I ka Vaccine and Health Conference, ua kāhea ka poʻe loea i "pono ​​​​ka poʻe a pau e hoʻolohe i nā kano mRNA, e hāʻawi ana i nā kānaka me ka noʻonoʻo ʻole."No laila he aha ke ʻano o ka maʻi mRNA?Pehea i ʻike ʻia ai a he aha kāna waiwai hoʻohana?Hiki iā ia ke pale aku i ka COVID-19 e huhū a puni ka honua?Ua hoʻomohala maikaʻi koʻu ʻāina i kahi kano mRNA?I kēia lā, e aʻo kākou e pili ana i ka wā i hala a me kēia manawa o nā lāʻau lapaʻau mRNA.

01
He aha ka mRNA i nā lāʻau lapaʻau mRNA?

ʻO ka mRNA (Messenger RNA), ʻo ia hoʻi, messenger RNA, he ʻano o ka RNA kaula hoʻokahi i unuhi ʻia mai kahi kaula DNA ma ke ʻano he laʻa a lawe i ka ʻike genetic e hiki ke alakaʻi i ka synthesis protein.Ma ka ʻōlelo a ka poʻe kamaʻāina, hoʻopili hou ka mRNA i ka ʻike moʻo o hoʻokahi kaula o ka DNA kaulua i loko o ka nucleus, a laila haʻalele i ka nucleus e hana i nā protein i loko o ka cytoplasm.I loko o ka cytoplasm, neʻe nā ribosomes ma ka mRNA, heluhelu i kona kaʻina kumu, a unuhi iā ia i loko o kāna waikawa amino e pili ana, a lilo i pūmua (Figure 1).

Kiʻi 1 mRNA kaʻina hana

02
He aha ka lāʻau lapaʻau mRNA a he aha ka mea ʻokoʻa?

Hoʻokomo nā lāʻau lapaʻau mRNA i ka mRNA e hoʻopili ana i nā antigens kikoʻī o ka maʻi i loko o ke kino, a hoʻohana i ka ʻōnaehana protein synthesis o ka host cell e hana i nā antigens, a laila e hoʻoulu ai i kahi pane kūlohelohe.ʻO ka maʻamau, hiki ke kūkulu ʻia nā kaʻina mRNA o nā antigens kikoʻī e like me nā maʻi like ʻole, hoʻopaʻa ʻia a lawe ʻia i loko o nā cell e nā ʻāpana nanocarrier lipid novel, a laila hoʻohana ʻia nā ʻāpana mRNA o nā ribosomes kanaka e unuhi i nā kaʻina mRNA e hana i nā protein antigen maʻi, i ʻike ʻia e ka ʻōnaehana autoimmune ma hope o ka huna ʻana e hoʻokō i ka pane ʻana o ka maʻi.

Kiʻi 2. In vivo hopena o ka mRNA kano

No laila, he aha ka mea ʻokoʻa e pili ana i kēia ʻano kano mRNA i hoʻohālikelike ʻia me nā maʻi maʻamau?ʻO nā lāʻau lapaʻau mRNA nā lāʻau lapaʻau ʻekolu o nā hanauna hou aʻe e pono ai e hoʻomaikaʻi i ko lākou kūpaʻa, hoʻoponopono i ko lākou immunogenicity, a hoʻomohala i nā ʻenehana lawe hou.

ʻO ka hanauna mua o nā lāʻau lapaʻau maʻamau ka nui o nā lāʻau lapaʻau inactivated a me nā lāʻau lapaʻau ola ola, ʻo ia ka mea i hoʻohana nui ʻia.ʻO nā lāʻau lapaʻau i hoʻohana ʻole ʻia e pili ana i ka kanu mua ʻana i nā maʻi maʻi a i ʻole bacteria, a laila hoʻopau ʻia me ka wela a i ʻole nā ​​mea kemika (maʻamau ka formalin);ʻO nā lāʻau lapaʻau ola ola e pili ana i nā pathogens e hoʻololi a hoʻonāwaliwali i ko lākou ʻona ma hope o nā lāʻau lapaʻau like ʻole.akā, paʻa mau kona immunogenicity.ʻO ka hoʻokomo ʻana i loko o ke kino ʻaʻole ia e hoʻomaka ai ka maʻi, akā hiki i ka pathogen ke ulu a hoʻonui i loko o ke kino, hoʻoulu i ka pane ʻana o ke kino, a pāʻani i ka loaʻa ʻana o ka pale no ka wā lōʻihi a i ʻole ke ola.

ʻO ka lua o ka hanauna o nā lāʻau lapaʻau hou e pili ana i nā lāʻau lapaʻau subunit a me nā kano protein recombinant.ʻO ka lāʻau lapaʻau subunit kahi maʻi maʻi subunit i hana ʻia me nā ʻāpana immunogen pale nui o nā bacteria pathogenic, ʻo ia hoʻi, ma o ka decomposition kemika a i ʻole ka proteolysis i hoʻomalu ʻia, lawe ʻia a hoʻopaʻa ʻia ke ʻano protein kūikawā o ka bacteria a me nā maʻi.Nā lāʻau lapaʻau i hana ʻia me nā ʻāpana immunologically;ʻO nā lāʻau lapaʻau recombinant he mau antigen recombinant protein i hana ʻia ma nā ʻōnaehana hōʻike cell like ʻole.

ʻO ke kolu o ka hanauna o nā lāʻau lapaʻau ʻokiʻoki e pili ana i nā kano DNA a me nā maʻi mRNA.ʻO ia ka hoʻolauna pololei ʻana i ka ʻāpana viral gene (DNA a i ʻole RNA) e hoʻopili ana i kekahi protein antigenic i loko o nā cell somatic holoholona (i ke kino o ke kanaka), a hana i ka protein antigenic ma o ka ʻōnaehana synthesis protein o ka cell host, e hoʻoulu ai i ka pūʻali e hana i ka pale ʻana i ka pane antigenic protein i mea e hoʻokō ai i ke kumu o ka pale ʻana a me ka mālama ʻana i nā maʻi.ʻO ka ʻokoʻa ma waena o nā mea ʻelua, ua kākau mua ʻia ʻo DNA i mRNA a laila synthesized ka protein, aʻo ka mRNA i hoʻopili pololei ʻia.

03
ʻO ka mōʻaukala ʻike a me ka waiwai o ka noi ʻana o ka maʻi mRNA

I ka hiki ʻana mai i nā lāʻau lapaʻau mRNA, pono mākou e haʻi i kahi ʻepekema wahine koʻikoʻi, ʻo Kati Kariko, nāna i hoʻokumu i kahi kumu noiʻi ʻepekema paʻa no ka hiki ʻana mai o nā kano mRNA.Ua piha ʻo ia i ka hoihoi noiʻi i ka mRNA i kāna aʻo ʻana.I loko o kāna ʻoihana noiʻi ʻepekema ʻoi aku ma mua o 40, ua loaʻa ʻo ia i nā setbacks mau, ʻaʻole i noi no nā kālā noiʻi ʻepekema, a ʻaʻole i loaʻa kahi kūlana noiʻi ʻepekema paʻa, akā ua koi mau ʻo ia i ka noiʻi mRNA.

Kati Karito

ʻEkolu node koʻikoʻi i ka hiki ʻana mai o nā lāʻau lapaʻau mRNA.

I ka hana mua, ua lanakila ʻo ia i ka hana ʻana i ka molekele mRNA i makemake ʻia ma o ka molekele cell, akā ua loaʻa iā ia kahi pilikia i ka hana ʻana i ka hana mRNA i loko o ke kino: ma hope o ka hoʻokomo ʻana i ka mRNA i loko o ka ʻiole, e ale ʻia e ka ʻōnaehana pale o ka ʻiole.A laila hui ʻo ia me Weissman.Ua hoʻohana lākou i kahi mole i loko o ka tRNA i kapa ʻia ʻo pseudouridine e hana i ka mRNA e pale i ka pane immune.][2].
Ma ka ʻanuʻu ʻelua, ma kahi o 2000, ua aʻo ʻo Prof. Pieter Cullis i ka lipid nanotechnology LNPs no ka lawe ʻana i vivo o siRNA no nā noi silencing gene [3][4].Weissman hui Kariko et al.Ua ʻike ʻo LNP he mea lawe kūpono o ka mRNA i loko o ka vivo, a lilo paha i mea waiwai nui no ka hoʻopuka ʻana i ka mRNA encoding therapeutic proteins, a ma hope i hōʻoia ʻia i ka pale ʻana i ka maʻi maʻi Zika, HIV a me nā maʻi koko [5] ][6][7][8].

Ma ke kolu o ka hana, ma 2010 a me 2013, ua loaʻa hou aku ʻo Moderna a me BioNTech i nā laikini patent e pili ana i ka synthesis mRNA mai ke Kulanui o Pennsylvania no ka hoʻomohala hou ʻana.Ua lilo ʻo Katalin i pelekikena poʻokela o BioNTech i ka makahiki 2013 e hoʻomohala hou i nā kano mRNA.

I kēia lā, hiki ke hoʻohana ʻia nā lāʻau lapaʻau mRNA i nā maʻi maʻi maʻi, nā ʻōpū, a me ka hānō.I ka hihia o COVID-19 e huhū ana a puni ka honua, hiki i nā lāʻau lapaʻau mRNA ke hana ma ke ʻano he alo.

04
ʻO ka manaʻolana noi o ka maʻi mRNA ma COVID-19

Me ka maʻi ahulau honua o COVID-19, ke hana ikaika nei nā ʻāina e hoʻomohala i kahi kano e pale ai i ka maʻi maʻi.Ma ke ʻano he ʻano kano hou, ua hana nui ka maʻi mRNA i ka hiki ʻana mai o ke ahulau lei hou.Ua hōʻike ka nui o nā nūpepa kiʻekiʻe i ke kuleana o ka mRNA i ka SARS-CoV-2 hou coronavirus (Figure 3).

Kiʻi 3 Hōʻike i nā lāʻau lapaʻau mRNA e pale i ka coronavirus hou (mai NCBI)

ʻO ka mea mua, ua hōʻike ka nui o nā ʻepekema i ka noiʻi ʻana o ka maʻi mRNA (SARS-CoV-2 mRNA) e kūʻē i ka coronavirus hou i nā ʻiole.No ka laʻana: lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP) vaccine, hoʻokahi-dose injection induces strong type 1 CD4+ T a me CD8+ T cell pane, lōʻihi ola plasma a me ka hoʻomanaʻo B cell pane, a paʻa a hoʻomau neutralizing antibody pane.Hōʻike kēia i ka lāʻau lapaʻau mRNA-LNP he moho hoʻohiki kūʻē iā COVID-19[9][10].

ʻO ka lua, ua hoʻohālikelike kekahi mau ʻepekema i nā hopena o SARS-CoV-2 mRNA a me nā kano kuʻuna.Hoʻohālikelike ʻia me nā lāʻau lapaʻau recombinant: ʻoi aku ka maikaʻi o nā lāʻau lapaʻau mRNA ma mua o nā lāʻau lapaʻau i ka pane germinal center, Tfh activation, neutralizing antibody production, specific memory B cell, and long-lived plasma cell [11] .

A laila, i ka wā i komo ai nā moho kano kano SARS-CoV-2 mRNA i nā hoʻokolohua lapaʻau, ua hāpai ʻia nā hopohopo e pili ana i ka manawa pōkole o ka pale ʻana i ka maʻi.Ua hoʻomohala ka poʻe ʻepekema i kahi ʻano lipid-encapsulated o kahi maʻi mRNA i hoʻololi ʻia nucleoside i kapa ʻia he mRNA-RBD.Hiki i kahi injection hoʻokahi ke hoʻoulu i nā antibodies neutralizing ikaika a me nā pane kelepona, a aneane hiki ke pale aku i nā ʻiole hoʻohālike i loaʻa i ka 2019-nCoV, me nā pae kiʻekiʻe o ka neutralizing antibodies i mālama ʻia no ka liʻiliʻi o 6.5 mau mahina.Hōʻike kēia mau ʻikepili i ka hāʻawi ʻana o ka mRNA-RBD i ka pale lōʻihi e kūʻē i ka hoʻokūkū SARS-CoV-2 [12].
Aia kekahi poʻe ʻepekema e hana ana e hoʻomohala i nā lāʻau lapaʻau palekana a maikaʻi hoʻi e kūʻē iā COVID-19, e like me ka BNT162b kano.Mālama ʻia nā macaques mai SARS-CoV-2, pale i ka ʻōpū hanu haʻahaʻa mai ka RNA viral, hana i nā antibodies ikaika loa, a ʻaʻohe hōʻailona o ka hoʻonui ʻana i ka maʻi.ʻElua mau moho i kēia manawa ma lalo o ka loiloi ʻana i nā hoʻāʻo ʻana o ka pae I, a ke hoʻomaka nei ka loiloi ma ka pae honua II / III hoʻāʻo, a aia ka noi ma kahi o ke kihi [13].

05
ʻO ke kūlana o ka lāʻau lapaʻau mRNA i ka honua

I kēia manawa, ʻike ʻia ʻo BioNTech, Moderna a me CureVac ʻo ia ka poʻe alakaʻi o ka mRNA therapy ʻekolu o ka honua.Ma waena o lākou, aia ʻo BioNTech a me Moderna i ka mua o ka noiʻi a me ka hoʻomohala ʻana i ke kano lei aliʻi hou.Ke kālele nei ʻo Moderna i ka noiʻi a me ka hoʻomohala ʻana i nā lāʻau lapaʻau e pili ana i ka mRNA a me nā kano.ʻO ka COVID-19 phase III hoʻāʻo kano mRNA-1273 ʻo ia ka papahana e ulu wikiwiki ana ka ʻoihana.ʻO BioNTech kekahi ʻoihana lapaʻau mRNA alakaʻi i ka honua a me ka hui noiʻi a me ka hoʻomohala ʻana i ka lāʻau lapaʻau, me ka huina o 19 mRNA mau lāʻau lapaʻau/vaccines, 7 o lākou i komo i ke kahua lapaʻau.Ke kālele nei ʻo CureVac i ka noiʻi ʻana a me ka hoʻomohala ʻana i nā lāʻau lapaʻau / kano mRNA, a ʻo ia ka ʻoihana mua ma ka honua e hoʻokumu i kahi laina hana RNA e pili ana i ka GMP, e kālele ana i nā maʻi maʻi, nā maʻi maʻi a me nā maʻi maʻamau.

Nā huahana pili:ʻO ka mea pale RNase
ʻO nā hua'ōlelo nui: ka maʻi miRNA, RNA Isolation, RNA extraction, RNase Inhibitor

Nānā Haʻawina:1.K Karikó, Buckstein M , Ni H , et al.Hoʻopau i ka ʻike ʻana o RNA e nā mea hoʻokipa e like me Toll: Ka hopena o ka hoʻololi ʻana o Nucleoside a me ka Evolutionary Origin o RNA [J].Imunity, 2005, 23 (2): 165-175.
2. K Karikó, Muramatsu H, Welsh FA, et al.ʻO ka hoʻohui ʻana o Pseudouridine i loko o ka mRNA e hāʻawi i ka Vector Nonimmunogenic kiʻekiʻe me ka hoʻonui ʻia o ka unuhi ʻana a me ke kūpaʻa olaola [J].Hoʻoponopono Molecular, 2008.3.Chonn A , Cullis PR .ʻO nā holomua hou i nā ʻenehana liposome a me kā lākou mau noi no ka lawe ʻana i nā gene systemic [J].Nā Manaʻo Hoʻolaha Lapaʻau Kiʻekiʻe, 1998, 30 (1-3): 73.4.Kulkarni JA , Witzigmann D , Chen S , a me al.ʻO Lipid Nanoparticle Technology no ka unuhi ʻana i ke kino o ka siRNA Therapeutics[J].Nā moʻolelo o ka noiʻi kemika, 2019, 52(9).5.Kariko, Katalin, Madden, et al.Hōʻike kinetics o nucleoside-modified mRNA i hāʻawi ʻia i loko o nā nanoparticles lipid i nā ʻiole ma nā ala like ʻole [J].Nūpepa o ka hoʻokuʻu ʻana i hoʻokuʻu ʻia i ka puke pai o ka hui hoʻokuʻu ʻia, 2015.6.ʻO ka pale ʻana i ka maʻi maʻi Zika e ka lāʻau lapaʻau mRNA i hoʻololi ʻia i ka nucleoside haʻahaʻa [J].Natura, 2017, 543(7644):248-251.7.Pardi N , Secreto AJ , Shan X , et al.ʻO ka hoʻokele ʻana o ka mRNA i hoʻololi ʻia i ka nucleoside e hoʻopili ana i ka antibody e pale i nā ʻiole kanaka mai ka hoʻokūkū HIV-1 [J].Nature Communications, 2017, 8:14630.8.Stadler CR , B?Hr-Mahmud H , Celik L , et al.ʻO ka hoʻopau ʻana i nā maʻi maʻi nui i nā ʻiole e nā antibodies bispecific i hoʻopili ʻia e mRNA [J].Nature Medicine, 2017.9.NN Zhang, Li XF , Deng YQ , et al.ʻO kahi maʻi mRNA Thermotable e kūʻē iā COVID-19[J].Kelepona, 2020.10.D Laczkó, Hogan MJ, Toulmin SA, et al.ʻO kahi maʻi hoʻokahi me ka Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice - ScienceDirect[J].2020.11.Lederer K , Castao D , Atria DG , et al.ʻO SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center pane i pili me ka Neutralizing Antibody Generation[J].Ka palekana, 2020, 53(6):1281-1295.e5.12.Huang Q , Ji K , Tian S , et al.Hāʻawi ka lāʻau lapaʻau mRNA hoʻokahi i kahi pale lōʻihi no nā ʻiole transgenic hACE2 mai SARS-CoV-2[J].Nature Communications.13.Vogel AB, Kanevsky I, Ye C, et al.ʻO nā lāʻau lapaʻau immunogenic BNT162b e pale i nā rhesus macaques mai SARS-CoV-2[J].ʻAno, 2021:1-10.