Pamsonkhano wa Vaccine and Health, akatswiri adapempha kuti "aliyense azilabadira katemera wa mRNA, womwe umapatsa anthu malingaliro opanda malire."Ndiye kodi katemera wa mRNA ndi chiyani kwenikweni?Kodi zinapezeka bwanji ndipo phindu lake ndi lotani?Kodi ingakane kufalikira kwa COVID-19 padziko lonse lapansi?Kodi dziko langa lapanga bwino katemera wa mRNA?Lero, tiyeni tiphunzire zakale komanso zamakono za katemera wa mRNA.

01
Kodi mRNA mu katemera wa mRNA ndi chiyani?

mRNA (Mthenga RNA), ndiko kuti, messenger RNA, ndi mtundu wa RNA yokhala ndi chingwe chimodzi yomwe imalembedwa kuchokera ku DNA ngati template ndipo imanyamula chidziwitso cha majini chomwe chingatsogolere kaphatikizidwe ka mapuloteni.M'mawu a layman, mRNA imabwereza chidziwitso cha chibadwa cha chingwe chimodzi cha DNA yamitundu iwiri mu nucleus, ndiyeno imasiya nyukiliya kuti ipange mapuloteni mu cytoplasm.Mu cytoplasm, ma ribosomes amayenda motsatira mRNA, amawerenga zotsatizana zake, ndikumasulira mu amino acid, kenako ndikupanga mapuloteni (Chithunzi 1).

Chithunzi 1 mRNA ntchito ndondomeko

02
Kodi katemera wa mRNA ndi chiyani ndipo amamupangitsa kukhala wapadera?

Katemera wa mRNA amalowetsa mRNA encoding antigens enieni m'thupi, ndikugwiritsa ntchito kaphatikizidwe ka mapuloteni a cell cell kupanga ma antigen, motero kumayambitsa kuyankha kwa chitetezo chamthupi.Nthawi zambiri, mndandanda wa mRNA wa ma antigen enieni amatha kupangidwa molingana ndi matenda osiyanasiyana, kupakidwa ndikutumizidwa m'maselo ndi tinthu tating'ono ta lipid nanocarrier, ndiyeno mndandanda wa mRNA wa ma ribosomes amunthu umagwiritsidwa ntchito kumasulira kutsata kwa mRNA kuti apange mapuloteni a antigen a matenda, omwe amadziwika ndi chitetezo chamthupi monga chitetezo chamthupi, kuteteza chitetezo chamthupi kuti chitetezeke.

Chithunzi 2. Mu vivo zotsatira za katemera wa mRNA

Ndiye, chapadera ndi chiyani pamtundu wotere wa katemera wa mRNA poyerekeza ndi katemera wakale?Katemera wa mRNA ndiye katemera wotsogola kwambiri wa m'badwo wachitatu, ndipo kafukufuku wina akufunika kuti apititse patsogolo kukhazikika kwawo, kuwongolera chitetezo chawo, ndikupanga matekinoloje atsopano operekera.

M'badwo woyamba wa katemera wachikhalidwe makamaka amaphatikizapo katemera wosagwiritsidwa ntchito ndi katemera wamoyo, omwe amagwiritsidwa ntchito kwambiri.Katemera wosagwiritsidwa ntchito amatanthawuza kukulitsa ma virus kapena mabakiteriya, kenako kuwayambitsa ndi kutentha kapena mankhwala (nthawi zambiri formalin);Katemera wokhala ndi moyo wocheperako amatanthawuza tizilombo toyambitsa matenda timene timasintha ndi kufooketsa kawopsedwe kawo akalandira mankhwala osiyanasiyana.koma amasungabe immunogenicity.Kulowetsa m'thupi sikungayambitse matenda, koma tizilombo toyambitsa matenda timatha kukula ndi kuchulukana m'thupi, kuyambitsa chitetezo cha mthupi, ndikuthandizira kupeza chitetezo cha nthawi yaitali kapena moyo wonse.

M'badwo wachiwiri wa katemera watsopano umaphatikizapo katemera wa subunit ndi katemera wa recombinant protein.Katemera wa subunit ndi katemera wa subunit wopangidwa ndi zigawo zazikulu zoteteza ma immunogen a mabakiteriya oyambitsa matenda, ndiye kuti, chifukwa cha kuwonongeka kwa mankhwala kapena kuwongolera proteolysis, mapuloteni apadera a mabakiteriya ndi ma virus amachotsedwa ndikufufuzidwa.Katemera wopangidwa ndi zidutswa za immunologically yogwira;Katemera wophatikizanso mapuloteni ndi mapuloteni ophatikizana ndi ma antigen omwe amapangidwa m'machitidwe osiyanasiyana amtundu wa cell.

M'badwo wachitatu wa katemera wamakono umaphatikizapo katemera wa DNA ndi katemera wa mRNA.Ndiko kudziwitsa mwachindunji kachilombo ka jini (DNA kapena RNA) yomwe imayika puloteni inayake ya antigenic m'maselo a nyama somatic (jekeseni wa katemera m'thupi la munthu), ndikupanga mapuloteni a antigenic kudzera mu dongosolo la kaphatikizidwe ka mapuloteni a cell, zomwe zimapangitsa kuti wolandirayo apangitse chitetezo cha antigenic protein poyankha kuti akwaniritse cholinga chopewera ndi kuchiza matenda.Kusiyana pakati pa ziwirizi ndikuti DNA imalembedwa koyamba kukhala mRNA kenako mapuloteni amapangidwa, pomwe mRNA imapangidwa mwachindunji.

03
Mbiri yopezeka ndi kufunika kwa katemera wa mRNA

Pankhani ya katemera wa mRNA, tiyenera kutchula wasayansi wodziwika bwino wamkazi, Kati Kariko, yemwe wayala maziko olimba a kafukufuku wa sayansi pakubwera kwa katemera wa mRNA.Anali wodzaza ndi chidwi chofufuza mRNA pomwe amaphunzira.Kwa zaka zoposa 40 za ntchito yake yofufuza za sayansi, adakumana ndi zolepheretsa mobwerezabwereza, sanapemphe ndalama zofufuzira za sayansi, komanso analibe malo okhazikika a kafukufuku wa sayansi, koma wakhala akuumirira pa kafukufuku wa mRNA.

Kati Karito

Pali mfundo zitatu zofunika pakubwera kwa katemera wa mRNA.

Mu gawo loyamba, adakwanitsa kupanga molekyulu ya mRNA yomwe akufuna kudzera mu chikhalidwe cha ma cell, koma adakumana ndi vuto kuti mRNA igwire ntchito m'thupi: atabaya mRNA mu mbewa, imamezedwa ndi chitetezo cha mbewa.Kenako anakumana ndi Weissman.Adagwiritsa ntchito molekyulu mu tRNA yotchedwa pseudouridine kuti mRNA ipewe kuyankha kwa chitetezo chamthupi.[2].
Mu sitepe yachiwiri, cha m'ma 2000, Prof. Pieter Cullis anaphunzira za lipid nanotechnology LNPs kwa mu vivo kutumiza siRNA kwa jini kuletsa ntchito [3][4].Bungwe la Weissman Kariko et al.anapeza kuti LNP ndi chonyamulira choyenera cha mRNA mu vivo, ndipo akhoza kukhala chida chofunika popereka mRNA encoding achire mapuloteni, ndipo kenako kutsimikiziridwa mu kupewa Zika HIV, HIV ndi zotupa [5] [6][7][8].

Mu gawo lachitatu, mu 2010 ndi 2013, Moderna ndi BioNTech motsatizana adalandira ziphaso zovomerezeka zokhudzana ndi kaphatikizidwe ka mRNA kuchokera ku University of Pennsylvania kuti apititse patsogolo.Katalin adakhalanso wachiwiri kwa Purezidenti wa BioNTech mu 2013 kuti apititse patsogolo katemera wa mRNA.

Masiku ano, katemera wa mRNA angagwiritsidwe ntchito pa matenda opatsirana, zotupa, ndi mphumu.Pankhani ya COVID-19 ikuchitika padziko lonse lapansi, katemera wa mRNA atha kuchitapo kanthu ngati wamkulu.

04
Chiyembekezo chogwiritsa ntchito katemera wa mRNA mu COVID-19

Ndi mliri wapadziko lonse wa COVID-19, mayiko akugwira ntchito molimbika kupanga katemera kuti athetse mliriwu.Monga mtundu watsopano wa katemera, katemera wa mRNA watenga gawo lalikulu pakubwera kwa mliri watsopano wa korona.Magazini ambiri apamwamba anena za udindo wa mRNA mu SARS-CoV-2 coronavirus yatsopano (Chithunzi 3).

Chithunzi 3 Lipoti la katemera wa mRNA kuti apewe coronavirus yatsopano (kuchokera ku NCBI)

Choyamba, asayansi ambiri anena za kafukufuku wa katemera wa mRNA (SARS-CoV-2 mRNA) motsutsana ndi coronavirus yatsopano mu mbewa.Mwachitsanzo: katemera wa lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP), jekeseni wamtundu umodzi umapangitsa mayankho amphamvu amtundu wa 1 CD4 + T ndi CD8 + T, plasma wamoyo wautali ndi kukumbukira B cell mayankho, ndi mphamvu ndi Kukhazikika kuyankha kwa antibody.Izi zikuwonetsa kuti katemera wa mRNA-LNP ndiwothandiza kwambiri polimbana ndi COVID-19[9][10].

Chachiwiri, asayansi ena adayerekeza zotsatira za SARS-CoV-2 mRNA ndi katemera wachikhalidwe.Poyerekeza ndi katemera ophatikizananso ndi mapuloteni: Katemera wa mRNA ndi wapamwamba kwambiri kuposa katemera wa mapuloteni mu majeremusi apakati poyankha, Tfh activation, neutralizing antibody kupanga, maselo enieni a kukumbukira B, ndi maselo a plasma amoyo wautali [11].

Kenako, pomwe ofuna katemera wa SARS-CoV-2 mRNA adalowa m'mayesero azachipatala, nkhawa zidadzutsidwa za nthawi yayitali yachitetezo cha katemera.Asayansi apanga mtundu wa lipid-encapsulated wa katemera wa nucleoside-modified mRNA wotchedwa mRNA-RBD.Jakisoni imodzi imatha kupanga ma antibodies amphamvu komanso mayankho amtundu wa ma cell, ndipo amatha kuteteza pafupifupi mbewa zomwe zili ndi 2019-nCoV, zokhala ndi ma antibodies ambiri omwe amasungidwa kwa miyezi 6.5.Izi zikusonyeza kuti mlingo umodzi wa mRNA-RBD umapereka chitetezo chanthawi yayitali ku zovuta za SARS-CoV-2 [12].
Palinso asayansi omwe akugwira ntchito yopanga katemera watsopano wotetezeka komanso wogwira mtima motsutsana ndi COVID-19, monga katemera wa BNT162b.Ma macaque otetezedwa ku SARS-CoV-2, adateteza njira yopumira yocheperako ku ma virus a RNA, amapanga ma antibodies amphamvu kwambiri, ndipo sanawonetse zizindikiro za kukulitsa matenda.Otsatira awiri pano akuwunikiridwa m'mayesero a Gawo I, ndipo kuyesa kwapadziko lonse lapansi kwa gawo II/III kukuchitikanso, ndipo ntchito yatsala pang'ono kutha [13].

05
Mkhalidwe wa katemera wa mRNA padziko lapansi

Pakadali pano, BioNTech, Moderna ndi CureVac amadziwika kuti ndi atsogoleri atatu apamwamba padziko lonse lapansi azachipatala a mRNA.Mwa iwo, BioNTech ndi Moderna ali patsogolo pa kafukufuku ndi chitukuko cha katemera watsopano wa korona.Moderna wakhala akuyang'ana kwambiri pa kafukufuku ndi chitukuko cha mankhwala ndi katemera okhudzana ndi mRNA.Katemera wa COVID-19 phase III mRNA-1273 ndiye ntchito yomwe ikukula mwachangu kwambiri pakampani.BioNTech ndiwotsogola padziko lonse lapansi wa mankhwala a mRNA ndi kafukufuku ndi chitukuko kampani, ndi okwana 19 mRNA mankhwala/makatemera, 7 amene alowa mu gawo lachipatala.CureVac yakhala ikuyang'ana kwambiri pa kafukufuku ndi chitukuko cha mankhwala / katemera wa mRNA, ndipo ndi kampani yoyamba padziko lapansi kukhazikitsa mzere wopanga RNA wogwirizana ndi GMP, womwe umayang'ana kwambiri zotupa, matenda opatsirana komanso matenda osowa.

Zogwirizana nazo:RNase Inhibitor
Mawu ofunikira: katemera wa miRNA, RNA Isolation, RNA m'zigawo, RNase Inhibitor

Maumboni:1.K Karikó, Buckstein M, Ni H, et al.Kuponderezedwa kwa Kuzindikiridwa kwa RNA ndi Ma Receptors ngati Toll: The Impact of Nucleoside Modification and Evolutionary Origin of RNA[J].Kusatetezedwa, 2005, 23 (2): 165-175.
2. K Karikó, Muramatsu H, Welsh FA, et al.Kuphatikizika kwa Pseudouridine Mu mRNA Kumatulutsa Vector Yapamwamba Yopanda Immunogenic Yokhala Ndi Mphamvu Yowonjezereka Yomasulira ndi Kukhazikika Kwachilengedwe[J].Therapy Molecular, 2008.3.Chonn A, Cullis PR.Kupita patsogolo kwaposachedwa kwa matekinoloje a liposome ndi momwe amagwiritsira ntchito popereka majini amtundu uliwonse[J].Ndemanga Zapamwamba Zopereka Mankhwala, 1998, 30 (1-3): 73.4.Kulkarni JA , Witzigmann D , Chen S , et al.Lipid Nanoparticle Technology for Clinical Translation of siRNA Therapeutics[J].Maakaunti a Chemical Research, 2019, 52(9).5.Kariko, Katalin, Madden, et al.Mawu kinetics a nucleoside-modified mRNA yoperekedwa mu lipid nanoparticles kwa mbewa ndi njira zosiyanasiyana[J].Journal of Controlled Release Official Journal of the Controlled Release Society, 2015.6.Kutetezedwa kwa kachilombo ka Zika ndi katemera wa nucleoside-modified mRNA wochepa [J].Chilengedwe, 2017, 543 (7644): 248-251.7.Pardi N, Secreto AJ, Shan X, et al.Ulamuliro wa nucleoside-modified mRNA encoding yochepetsetsa kwambiri imateteza mbewa zaumunthu ku zovuta za HIV-1[J].Kulankhulana Kwachilengedwe, 2017, 8:14630.8.Stadler CR , B?Hr-Mahmud H , Celik L , et al.Kuchotsa zotupa zazikulu mu mbewa ndi mRNA-encoded bispecific antibodies[J].Mankhwala a Zachilengedwe, 2017.9.NN Zhang, Li XF, Deng YQ, et al.Katemera wa Thermostable mRNA motsutsana ndi COVID-19[J].Cell, 2020.10.D Laczkó, Hogan MJ , Toulmin SA , et al.Katemera Mmodzi Wokhala ndi Katemera wa Nucleoside-Modified mRNA Amapereka Mayankho Olimba a Ma Cellular ndi Humoral Immune motsutsana ndi SARS-CoV-2 mu Mbewa - ScienceDirect[J].2020.11.Lederer K , Castao D , Atria DG , et al.Katemera wa SARS-CoV-2 mRNA Amalimbikitsa Mayankho Amphamvu a Antigen-Specific Germinal Center Ogwirizana ndi Neutralizing Antibody Generation[J].Kutetezedwa, 2020, 53 (6): 1281-1295.e5.12.Huang Q, Ji K, Tian S, et al.Katemera wa mlingo umodzi wa mRNA amapereka chitetezo chanthawi yayitali kwa mbewa za haACE2 kuchokera ku SARS-CoV-2[J].Kulankhulana Zachilengedwe.13.Vogel AB , Kanevsky I , Ye C , et al.Katemera wa Immunogenic BNT162b amateteza ma rhesus macaques ku SARS-CoV-2[J].Chilengedwe, 2021:1-10.