indima njengeyanguard.

04
Ithemba lokusetyenziswa kogonyo lwe-mRNA kwi-COVID-19

Ngobhubhani wehlabathi jikelele we-COVID-19, amazwe asebenza nzima ukuphuhlisa isitofu sokugonya ukunqanda lo bhubhani.Njengohlobo olutsha lwesitofu, isitofu sokugonya se-mRNA sidlale indima ephambili ekufikeni kwesibetho esitsha sesithsaba.Iijenali ezininzi eziphezulu zinike ingxelo ngendima ye-mRNA kwi-SARS-CoV-2 entsha ye-coronavirus (Umfanekiso 3).

Umzobo 3 Ingxelo malunga nogonyo lwe-mRNA ukuthintela i-coronavirus entsha (ukusuka kwi-NCBI)

Okokuqala, izazinzulu ezininzi zixele uphando lwesitofu sokugonya se-mRNA (SARS-CoV-2 mRNA) ngokuchasene ne-coronavirus entsha kwiimpuku.Umzekelo: i-lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP) yokugonya, i-injection ye-dose eyodwa yenza uhlobo oluqinileyo lwe-1 CD4 + T kunye ne-CD8 + T yeempendulo ze-cell, i-plasma ehlala ixesha elide kunye neempendulo zeeseli ze-B, kunye ne-robust and Sustained neutralizing antibody response.Oku kubonisa ukuba isitofu sokugonya se-mRNA-LNP ngumgqatswa othembisayo ngokuchasene ne-COVID-19[9][10].

Okwesibini, ezinye izazinzulu zithelekisa iziphumo ze-SARS-CoV-2 mRNA kunye nogonyo lwemveli.Xa kuthelekiswa nezitofu zokugonya eziphinda ziphinde zisebenze: izitofu zokugonya ze-mRNA ziphezulu kakhulu kuneeprotheyini zokugonya kwi-germinal center response, i-Tfh activation, i-neutraizing imveliso ye-antibody, imemori ethile yeeseli ze-B, kunye neeseli ze-plasma ezihlala ixesha elide [11].

Ke, njengoko abaviwa bogonyo lwe-SARS-CoV-2 mRNA bangena kulingo lwezonyango, iinkxalabo zaphakanyiswa malunga nexesha elifutshane lokhuseleko lwesitofu.Iingcali zenzululwazi zenze uhlobo lwe-lipid-encapsulated lwe-nucleoside-modified mRNA isitofu esibizwa ngokuba yi-mRNA-RBD.Inaliti enye inokuvelisa ii-antibodies ezinamandla kunye neempendulo zeselula, kwaye ingaphantse ikhusele ngokupheleleyo imodeli yeempuku ezosulelwe yi-2019-nCoV, enamanqanaba aphezulu e-anti-anti-antibody egcinwe ubuncinci iinyanga eziyi-6.5.Ezi datha zibonisa ukuba idosi enye ye-mRNA-RBD ibonelela ngokhuseleko lwexesha elide kumngeni we-SARS-CoV-2 [12].
Kukwakho izazinzulu ezisebenzela ukuphuhlisa izitofu ezintsha ezikhuselekileyo nezisebenzayo ngokuchasene ne-COVID-19, ezifana nesitofu sokugonya se-BNT162b.Iimacaques ezikhuselweyo ezivela kwi-SARS-CoV-2, zikhusele indlela esezantsi yokuphefumla kwi-RNA yentsholongwane, zivelise izilwa-buhlungu ezinamandla kakhulu, kwaye zingabonisi zimpawu zokuphucula isifo.Abaviwa ababini ngoku baphantsi kovavanyo kulingo lwesigaba I, kwaye uvavanyo kwisigaba sehlabathi II/III solingo luyaqhubeka, kwaye isicelo sikufuphi nekona [13].

05
Ubume bogonyo lwe-mRNA kwihlabathi

Okwangoku, iBioNTech, iModerna kunye neCureVac zaziwa njengezona nkokeli zintathu zonyango lwe-mRNA zehlabathi.Phakathi kwabo, iBioNTech kunye neModerna baphambili kuphando kunye nophuhliso lwesitofu esitsha sokugonya.IModerna ibigxile kuphando nakuphuhliso lwamachiza anxulumene ne-mRNA kunye nogonyo.Isitofu sokugonya se-COVID-19 isigaba III se-mRNA-1273 yeyona projekthi ikhula ngokukhawuleza kwinkampani.I-BioNTech ikwalichiza le-mRNA elihamba phambili kwihlabathi kunye nophando kunye nenkampani yokugonya kunye nophuhliso, kunye ne-19 ye-mRNA yamachiza / ugonyo, isi-7 sayo singene kwinqanaba lonyango.I-CureVac igxile kuphando kunye nophuhliso lwamachiza e-mRNA / ugonyo, kwaye yinkampani yokuqala emhlabeni ukuseka umgca wokuvelisa we-RNA ohambelana ne-GMP, ugxininise kwiithumba, izifo ezosulelayo kunye nezifo ezinqabileyo.

Iimveliso eziyeleleneyo:RNase Inhibitor
Amagama aphambili: isitofu sokugonya se-miRNA, iRNA Isolation, iRNA extraction, RNase Inhibitor

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