Gene therapy yog raug tshawb xyuas raws li kev kho mob muaj peev xwm rau ntau yam kab mob hauv paj hlwb, suav nrog Alzheimer's disease,Tus kab mob Parkinson, Huntington's disease, thiab spinal muscular atrophy. Hauv cov txheej txheem no, cov khoom siv tshuaj kho caj ces raug xa mus rau lub hom phiaj siv cov vector lossis cov cab kuj. Adeno-tus kab mob koom nrog (AAV) yog ib qho ntawm cov kab mob kis tau dav tshaj plaws vim nws tuaj yeem hloov pauv ob qho kev faib tawm thiab tsis yog- faib cov hlwb thiab tau tsim los xa mus rau ntau cov ntaub so ntswg.
Txawm li cas los xij, rau kev siv neurological, txawm li cas los xij, kev xa cov noob zoo tseem nyuaj. Lub hauv paus paj hlwb (CNS) yog kev tiv thaiv los ntawm cov ntshav - lub paj hlwb teeb meem, thiab ua kom tiav txaus thiab tsim nyog faib vector kis nyob rau hauv lub hlwb thiab qaum qaum yuav nyuaj. Kev tiv thaiv kab mob rau cov vector lossis transgene tuaj yeem cuam tshuam rau kev ua tau zoo thiab kev nyab xeeb. Tsis yog tib neeg primates (NHPs) yog li no siv rau hauv kev tshawb fawb preclinical los soj ntsuam cov tswv yim kev xa khoom, kev faib cov vector, transgene qhia, thiab kev tiv thaiv kab mob hauv cov qauv tsiaj uas muaj feem cuam tshuam txog anatomical thiab physiological zoo sib xws rau tib neeg.
Xa AAV rau CNS
Ib qho ntawm cov teeb meem hauv nruab nrab hauv CNS gene therapy yog ua kom tiav txaus thiab nthuav dav ntawm cov vector. Ntau txoj kev tswj hwm tau raug tshawb xyuas, suav nrog kev tswj hwm parenchymal ncaj qha thiab xa mus rau hauv cov kua dej cerebrospinal (CSF).
Convection -kev xa khoom zoo (CED)Kev tswj hwm tus vector ncaj qha mus rau hauv lub hlwb parenchyma nyob rau hauv kev tswj siab. Qhov tshwm sim convective ntws tuaj yeem pab txhawb kev faib cov vector los ntawm cov ntaub so ntswg tsom. Cov kev tshawb fawb NHP tau pom cov kev hloov pauv hloov tom qab CED hauv ntau thaj tsam ntawm lub hlwb, suav nrog putamen, thalamus, thiab cortex.
Lwm txoj hauv kev yog tswj hwm AAV ncaj qha rau hauv CSF.Intrathecal (IT) kev tswj hwmxa cov vector rau hauv CSF nyob ib puag ncig tus txha caj qaum, thaumIntracerebroventricular (ICV) kev tswj hwmxa nws mus rau hauv lub ventricular system ntawm lub paj hlwb. Ob txoj hauv kev tau tshawb xyuas kom ua tiav CNS kev faib tawm dav dua.
Kev faib tawm thiab cellular tropism ntawm AAV tuaj yeem sib txawv raws li txoj hauv kev capsid thiab kev tswj hwm. Kev tshawb fawb hauv cynomolgus macaques piv rau IT thiab ICV kev tswj hwm ntawm AAV9 thiab AAVrh10. Txoj kev tshawb no tau tshaj tawm tias IT kev tswj hwm ntawm AAV9 tau tsim cov kev hloov pauv hloov pauv zoo ib yam hauv cov hlwb txha caj qaum neurons nrog rau cov neurons thiab glial hlwb hauv ntau lub hlwb. Hauv qhov sib piv, AAV9 tswj hwm los ntawm ICV txoj hauv kev tau pom ntau qhov kev qhia zoo sib xws hauv lub hlwb, thaum AAVrh10 tswj hwm intrathecally pom qhov txwv lub cev muaj zog neuron lub hom phiaj. Cov kev tshawb pom no qhia txog qhov tseem ceeb ntawm kev txiav txim siab ob qho kev xaiv capsid thiab kev tswj hwm txoj hauv kev thaum tsim CNS- qhia AAV kev kho mob.
Immune Responses to AAV Gene Therapy
Cov lus teb tiv thaiv kab mob sawv cev rau lwm qhov kev xav tseem ceeb hauv AAV-raws li kev kho noob caj noob ces. Ob leeg innate thiab adaptive lub cev tiv thaiv kab mob tuaj yeem teb rau cov vector, nws cov khoom siv caj ces, lossis cov transgene qhia. Cov lus teb no tuaj yeem cuam tshuam rau vector persistence, transgene qhia, thiab kev kho kom haum.
Innate immune sensing tuaj yeem koom nrog cov qauv- lees paub receptors thiab tuaj yeem ua rau muaj teeb meem inflammatory, cytokine ntau lawm, ntxiv ua kom muaj zog, thiab lwm yam lus teb hauv qab. Kev tiv thaiv kab mob tuaj yeem suav nrog kev txhim kho cov tshuaj tiv thaiv kab mob tiv thaiv AAV capsid thiab cov tshuaj tiv thaiv kab mob ntawm tes tiv thaiv vector- koom nrog lossis hloov pauv- muab cov antigens.
Qhov loj thiab qhov xwm txheej ntawm cov lus teb no tuaj yeem cuam tshuam los ntawm cov xwm txheej suav nrog vector koob tshuaj, capsid serotype, txoj kev tswj hwm, vector genome tsim, txhawb nqa, hloov pauv, thiab ua ntej - muaj kev tiv thaiv kab mob. Cov xwm txheej no yog li yuav tsum tau txiav txim siab thaum tsim AAV-raws li kev kho mob rau cov hom phiaj CNS.
Cov tswv yim los tswj kev tiv thaiv kab mob
Ob peb txoj hauv kev tau tshawb xyuas los txo lossis tswj kev tiv thaiv kab mob rau AAV vectors. Immunomodulatory lossis immunosuppressive kev kho mob, suav nrog corticosteroids, tau siv nyob rau hauv qee qhov kev kho mob kho mob los tswj cov kab mob inflammatory tom qab AAV tswj hwm. Txawm li cas los, systemickev tiv thaiv kab mobtuaj yeem nqa nws tus kheej txaus ntshai thiab yuav tsum tau ua tib zoo xav.
Vector engineering muab lwm lub tswv yim zoo. Hloov kho AAV capsids tuaj yeem hloov kho cov ntaub so ntswg tropism thiab kev cuam tshuam nrog lub cev tiv thaiv kab mob. Vector genome engineering kuj tseem tuaj yeem cuam tshuam rau lub cev tiv thaiv kab mob, thaum cov ntaub so ntswg - tshwj xeeb lossis kev tswj hwm tus neeg txhawb nqa tuaj yeem pab tswj qib thiab kev faib tawm ntawm kev hloov pauv.
Cov kev tshawb fawb NHP tau pab txhawb rau kev nkag siab txog kev tiv thaiv kab mob tom qab AAV cov thawj coj thiab tau muab cov ntaub ntawv uas tuaj yeem ntxiv cov kev tshawb pom los ntawm nas thiab hauv vitro kev tshawb fawb. Kev tshawb fawb hauv NHPs kuj tau qhia tias kev tiv thaiv kab mob hauv lub cev tuaj yeem tshwm sim tom qab kev tswj hwm rau cov ntaub so ntswg yav dhau los suav tias yog lub cev tiv thaiv kab mob, hais txog qhov yuav tsum tau xav txog txoj hauv kev - thiab cov ntaub so ntswg - cov txheej txheem tiv thaiv kab mob tshwj xeeb thaum lub sij hawm kev loj hlob vector.
Lub luag haujlwm ntawm NHPs hauv CNS Gene Therapy Development
Cov kev tshawb fawb NHP tuaj yeem muab cov ntaub ntawv txhais lus tseem ceeb thaum lub sij hawm txhim kho AAV-raws li kev kho mob rau cov kab mob neurological. Ntxiv nrog rau kev ntsuam xyuas vector faib thiab kev hloov pauv hloov pauv, kev tshawb fawb NHP tuaj yeem siv los tshawb xyuas cov txheej txheem kev tswj hwm, koob tshuaj - teb kev sib raug zoo, biomarkers, thiab kev tiv thaiv kab mob.
Kev xaiv ntawm AAV serotype, txoj kev tswj hwm, koob tshuaj, thiab cov ntsiab lus ntawm kev kawm yuav tsum tau coj los ntawm cov hom phiaj kho mob thiab cov hom phiaj kev loj hlob. Tsis muaj ib qho vector lossis kev tswj hwm lub tswv yim yuav tsum ua kom zoo rau txhua yam kab mob neurological. Qhov sib txawv ntawm lub hom phiaj ntawm lub hlwb, kev faib tawm anatomical, kab mob mechanism, thiab qib yuav tsum tau muaj ntawm cov noob qhia tuaj yeem cuam tshuam rau txoj hauv kev tsim nyog.
Xaus
AAV-raws li kev kho noob caj noob ces muaj peev xwm ua rau cov kab mob hauv lub paj hlwb, tab sis kev xa CNS zoo thiab kev tswj hwm lub cev tiv thaiv kab mob tseem ceeb heev. Cov kev tshawb fawb NHP tuaj yeem pab qhia cov yam ntxwv no hauv tus qauv nrog cov yam ntxwv ntawm lub cev, lub cev, thiab kev tiv thaiv kab mob.
Kev tshawb fawb ntawm CED, intrathecal thiab intracerebroventricular kev tswj hwm tau pom tias ob qho tib si kev xa khoom thiab AAV capsid tuaj yeem cuam tshuam rau kev faib tawm thiab lub hom phiaj ntawm tes ntawm cov kab mob kho. Nyob rau tib lub sijhawm, kev tshawb fawb txuas ntxiv mus rau hauv lub cev tiv thaiv kab mob thiab vector engineering yuav yog qhov tseem ceeb rau kev txhim kho kev nyab xeeb thiab kav ntev ntawm CNS gene kho.
Zoo-Cov kev tshawb fawb NHP tau tsim tuaj yeem muab cov ntaub ntawv txhais lus tseem ceeb los txhawb kev ua kom zoo ntawm AAV-raws li txoj hauv kev ua ntej kev kho mob.
