Ngophuhliso oluqhubekayo lwetekhnoloji yebhayoloji yemolekyuli, ubudlelwane phakathi kokuguqulwa kofuzo kunye neziphene kunye nezifo ziye zafumana ukuqonda okunzulu ngakumbi.I-Nucleic acids itsale ingqalelo enkulu ngenxa yamandla abo amakhulu okusetyenziswa ekuxilongeni nasekunyangeni izifo.Amachiza e-Nucleic acid abhekisela kwi-DNA eyenziwe ngokwenza okanye amaqhekeza e-RNA anemisebenzi yonyango lwezifo.Amachiza anjalo angenza ngokuthe ngqo kwiijini ezijoliswe kuzo ezibangela isifo okanye iimRNAs ezibangela izifo, kwaye zidlale indima ekunyangeni izifo kwinqanaba lemfuza.Xa kuthelekiswa neziyobisi zemveli ze-molecule kunye neziyobisi ze-antibody, iziyobisi ze-nucleic acid ziyakwazi ukulawula ukubonakaliswa kwezifo ezibangela izifo ezisuka kwingcambu, kwaye zineempawu "zokuphatha iimpawu kunye nokunyanga unobangela".Amachiza e-Nucleic acid nawo aneenzuzo ezicacileyo ezifana nokusebenza okuphezulu, ubuthi obuphantsi, kunye nokucaciswa okuphezulu.Ukususela ekubeni iyeza lokuqala le-nucleic acid i-fomivirsen sodium yasungulwa ngo-1998, amaninzi amachiza e-nucleic acid avunyiwe ukuba afumane unyango lweklinikhi.

Amachiza e-nucleic acid ngoku akwintengiso kwihlabathi ngokubanzi abandakanya i-antisense nucleic acid (ASO), i-RNA encinci ephazamisayo (siRNA), kunye ne-nucleic acid aptamers.Ngaphandle kwe-nucleic acid aptamers (enokuthi idlule i-nucleotides engama-30), iziyobisi ze-nucleic acid zidla ngokuba yi-oligonucleotides eyenziwe nge-nucleotides eyi-12 ukuya kwe-30, eyaziwa ngokuba yi-oligonucleotide iziyobisi.Ukongeza, i-miRNAs, i-ribozymes kunye ne-deoxyribozymes nazo zibonise ixabiso elikhulu lophuhliso kunyango lwezifo ezahlukeneyo.Amachiza e-Nucleic acid abe yenye yezona ndawo zithembisayo kuphando kunye nophuhliso lwe-biomedicine namhlanje.

Imizekelo yamachiza avunyiweyo e-nucleic acid

I-Antisense nucleic acid

Itekhnoloji ye-Antisense yitekhnoloji entsha yophuhliso lwamachiza esekelwe kumgaqo-siseko we-Watson-Crick wokuzaliswa kwesiseko, kusetyenziswa i-DNA ethile okanye amaqhekeza e-RNA adityaniswe ngokufanelekileyo okanye adityaniswe yinto ephilayo ukuze kulawulwe ngokuthe ngqo ukubonakaliswa kwemfuza ekujoliswe kuyo.I-antisense nucleic acid inolandelelwano lwesiseko oluncedisayo kwi-RNA ekujoliswe kuyo kwaye inokubophelela ngokuthe ngqo kuyo.I-Antisense nucleic acids ngokubanzi ibandakanya i-antisense DNA, i-antisense RNA kunye ne-ribozymes.Phakathi kwabo, ngenxa yeempawu zokuzinza okuphezulu kunye neendleko eziphantsi ze-antisense DNA, i-antisense DNA ithatha indawo ephambili kuphando lwangoku kunye nokusetyenziswa kwezidakamizwa ze-antisense ze-nucleic acid.

I-Fomivirsen sodium (igama lorhwebo iVitravene) yaphuhliswa ngu-Ionis Novartis.Ngo-Agasti 1998, i-FDA yavuma ukuba unyango lwe-cytomegalovirus retinitis kwizigulana ezingenasifo (ingakumbi izigulane ze-AIDS), ibe liyeza lokuqala le-nucleic acid eliza kuthengiswa.I-Fomivirsen inqanda ukubonakaliswa kweprotheyini ye-CMV ngokubophelela kwi-mRNA ethile (IE2), ngaloo ndlela ilawula ukubonakaliswa kweejene zentsholongwane ukuze kuphunyezwe iziphumo zonyango.Nangona kunjalo, ngenxa yokuvela konyango oluphezulu lwe-antiretroviral, oluthe lwanciphisa kakhulu inani lezigulana, ngo-2002 kunye no-2006, uNovartis warhoxisa ugunyaziso lwentengiso lwamachiza eFomivirsen eYurophu nase-United States ngokulandelelana, kwaye imveliso iye yanqunyanyiswa kwimarike.

I-Mipomersen sodium (igama lorhwebo i-Kynamro) lichiza le-ASO eliphuhliswe yinkampani yaseFransi iGenzyme.NgoJanuwari 2013, i-FDA yavuma ukuba unyango lwe-homozygous family hypercholesterolemia.I-Mipomersen inqanda ukubonakaliswa kweprotheyini ye-ApoB-100 (i-apolipoprotein) ngokuzibophelela kwi-ApoB-100mRNA, ngaloo ndlela inciphisa kakhulu i-cholesterol ephantsi yabantu, i-low-density lipoprotein kunye nezinye izibonakaliso, kodwa ngenxa yeziphumo ebezingalindelekanga ezifana nobutyhefu besibindi, uDisemba 13, 2012 ilayisensi yokuthengisa ichiza kwakhona ngosuku olufanayo lwe-EMA.

NgoSeptemba 2016, u-Eteplirsen (igama lokurhweba i-Exon 51) ephuhliswe nguSarepta kunyango lwe-Duchenne muscular dystrophy (DMD) yamkelwa yi-FDA.Izigulane ze-DMD azikwazi ukubonisa iprotheni esebenzayo ye-anti-atrophic ngenxa yeenguqu kwi-DMD gene emzimbeni.I-Eteplirsen ibophelela ngokukodwa kwi-exon 51 ye-RNA yangaphambi kwesithunywa (Pre-mRNA) yeprotheni, isusa i-exon 51, kwaye ibuyisela ezinye iijene ezisezantsi Ukubonakalisa okuqhelekileyo, ukubhalwa kunye nokuguqulelwa ukufumana inxalenye ye-dystrophin, ukuze kuphunyezwe umphumo wonyango.

I-Nusinersen ichiza le-ASO eliphuhliswe nguSpinraza kunyango lwe-spinal muscular atrophy kwaye yavunywa yi-FDA ngoDisemba 23, 2016. Kwi-2018, i-Inotesen iphuhliswe nguTegsedi kunyango lwe-hereditary transthyretin amyloidosis yabantu abadala yavunywa yi-FDA.Ngo-2019, iGolodirsen, ephuhliswe nguSarepta kunyango lwe-Duchenne muscular dystrophy, yamkelwa yi-FDA.Inomsebenzi ofanayo we-Eteplirsen, kwaye indawo yayo yesenzo iba yi-exon 53. Ngaloo nyaka, iVolanesorsen, iphuhliswe ngokudibeneyo yi-Ionisand Akcea yonyango lwe-familial hyperchylomicronemia, yavunywa yi-European Medicines Agency (EMA).I-Volanesorsen ilawula i-triglyceride metabolism ngokuvimbela ukuveliswa kwe-apolipoprotein C-Ⅲ, kodwa nayo inempembelelo yecala lokunciphisa amanqanaba eplatelet.

I-Defibrotide ngumxube we-oligonucleotide kunye neempawu ze-plasmin eziphuhliswe yiJazz.Iqulethe i-90% ye-DNA enemisonto enye kunye ne-10% ye-DNA ephindwe kabini.Yavunywa yi-EMA kwi-2013 kwaye emva koko yamkelwa yi-FDA yonyango lwemithambo ye-hepatic enzima.Isifo se-Oclusive.I-Defibrotide inokunyusa umsebenzi we-plasmin, inyuse i-activator ye-plasminogen, ikhuthaze ukunyuswa kwe-thrombomodulin, kwaye inciphise ukubonakaliswa kwe-von Willebrand factor kunye ne-plasminogen activator inhibitors ukufezekisa iziphumo zonyango.

siRNA     

I-siRNA iqhekeza elincinci le-RNA kunye nobude obuthile kunye nolandelelwano oluveliswa ngokusika i-RNA ekujoliswe kuyo.Ezi siRNAs zinokuphembelela ngokuthe ngqo ukuthotywa kwethagethi ye-mRNA kwaye ifezekise iziphumo zokuthi cwaka kwemfuza.Xa kuthelekiswa namachiza emolekyuli encinci yeekhemikhali, isiphumo sokuthulisa imfuza samachiza e-siRNA sinokucaciswa okuphezulu kunye nokusebenza kakuhle.

Ngomhla we-11 ku-Agasti, i-2018, i-patisiran yokuqala ye-siRNA ichiza (igama lorhwebo i-Onpattro) yamkelwa yi-FDA kwaye yasungulwa ngokusemthethweni.Esi sesinye seziganeko ezibalulekileyo kwimbali yophuhliso lwetekhnoloji yokuphazamiseka kwe-RNA.I-Patsiran yaphuhliswa ngokudibeneyo yi-Alnylam kunye ne-Genzyme, i-subsidiary ye-Sanofi.Lichiza le-siRNA lonyango lwe-thyroxine-mediated amyloidosis yelifa.Ngo-2019, i-givosiran (igama lorhwebo i-Givlaari) yamkelwa yi-FDA njengechiza lesibini le-siRNA kunyango lwe-acute hepatic porphyria kubantu abadala.Ngo-2020, uAlnylam wavelisa ichiza lokuqala lonyango lwabantwana kunye nabantu abadala.I-Lumasiran ene-oxaluria ephezulu ivunywe yi-FDA.NgoDisemba ka-2020, i-Inclisiran, iphuhliswe ngokudibeneyo nguNovartis kunye ne-Alnylam kunyango lwe-hypercholesterolemia yabantu abadala okanye i-dyslipidemia edibeneyo, yamkelwa yi-EMA.

Isixhobo

Ii-aptamers ze-Nucleic acid ziyi-oligonucleotides ezinokubophelela kwiimolekyuli ezijoliswe kuzo ezifana neemolekyuli ezincinci zezinto eziphilayo, i-DNA, i-RNA, i-polypeptides okanye iiprotheni ezinobudlelwane obuphezulu kunye neenkcukacha.Xa kuthelekiswa nama-antibodies, i-nucleic acid aptamers ineempawu ze-synthesis elula, iindleko eziphantsi kunye noluhlu olubanzi lweenjongo, kwaye zinamandla abanzi okusetyenziswa kweziyobisi ekuxilongweni kwesifo, unyango kunye nokukhusela.

I-Pegaptanib lichiza lokuqala le-nucleic acid aptamer eliphuhliswe yi-Valeant kunyango lwe-macular degeneration emanzi enxulumene neminyaka kwaye yamkelwa yi-FDA ngo-2004.I-Pegaptanib inqanda i-angiogenesis ngokudityaniswa kwesakhiwo sendawo kunye ne-vascular endothelial growth factor ukuphumeza iziphumo zonyango.Ukusukela ngoko, iye yadibana nokhuphiswano oluvela kumachiza afanayo uLucentis, kwaye isabelo sayo semarike sehle kakhulu.

Amachiza e-Nucleic acid abe yindawo eshushu kwichiza leklinikhi kunye nemarike entsha yamachiza ngenxa yesiphumo esimangalisayo sokunyanga kunye nomjikelo wophuhliso omfutshane.Njengechiza elikhulayo, lijongene nemingeni ngelixa lijongene namathuba.Ngenxa yeempawu zayo zangaphandle, ukuchaneka, ukuzinza kunye nokuhanjiswa okusebenzayo kwe-nucleic acids kuye kwaba yinkqubo ephambili yokugweba ukuba i-oligonucleotides ingaba ngamachiza asebenzayo kakhulu e-nucleic acid.Iziphumo ezingekho ekujoliswe kuzo ziye zahlala ziyingongoma ephambili yeziyobisi ze-nucleic acid ezingenakunakwa.Nangona kunjalo, iziyobisi ze-nucleic acid zinokuchaphazela ukubonakaliswa kwezifo ezibangelwa izifo ezisuka kwingcambu, kwaye zinokufikelela ukulandelelana ngokuthe ngqo kwinqanaba lesiseko esisodwa, elineempawu "zokuphatha ingcambu kunye nokunyanga iimpawu".Ngenxa yokuguquguquka kwezifo ezininzi, unyango lwemfuza kuphela lunokufikelela kwiziphumo ezisisigxina.Ngophuculo oluqhubekayo, ukugqibelela kunye nenkqubela phambili yetekhnoloji ehambelanayo, amachiza e-nucleic acid amelwe yi-antisense nucleic acids, i-siRNA, kunye ne-nucleic acid aptamers ngokuqinisekileyo iya kumisa i-wave entsha kunyango lwezifo kunye neshishini lamachiza.

Rimizekelo:

[1] Liu Shaojin, Feng Xuejiao, Wang Junshu, Xiao Zhengqiang, Cheng Pingsheng.Uhlalutyo lwemarike yamachiza e-nucleic acid kwilizwe lam kunye nemilinganiselo yokuchasana[J].Ijenali yaseTshayina yobuNjineli bebhayoloji, 2021, 41(07): 99-109.

[2] Chen Wenfei, Wu Fuhua, Zhang Zhirong, Sun Xun.Inkqubela phambili yophando kwi-pharmacology yamachiza e-nucleic acid [J].Ijenali yaseTshayina yezaMayeza, 2020, 51(12): 1487-1496.

[3] Wang Jun, Wang Lan, Lu Jiazhen, Huang Zhen.Uhlalutyo lokusebenza ngempumelelo kunye nenkqubela phambili yophando lwamachiza athengiswayo e-nucleic acid[J].Ijenali yaseTshayina yamachiza amatsha, 2019, 28(18): 2217-2224.

Malunga nombhali: u-Sha Luo, uphando lwamayeza aseTshayina kunye nomsebenzi wophuhliso, okwangoku usebenzela inkampani enkulu yophando lwamachiza asekhaya kunye nophuhliso, kwaye uzibophelele kuphando nophuhliso lwamayeza amatsha aseTshayina.

Iimveliso eziyeleleneyo:

Isethi yeSeli eNgqo RT-qPCR