Gene therapy muab lub peev xwm los kho cov kab mob caj ces los ntawm kev xa cov khoom siv tshuaj kho caj ces rau cov hlwb. Txawm li cas los xij, kev xa cov noob tau zoo yuav tsum tau kov yeej ntau yam kab mob lom, nrog rau kev paub txog kev tiv thaiv kab mob, kev siv ntawm tes, kev lag luam hauv lub cev, thiab kev qhia tau zoo ntawm kev kho mob payload. Viral thiab tsis yog -Viral vectors tau tsim los daws cov teeb meem no.
Ntawm cov kab mob kab mob, adeno- kab mob sib txuas (AAV) tau dhau los ua lub platform tseem ceeb rau hauv vivo gene xa. AAV vectors tuaj yeem hloov pauv ob qho kev faib tawm thiab tsis yog- faib cov hlwb thiab txhawb nqa kev hloov pauv hloov pauv. Txawv AAV capsids kuj nthuav tawm cov ntaub so ntswg tropism, muab lub sijhawm los tsim cov vectors rau cov kabmob tshwj xeeb thiab hom cell.
AAV-Txawm li cas los xij, txoj hauv kev muaj kev txwv tseem ceeb. Cov no suav nrog lub peev xwm ntim me me ntawm AAV, ua ntej- muaj kev tiv thaiv kab mob rau qee qhov capsids, kev tiv thaiv kab mob tom qab kev tswj hwm, thiab cov teeb meem cuam tshuam nrog kev ua kom tau txais txiaj ntsig zoo thiab kev xa khoom txaus rau qee cov ntaub so ntswg. Cov kev txwv no tau txhawb nqa kev siv zog txuas ntxiv los txhim kho AAV vector tsim thiab kev ua tau zoo.
Vim li cas NHPs tseem ceeb hauv AAV Kev Tshawb Fawb?
Nonhuman primates (NHPs) tuaj yeem muab cov ntaub ntawv txhais lus tseem ceeb thaum lub sijhawm kev txhim kho ntawm AAV-raws li kev kho mob vim lawv qhov zoo sib xws rau tib neeg hauv lub cev, lub cev nqaij daim tawv, noob caj noob ces, thiab kev tiv thaiv kab mob. Cov kev tshawb fawb NHP tuaj yeem siv los ntsuas vector biodistribution, hloov cov ntaub so ntswg, kev qhia transgene, kev ua tshuaj, thiab kev tiv thaiv kab mob hauv vivo.
Qhov tseem ceeb, AAV capsid kev ua tau zoo tuaj yeem sib txawv ntawm ntau hom. Ib tug vector uas qhia tau hais tias muaj zog tropism nyob rau hauv nas yuav tsis pom tib yam tis los yog transduction profile nyob rau hauv primates. Cov kev tshawb fawb NHP tuaj yeem muab cov ntaub ntawv ntxiv thaum ntsuas seb AAV vector puas muaj cov yam ntxwv tsim nyog rau kev txhim kho ntxiv.
Developing Novel AAV Capsids
Ib cheeb tsam loj ntawm AAV kev tshawb fawb yog kev txhim kho ntawm capsids nrog kev txhim kho cov nqaij mos tropism thiab kev hloov pauv tau zoo. Cov kws tshawb fawb tau siv txoj hauv kev xws li kev coj mus hloov pauv, kev tsim qauv tsim nyog, thiab peptide zaub los tsim cov AAV sib txawv nrog cov khoom siv lom neeg hloov pauv.
Cov txheej txheem no txhawm rau txhim kho kev xa mus rau cov ntaub so ntswg tshwj xeeb, suav nrog lub hauv nruab nrab lub paj hlwb, lub siab, lub plawv, thiab retina, thaum muaj peev xwm txo qis cov ntaub so ntswg tsis xav tau lossis kev paub txog kev tiv thaiv kab mob. Cov kev tshawb fawb NHP tuaj yeem pab txiav txim seb cov khoom puas tau pom nyob rau yav dhau los- kev tshuaj ntsuam theem txhais mus rau tus qauv tsiaj loj dua nrog rau tib neeg lub cev muaj feem cuam tshuam ntau dua.
Cov ntaub so ntswg-Tshwj xeeb thiab tswj cov noob caj ces
Vector kev ua tau zoo tsis yog nyob ntawm kev xaiv capsid nkaus xwb tab sis kuj nyob ntawm seb cov tshuaj kho cov noob tau qhia li cas tom qab yug me nyuam. Kev txhawb nqa thiab kev tswj hwm cov ntsiab lus tuaj yeem tsim kho kom cuam tshuam rau qib thiab cellular tshwj xeeb ntawm transgene qhia.
Cov ntaub so ntswg- lossis cell- cov neeg txhawb nqa tshwj xeeb tuaj yeem pab txwv tsis pub qhia tawm rau lub hom phiaj lub hlwb, thaum cov txheej txheem tswj tsis tau tuaj yeem muab kev tswj xyuas ntxiv rau lub sijhawm lossis theem ntawm kev qhia. Cov tswv yim no tuaj yeem txhim kho qhov kho qhov rai los ntawm kev txwv cov lus qhia hauv cov ntaub ntawv tsis yog - cov hom phiaj.
Cov kev tshawb fawb NHP tuaj yeem pab tau rau kev ntsuam xyuas qhov kev faib tawm thiab qhov tshwj xeeb ntawm kev hloov pauv hauv vivo, tshwj xeeb tshaj yog thaum txhawb kev ua haujlwm thiab cov ntaub so ntswg biology txawv ntawm hom.
AAV thiab CRISPR-Cas9 Genome Editing
AAV vectors kuj tuaj yeem siv los xa cov khoom ntawm genome- kho cov tshuab xws li CRISPR-Cas9. Ntau dua li tsuas yog muab cov noob ua haujlwm tau zoo, AAV-raws li genome kho lub hom phiaj los hloov kho cov kab mob tshwj xeeb hauv cov hlwb.
Cov kev tshawb fawb hauv tsev kho mob tau tshawb xyuas AAV- xa cov genome- kho cov kab mob xws li Duchenne muscular dystrophy, hemophilia, cysticfibrosis, thiab muaj kev cuam tshuam ntawm retinal. Cov kev tshawb fawb NHP tuaj yeem muab cov ntaub ntawv tseem ceeb ntawm kev xa khoom zoo, kho cov haujlwm, faib cov ntaub so ntswg, thiab kev tiv thaiv kab mob ua ntej kev kho mob txhais lus.
Txawm li cas los xij, AAV-raws li CRISPR txoj hauv kev ntsib cov teeb meem ntxiv, suav nrog kev txwv ntim ntawm AAV vectors, muaj peev xwm tawm - lub hom phiaj kho, tiv thaiv kab mob tiv thaiv cov khoom siv vector lossis kho cov proteins, thiab qhov xav tau kom ua tiav kev kho kom txaus hauv cov phiaj xwm phiaj xwm.
Lub luag haujlwm ntawm NHP Kev Tshawb Fawb hauv AAV Development
AAV vector txoj kev loj hlob nce ntxiv yuav tsum muaj kev ntsuas kev sib koom ua ke ntawm capsid biology, kev faib cov ntaub so ntswg, kev qhia transgene, kev ua tshuaj, thiab kev tiv thaiv kab mob. NHP qauv tuaj yeem ua tiav hauv vitro thiab nas kev tshawb fawb los ntawm kev muab cov ntaub ntawv txhais lus uas yuav nyuaj rau tau txais los ntawm lwm cov qauv.
Cov hom NHP tsim nyog, txoj kev tswj hwm, koob tshuaj, cov qauv qauv, thiab cov ntsiab lus kawg yuav tsum tau txiav txim siab raws li vector, lub hom phiaj cov ntaub so ntswg, kho cov txheej txheem, thiab kev loj hlob theem. Kev tshawb fawb NHP yog li cov ntaub ntawv tseem ceeb tshaj plaws thaum muab tso rau hauv qhov dav dav preclinical lub tswv yim tsim los daws cov lus nug tshwj xeeb.
Raws li AAV thev naus laus zis txuas ntxiv mus, kev nce qib hauv capsid engineering, kev tswj hwm cov ntsiab lus, thiab genome- kho cov kab ke yuav nthuav dav cov kev siv ntawm kev kho noob. Zoo-Cov kev tshawb fawb NHP tau tsim tuaj yeem pab ua tus yam ntxwv ntawm cov thev naus laus zis no thiab muab cov ntaub ntawv txhais lus tseem ceeb los txhawb lawv txoj kev txhim kho ntxiv.
