Umthombo: WuXi AppTec

Eminyakeni yamuva nje, umkhakha we-RNA therapy ubonise umkhuba wokuqhuma-eminyakeni engu-5 edlule iyodwa, i-FDA igunyazwe imishanguzo ye-RNA engu-11, futhi leli nani lize lidlule isamba semithi yokwelapha ye-RNA egunyazwe ngaphambili!Uma kuqhathaniswa nemithi yokwelapha yendabuko, ukwelashwa kwe-RNA kungathuthukisa ngokushesha izindlela zokwelapha ezihlosiwe ngezinga eliphezulu lempumelelo inqobo nje uma ukulandelana kwezakhi zofuzo kwaziwa.Ngakolunye uhlangothi, izindlela zokwelapha eziningi ze-RNA zisatholakala kuphela ukwelapha izifo ezingavamile, futhi ukuthuthukiswa kwalezi zindlela zokwelapha kusabhekene nezinselele eziningi mayelana nokuqina kokwelashwa, ukuphepha, nokulethwa.Esihlokweni sanamuhla, iithimba lokuqukethwe le-WuXi AppTec lizobuyekeza inqubekelaphambili emkhakheni wokwelapha nge-RNA onyakeni odlule, futhi libheke ngabomvu ikusasa lalo mkhakha osafufusa onabafundi.

▲ Imithi yokwelapha ye-RNA eyi-11 noma imithi yokugoma igunyazwe yi-FDA eminyakeni emi-5 edlule

Kusukela ezifweni ezingavamile kuya ezifweni ezivamile, izimbali eziningi ziyaqhakaza

Kulolu bhubhane olusha lomqhele, umuthi wokugomela i-mRNA wazalwa ngokungekho ndawo futhi uthole ukunakwa okusabalele embonini.Ngemva kweimpumelelo ekuthuthukisweni kwemithi yokugomela izifo ezithathelwanayo, enye inselele enkulu ebhekene nobuchwepheshe be-mRNA ukukhulisa ububanzi bokufaka isicelo sokwelashwa nokuvimbela izifo ezengeziwe.
Phakathi kwazo,imithi yokugomela umdlavuza yomuntu ngamunye iwumkhakha wokusetshenziswa obalulekile wobuchwepheshe be-mRNA, futhi sibone imiphumela emihle yomtholampilo yemithi yokugomela umdlavuza eminingana kulo nyaka.Kule nyanga nje, umuthi wokugomela umdlavuza womuntu ngamunye owenziwe ngokuhlanganyela yiModerna noMerck, uhlanganiswe ne-PD-1 inhibitor Keytruda,yehlisa ingoziukuphindaphinda noma ukufa ezigulini ezine-melanoma yesigaba III kanye ne-IV ngemva kokuqedwa okuphelele kwesimila ngo-44% (uma kuqhathaniswa ne-Keytruda monotherapy).Ukukhululwa kwabezindaba kuveze ukuthi kungokokuqala ukuthi umuthi wokugomela umdlavuza we-mRNA ukhombise ukusebenza kahle ekwelapheni i-melanoma ocwaningweni lomtholampilo olungahleliwe, okuyisigameko esiyingqopha-mlando ekuthuthukisweni kwemithi yokugomela umdlavuza we-mRNA.
Ngaphezu kwalokho, imigomo ye-mRNA ingase futhi ithuthukise umphumela wokwelapha wokwelashwa kwamaseli .Isibonelo, ucwaningo olwenziwa yi-BioNTech luveze ukuthi uma iziguli ziqale zifakwe umthamo ophansi we-CLDN6 ehloselwe ukwelashwa kwe-CAR-T.I-BNT211, bese bejova ngomuthi wokugomela we-mRNA ofaka ikhodi ye-CLDN6, bangashukumisa amaseli e-CAR-T ku-vivo ngokuveza i-CLDN6 ebusweni bamaseli abonisa i-antigen.Ukukhulisa, ngaleyo ndlela kuthuthukisa umphumela we-anticancer.Imiphumela yokuqala ibonise ukuthi iziguli ezi-4 kwezi-5 ezithole ukwelashwa okuhlangene zithole ukusabela okuyingxenye, noma u-80%.

Ngaphezu kokwelashwa kwe-mRNA, ukwelashwa kwe-oligonucleotide kanye nokwelashwa kwe-RNAi nakho kuzuze imiphumela emihle ekwandiseni ububanzi bezifo.Ekwelapheni isifo sokusha kwesibindi kohlobo B esingamahlalakhona, cishe amaphesenti angama-30 eziguli awakwazi ukubona i-antigen ye-hepatitis B kanye negciwane le-hepatitis B ku-vivo ngemva kokusebenzisa i-antisense oligonucleotide therapy.i-bepirovirsen ithuthukiswe ngokuhlanganyela yi-GSK kanye ne-Ionisamaviki angama-24.Kwezinye iziguli, ngisho namasonto angu-24 ngemva kokuyeka ukwelashwa, lezi zimpawu ze-hepatitis B zazingakabonakali emzimbeni.
Ngokuzenzakalelayo, ukwelashwa kwe-RNAiI-VIR-2218 ithuthukiswe ngokuhlanganyela yi-Vir Biotechnology kanye ne-Alnylam yahlanganiswange-interferon α, nasezivivinyweni zomtholampilo zesigaba sesi-2, cishe amaphesenti angama-30 eziguli ze-hepatitis B ezingapheli nazo zehlulekile ukuthola i-antigen ye-hepatitis B ebusweni (HBsAg).Ngaphezu kwalokho, lezi ziguli zakha amasosha omzimba ngokumelene namaprotheni e-hepatitis B, okubonisa impendulo enhle yamasosha omzimba.Ihlanganisa le miphumela, imboni iveza ukuthi ukwelashwa kwe-RNA kungase kube ukhiye wokwelapha okusebenzayo kwe-hepatitis B.
Lokhu kungaba yisiqalo nje sokwelashwa kwe-RNA kwezifo ezivamile.Ngokusho kwepayipi le-R&D lakwa-Alnylam, iphinde ithuthukise izindlela zokwelapha ze-RNAi zokwelapha umfutho wegazi ophakeme, isifo i-Alzheimer's, kanye ne-steatohepatitis engeyona utshwala, futhi ikusasa kufanele silibheke ngabomvu.

Ukweqa ibhodlela lokulethwa kokwelashwa kwe-RNA

Ukulethwa kokwelashwa kwe-RNA kungenye yezingqinamba ezikhawulela ukusetshenziswa kwayo.Ososayensi bakha nobuchwepheshe obuhlukahlukene ukuze balethe ukwelashwa kwe-RNA ezithweni nasezithweni ngaphandle kwesibindi.
Enye yezindlela ezingenzeka “iwukubopha” ama-RNA okwelapha ngama-molecule aqondene nezicubu .Isibonelo, i-Avidity Biosciences isanda kumemezela ukuthi inkundla yayo yobuchwepheshe ingahlanganisa amasosha omzimba e-monoclonal kuma-oligonucleotideshlanganisa ngempumelelo ama-siRNA.ithunyelwe emisipha yamathambo.Ukukhishwa kwabezindaba kuveze ukuthi kungokokuqala ngqa ukuthi i-siRNA iqondiswe ngempumelelo futhi ihanjiswe ezicutshini zemisipha yomuntu, okuwumphumela omkhulu emkhakheni we-RNA therapy.

Umthombo wesithombe: 123RF

Ngokungeziwe kubuchwepheshe bokuhlanganiswa kwe-antibody, izinkampani ezimbalwa ezakha i-lipid nanoparticles (LNP) nazo "ziyathuthukisa" abathwali abanjalo.Ngokwesibonelo, ReCode Therapeuticisebenzisa i-Selective Organ Targeting LNP Technology (SORT) yayo eyingqayizivele ukuze ilethe izinhlobo ezihlukahlukene zokwelashwa kwe-RNA emaphashini, ubende, isibindi nezinye izitho.Kulo nyaka, inkampani imemezele ukuphothulwa komjikelezo wezimali we-US $ 200 wezigidigidi ze-Series B, kanye neminyango ye-venture capital ye-Pfizer, i-Bayer, i-Amgen, i-Sanofi nezinye izinkampani ezinkulu zemithi ezibamba iqhaza ekutshalweni kwezimali.I-Kernal Biologics, ephinde yathola amaRandi ayizigidi ezingu-25 ku-Series A ngezimali kulo nyaka, iphinde ithuthukise ama-LNP angaqoqi esibindi, kodwa angaletha i-mRNA ukuze iqondise amangqamuzana afana nobuchopho noma izimila ezithile.
I-Orbital Therapeutics, eyaqala kulo nyaka, iphinde ithathe ukulethwa kokwelashwa kwe-RNA njengesiqondiso esibalulekile sokuthuthukiswa.Ngokuhlanganisa ubuchwepheshe be-RNA kanye nezindlela zokulethwa, inkampani ilindele ukwakha inkundla yobuchwepheshe be-RNA eyingqayizivele enganweba ukuphikelela kanye nengxenye yempilo ye-RNA yokwelapha emisha futhi iwahambise ezinhlotsheni ezihlukahlukene zamangqamuzana nezicubu.

Uhlobo olusha lokwelapha nge-RNA luyavela esikhathini esiyingqopha-mlando

Kusukela ngomhla ka-21 kuZibandlela kulo nyaka, emkhakheni wezokwelashwa kwe-RNA, kube nemicimbi engama-31 yokuxhasa ngezimali kusenesikhathi (bheka indlela yokusebenza ekugcineni kwesihloko ukuze uthole imininingwane), ebandakanya izinkampani ezisezingeni eliphezulu ezingama-30 (inkampani eyodwa ithole uxhaso kabili), nesamba semali esiphelele samadola ayizigidi eziyizinkulungwane eziyi-1.74.Ukuhlaziywa kwalezi zinkampani kukhombisa ukuthi abatshalizimali banethemba elikhulu ngalezo zinkampani ezisezingeni eliphezulu okulindeleke ukuthi zixazulule izinselele eziningi zokwelapha i-RNA, ukuze zibone ngokugcwele amandla okwelashwa kwe-RNA futhi kusizakale iziguli eziningi.
Futhi kunezinkampani ezisafufusa ezithuthukisa izinhlobo ezintsha zokwelapha ze-RNA.Ngokungafani nama-oligonucleotides endabuko, i-RNAi noma i-mRNA, izinhlobo ezintsha zama-molecule e-RNA athuthukiswe yilezi zinkampani kulindeleke ukuthi zibhodloze ibhodlela lezindlela zokwelapha ezikhona.
I-RNA eyindilinga ingenye yezindawo ezishisayo embonini.Uma kuqhathaniswa ne-mRNA eqondile, ubuchwepheshe obuyindilinga be-RNA obuthuthukiswe inkampani esezingeni eliphezulu ebizwa nge-Orna Therapeutics bungagwema ukuqashelwa amasosha omzimba azalwa nawo kanye nama-exonuclease, angagcini nje ngokunciphisa kakhulu i-immunogenicity, kodwa futhi enokuqina okuphezulu.Ngaphezu kwalokho, uma kuqhathaniswa ne-RNA yomugqa, ukuhambisana okugoqiwe kwe-RNA eyindilinga kuncane, futhi i-RNA eyindilinga eyengeziwe ingalayishwa nge-LNP efanayo, ithuthukise ukusebenza kahle kokulethwa kokwelashwa kwe-RNA.Lezi zici zingasiza ukuthuthukisa amandla nokuqina kokwelashwa kwe-RNA.
Kulo nyaka, inkampani iphothule uxhaso lwezimali lwama-US$221 million Series B, yaphinde yafinyelela ocwaningweniukubambisana kwentuthuko ne-Merck kufika ku-US$3.5 billion.Ngaphezu kwalokho, u-Orna futhi usebenzisa i-RNA eyindilinga ukuze akhiqize ngokuqondile ukwelashwa kwe-CAR-T ezilwaneni, egcwalisa ubufakazi bokuthiumqondo.
Ngaphezu kwe-RNA eyindilinga, ubuchwepheshe obuzikhulisayo be-mRNA (samRNAs) nabo buye bathandwa ngabatshalizimali.Lobu buchwepheshe busekelwe kumshini wokuzikhulisa wegciwane le-RNA, elingaheha ukuphindaphinda kokulandelana kwe-samRNA ku-cytoplasm, kwandise inkulumo ye-kinetics ye-mRNA Therapeutics, ngaleyo ndlela yehlise imvamisa yokuphatha.Uma kuqhathaniswa ne-mRNA yomugqa yendabuko, i-samRNA iyakwazi ukugcina amazinga afanayo wokusho amaprotheni cishe imithamo ephansi ephindwe ka-10.Kulo nyaka, i-RNAimmune, egxile ekuthuthukisweni kwalo mkhakha, ithole ama-US $ 27 wezigidi ku-Series A ngezimali.
Ubuchwepheshe be-tRNA nakho kufanelekile ukubheka phambili.Ukwelapha okusekelwe ku-tRNA “kungakwazi ukuziba” i-stop codon engalungile lapho iseli lenza iphrotheni, ukuze kukhiqizwe iphrotheni yobude obugcwele obujwayelekile.Ngenxa yokuthi kunezinhlobo ezimbalwa kakhulu zama-stop codon kunezifo ezihlotshaniswa nazo, ukwelashwa kwe-tRNA kunamandla okwenza ukwelapha okukodwa okungalapha izifo eziningi.Kulo nyaka, i-hC Bioscience, egxile ekwelashweni kwe-tRNA, iqoqe isamba semali engu-US$40 wezigidi ku-Series A ngezimali.

Epilogue

Njengemodeli yokwelapha evelayo, ukwelashwa kwe-RNA kuye kwazuza ukuthuthukiswa okusheshayo eminyakeni yamuva, futhi izindlela eziningi zokwelapha sezivunyelwe.Kusukela ekuthuthukisweni kwakamuva embonini, kungabonakala ukuthi izindlela zokwelapha ze-RNA ezisezingeni eliphezulu zandisa uchungechunge lwezifo ezingalashwa yilezo zindlela zokwelapha, zinqobe izingqinamba ezihlukahlukene ekulethweni okuhlosiwe, nokuthuthukisa ama-molecule e-RNA amasha ukuze anqobe ukulinganiselwa kwezindlela zokwelapha ezikhona mayelana nokusebenza kahle nokuqina.izinselelo eziningi.Kule nkathi entsha yokwelashwa kwe-RNA, lezi zinkampani ezisezingeni eliphezulu zingase zibe imboni egxile kuyo eminyakeni embalwa ezayo.

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