Tam sim no Clinical Applications Of In Vivo Gene Therapy With AAVs Part 3

GAN

GAN yog ib qho autosomal recessive neurodegenerative teeb meem ntawm lub hauv nruab nrab thiab peripheral paj hlwb uas feem ntau tshwm sim nrog kev tsis muaj zog thiab ataxia. Cov tib neeg kuj raug kev puas tsuaj thiab poob ntawm kev thauj mus los thiab succumb ua pa tsis ua haujlwm.62

Recessive qub txeeg qub teg thiab kev nco yog ob lub ntsiab lus uas zoo li tsis muaj kev sib txuas ncaj qha, tab sis muaj kev sib raug zoo ntawm lawv. Recessive qub txeeg qub teg hais txog cov noob caj noob ces phenomenon uas muaj nyob rau hauv lub genome tab sis tsis ua kom pom tseeb phenotypic hloov. Kev nco yog hais txog lub peev xwm ntawm tib neeg kom tau txais, khaws cia, thiab khaws cov ntaub ntawv thaum lub sijhawm kev paub txog kev paub. Yog li, ob lub ntsiab lus no txuas li cas?

Ua ntej ntawm tag nrho cov, recessive qub txeeg qub tes thiab nco yog ob yam khoom ntawm lub paj hlwb. Muaj kaum tawm txhiab tus neurons hauv peb lub hlwb, uas xa cov ntaub ntawv los ntawm preganglionic substantia nigra thiab synapses. Kev sib txuas ntawm neurons thiab kev sib kis tau zoo ntawm synapses yog txhua yam cuam tshuam los ntawm cov noob. Yog li ntawd, peb tuaj yeem hais tias txoj kev loj hlob thiab kev ua haujlwm ntawm lub paj hlwb yog tus choj ntawm qhov qub txeeg qub teg thiab kev nco.

Qhov thib ob, kev ua tsis tiav thiab kev nco qab kuj tseem muaj kev cuam tshuam kev sib raug zoo. Qee qhov kev tshawb fawb tau pom tias kev hloov pauv noob tuaj yeem cuam tshuam rau kev ua haujlwm ntawm kev nco. Piv txwv li, kev poob lossis kev hloov ntawm qee cov noob tuaj yeem cuam tshuam rau kev tsim thiab kev ruaj ntseg ntawm synapses hauv lub hlwb, yog li cuam tshuam rau tib neeg lub cim xeeb. Nyob rau tib lub sijhawm, kev cob qhia kev nco kuj tuaj yeem cuam tshuam cov qub txeeg qub teg. Qee qhov kev sim tau pom tias nyob rau hauv qee qhov xwm txheej, cov yas ntawm lub cim xeeb tuaj yeem cuam tshuam rau kev qhia thiab kev hloov pauv ntawm cov noob tshwj xeeb, yog li hloov cov yam ntxwv phenotypic ntawm cov xeeb ntxwv.

Thaum kawg, ob qho tib si recessive qub txeeg qub teg thiab kev nco tuaj yeem hloov pauv thiab txhim kho. Txawm hais tias peb tsis tuaj yeem hloov peb cov genome, peb tuaj yeem txhim kho peb lub cim xeeb los ntawm kev tsim kom muaj ib puag ncig zoo thiab kev xyaum. Piv txwv li, txoj kev ua neej noj qab nyob zoo, pw tsaug zog zoo, thiab kev txawj ntse tuaj yeem txhim kho kev nco. Ib yam li ntawd, qee cov thev naus laus zis tshiab thiab kev kho mob, xws li kev kho cov noob caj noob ces thiab kev kho cov noob caj noob ces, kuj tuaj yeem siv los kho thiab txhim kho cov kab mob cuam tshuam txog kev cuam tshuam.

Nyob rau hauv cov ntsiab lus, muaj kev sib raug zoo ntawm recessive qub txeeg qub tes thiab nco. Txawm hais tias peb tsis tuaj yeem tswj hwm peb cov noob caj noob ces, peb tuaj yeem hloov pauv thiab txhim kho peb lub cim xeeb los ntawm kev tsim kom muaj ib puag ncig zoo thiab kev coj ua, uas kuj yog ib yam uas peb yuav tsum ua kom zoo. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho peb lub cim xeeb, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj khoom haus txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Raws li kev tshawb fawb neuropathological, muaj qhov poob ntawm gigatons qhia uas cuam tshuam rau lub paj hlwb cortex, lub paj hlwb, thiab cov kab mob tom qab ntawm tus txha caj qaum, ua rau nws yog qhov zoo tshaj plaws tus neeg sib tw tsis meej rau intrathecal tus me nyuam ntawm AAV9 noob hloov (saib los ntawm Bailey li al.63).

Gigaxonin yuav tsum tau npaj thiab degrade intermediate filaments thiab ua rau kom loj axons nrog densely bundled intermediate filaments (saib los ntawm Bailey li al.63).

Ib theem 1 koob tshuaj nce ntxiv kev kawm ntawm intrathecal AAV9/GAN tab tom pib ntawm National Institutes of Health (NIH; ClinicalTrials.gov: NCT02362438).

Yav tom ntej Outlook

Ze li ntawm 2 xyoo caum tom qab thawj zaug intracerebral gene-hloov sim siv AAV2, txoj hauv kev hloov cov noob mus rau CNS tau nthuav dav heev. Thaum xav tau kev hloov pauv noob caj noob ces, xws li rau PD thiab AADC, kev hloov cov noob muaj tseeb dua mus rau qhov ntim ntau dua ntawm lub hlwb tuaj yeem ua tiav nrog AAV2 vectors siv txoj hauv kev xws li MRI-guided convection-enhanced delivery.64-66.

Txawm li cas los xij, feem ntau cov kab mob CNS yuav xav tau qhov dav thiab muaj txiaj ntsig zoo hloov mus rau tag nrho CNS. Kev tshawb pom ntawm AAV capsids tshiab, xws li AAV9, tau tso cai rau ntau qhov kev hloov pauv ntawm cov noob caj noob ces ntau dua li kev txhaj tshuaj stereotaxic ntau dua.9,10,67-69 Ib cag ntawm ntau cov kev tshawb fawb hauv tsiaj qauv, daim ntawv thov ntawm AAV9 tau pom muaj kev sim tshuaj tom qab txhaj tshuaj intrathecal. (xws li GAN) lossis los ntawm kev txhaj tshuaj intravenous (raws li SMA13).

Nws tau cia siab tias kev siv AAV9 lossis zoo sib xws AAV capsids yuav nthuav dav daim ntawv thov kev kho noob rau ntau CNS mob sai sai. Txawm li cas los xij, whereas AAV9 tau nthuav dav ntau lub peev xwm los kho cov kab mob CNS ntau dua, nws tseem tsom rau cov neeg tsawg ntawm cov hlwb thoob plaws hauv hlwb.70.

Saib rau pem hauv ntej, tiam tshiab ntawm AAV capsids nrog ntau dua CNS lub hom phiaj kev ua tau zoo yuav ua rau kom muaj txiaj ntsig ntawm CNS-kev coj noj coj ua kev kho mob, nrog rau nthuav dav cov kab mob uas tuaj yeem kho tau nrog kev kho noob.

Clinical In Vivo Gene Therapy for Ocular Disorders

Gene therapy tau txais nws qhov chaw hauv kev kho mob tseem ceeb raws li FDA pom zoo ntawm Luxturna, AAV2-raws li kev kho mob rau cov kab mob retinal (IRD) retinal pigment epithelium (RPE)65-LCA (LCA2).

Qhov kev vam meej no yog ua raws li ntau xyoo ntawm kev ua haujlwm los ntawm ntau pab pawg, ib qho ntawm cov khoom lag luam mus rau kev lag luam.71-76 Cov neeg mob kho tau nthuav tawm kev hloov pauv lub neej nyob rau hauv lub teeb rhiab heev thiab pom kev coj cwj pwm.

Cov ntsiab lus ntxaws ntxaws ntawm RPE65 biology, kev tshawb fawb ua ntej hauv cov qauv tsiaj, thiab kev kho LCA2 nrog kev kho noob los ntawm ntau pab pawg tau tshaj tawm.77,78

Qhov kev vam meej ntawm qhov kev pabcuam no catalyzedacademia thiab kev lag luam zoo ib yam los tsim cov ntaub ntawv pov thawj ntawm lub tswv yim tias kev kho noob tuaj yeem kho lossis khaws tsis pom kev hauv cov qauv tsiaj ntawm lwm cov kab mob hauv lub qhov muag, suav nrog, tab sis tsis txwv rau, AMD, choroideremia, ACHM, retinitis pigmentosa, thiab XLRS.79– 85

Interestingly, txawm li cas los xij, cov kev ua tiav preclinical no tsis tau txhais mus tas li rau cov txiaj ntsig kev kho mob zoo li cov uas tau pom hauv cov neeg mob LCA2. thiab/los yog lub cev tiv thaiv kab mob yuav ua lub luag haujlwm.

Kev vam meej yav tom ntej hauv qhov chaw kho cov noob caj noob ces thiab kev kho cov noob dav dav yuav nyob ntawm seb muaj peev xwm kho tau cov koob tshuaj uas ua tau raws li qhov muaj peev xwm ua pov thawj rau (1) lub hom phiaj tsim nyog ntawm cov xov tooj ntawm tes hauv primate retina thiab (2) tsav cov theem txaus ntawm kev kho transgene qhia. . Txawm hais tias muaj ntau yam ua rau AAV lub tropism, transduction efficiency, thiab cuam tshuam txog kev tiv thaiv kab mob hauv lub retina, txoj kev xa khoom yog qhov tseem ceeb. Cov ntsiab lus ntawm tam sim no thiab kev txhim kho txoj hauv kev, lawv qhov zoo thiab qhov tsis zoo, thiab cov piv txwv kho mob cuam tshuam tau tham hauv qab no.

Kev txhaj tshuaj subretinal (SRI)

SRI yog ua hauj lwm nyob rau hauv feem ntau ntawm cov kev sim tshuaj vim hais tias nws tso cai rau qhov chaw ntawm cov kev kho mob nyob rau hauv situ (nyob rau hauv ib tug phais tsim qhov chaw ntawm photoreceptors (PRs) thiab RPE hu ua subretinal "bleb").

Feem ntau ntawm IRDs yog tshwm sim los ntawm kev hloov pauv hauv PR-specificgenes. Ntxiv rau nws qhov sib thooj rau cov chaw kho mob uas muaj ntau tshaj plaws (piv txwv li, RPE thiab PR), SRI yog qhov txaus nyiam vim tias qhov chaw tiv thaiv kab mob no muaj cai. Tsis zoo li kev xa tawm AAV, subretinally xa cov vectors elicit ib qho kev txo qis hauv lub cev tiv thaiv kab mob rau anterior chamber-associated immune deviation (ACAID).93,94.

Txawm li cas los xij, SRI yog cov txheej txheem nyuaj, piav qhia tias "yuav luag ib qho tshwj xeeb rau nws tus kheej." 95 Nws yuav tsum muaj vitrectomy (tshem tawm ntawm vitreoushumor) thiab retinotomy (kev hla ntawm rab koob los ntawm retina), uas tuaj yeem cuam tshuam nrog cov teeb meem, xws li cov kua muag retinal. , cataractprogression, lossis retinal/choroidal hemmorage.96

Kev tsim ntawm subretinal bleb yuav tsum tau tshem lub retina los ntawm lub hauv paus RPE. Thecone-exclusive fovea yog tshwj xeeb tshaj yog rhiab rau detachment. SRI ntawm vector nyob rau hauv lub fovea ntawm qee cov neeg mob LCA2 coj mus rau hauv nruab nrab retinal thinning thiab tsis pom kev acuity.75

Cov kev txo qis hauv retinal tuab zoo sib xws tau pom nyob rau hauv cov neeg mob choroideremia.96Cov txheej txheem phais ntawm subretinal gene therapy yog predicated uponestablished subretinal cov txheej txheem, xws li cov ntaub so ntswg subretinal plasminogen activator (tPA) txhaj rau subretinal hemorrhage txuam nrog neovascular AMD.96.

Txawm li cas los xij, kev txiav txim siab tshwj xeeb yuav tsum tau ua kom hloov cov txheej txheem rau cov yam ntxwv tshwj xeeb ntawm cov qauv retinal tam sim no hauv IRDs. Vitreoretinal kws phais neeg zoo versedin subretinal noob kev kho mob tau tshaj tawm cov nqi hluav taws xob ntawm intraoperativeoptical coherence tomography (OCT), tso cai rau hauv vivo real-timefeedback thaum lub sij hawm phais.97

Kev tsim cov subretinalbleb nrog microneedle (feem ntau yog 38- rau 41-gauge, Teflon-tipped, ob qho tib si extendable los yog non-extendable, ib tug cannula uas muab tso rau hauv apars plana trocar) yog ib qho nyuaj thiab tseem ceeb heev. kauj ruam hauv cov txheej txheem.98

Cov kauj ruam ntawm rab koob muaj qhov nqaim ntawm qhov yuam kev: kev nkag mus tob heev ntawm rab koob tuaj yeem ua rau hemorrhage, cannula tip obstruction, unintentional suprachoroidal xa ntawm vector, los yog kev raug mob RPE tas li; Txawm li cas los xij, qhov tob tob tob tob tuaj yeem tsim cov retinoschisis los ntawm intraretinal hydration thaum lub sij hawm tsim bleb.97

Qee tus kws phais neeg tsim ib qho "pre-bleb" ua nrog cov kua ntsev sib npaug (BSS) ua ntej txhaj tshuaj vector rau hauv qhov chaw no, uas tuaj yeem tiv thaiv qhov poob ntawm vector mus rau hauv vitreouscavity thaum lub sijhawm tsim bleb.

Lwm qhov kev txiav txim siab txog kev phais yog qhov nyuaj ntawm qhov tsis sib xws thiab qhov tseeb ntim khoom xa tuaj nrog rau txoj kev xa tawm tam sim no subretinal.

Vector ntim tuaj yeem cuam tshuam los ntawm kev siv BSS pre-bleb, poob ntawm vector los ntawm vitreous egress los ntawm qhov chaw retinotomy, thiab tsis tiav lub hom phiaj ntim ntim vim yog kev txiav txim siab ntawm kws phais (kev txhawj xeeb rau fovealstretching lossis macular qhov tsim lossis lwm yam kev xav txog kev nyab xeeb).

Hauv kev sim tshuaj ntsuam xyuas qhov kev txiav txim siab nce koob tshuaj tau raug txiav txim siab nrog cov ncauj lus me me, nws yuav nyuaj kom tsim nyog ua kom muaj kev nyab xeeb lossis kev txiav txim siab ua tau zoo tshwj tsis yog tias kev lees paub qhov tseeb thiab zoo ib yam vector ntim khoom tuaj yeem ua tiav hauv txhua tus neeg mob dosed.

Nws tseem yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias, txawm tias nws txoj cai tiv thaiv kab mob, AAV vectors tseem muaj peev xwm ncav cuag qhov cuam tshuam tsis zoo thiab tshem tawm cov lus teb ntawm tus tswv tsev hauv lub subretinal.

Hauv theem I/II kev sim tshuaj kho mob rau RPE65-LCA ntawm University College London(ClinicalTrials.gov: NCT00643747), ocular ocular tau sau tseg raws li SRI ntawm 1 1012 vg ntawm AAV2-RPE65.71,99

Tsis muaj kev mob tshwm sim hauv University of Pennsylvania/University ofFlorida sim (ClinicalTrials.gov: NCT00481546). Hauv NantesUniversity Tsev Kho Mob sim (ClinicalTrials.gov: NCT01496040), uas tshwj xeeb yog siv qhov sib txawv AAV capsid (AAV4), qhov mob tau sau tseg ntawm 4.8 1010 vg.100 Hauv Spark Therapeutics 'theem III sim (ClinicalTrials.gov: NCT09), observedat 1.5 1011 vg.76,101 Qhov mob tseem ceeb kuj tau pom ntawm 1 1011 vg hauv kev sim tshuaj rau choroideremia.90,102

Cov koob tshuaj sib txawv ntawm qhov kev mob tshwm sim tau pom hauv kev kho mob tuaj yeem raug ntaus nqi rau qhov sib txawv ntawm vector ntau lawm thiab tus cwj pwm, AAV capsid, thiab cov kab mob hauv lub cev.

Raws li lub hom phiaj tam sim no tau hloov mus rau kev ntsuam xyuas cov tshuaj kho noob rau IRDs qhov twg lub hom phiaj hlwb yog PRs, nws tsim nyog xav txog kev sib raug zoo ntawm kev nplua nuj ntawm cov khoom hloov noob caj noob ces thiab vector dosing.

Rau txhua txoj kev kho noob kom ua tiav, kev kho mob kom txaus (piv txwv li, cov protein) yuav tsum tau ua tiav ntawm cov koob tshuaj uas tsis ua rau mob tsis tuaj yeem. Qhov zoo tshaj plaws, qhov ntau txaus ntawm qhov tsawg kawg nkaus koob tshuaj hauv cov qauv tsiaj thiab NOAEL (noobservable adverse effect level) yuav tsum muaj xws li qhov kev tshawb fawb theem I / IIdose-escalation tuaj yeem ua tau.

Logic dictates tias IRDs tshwm sim los ntawm qhov tsis xws luag hauv retinal proteins qhia nyob rau theem qis tej zaum yuav yooj yim dua los ntawm kev kho noob.

Kev sib piv ntawm preclinicalfindings hauv cov qauv tsiaj loj ntawm IRD piv rau cov txiaj ntsig kev kho mob txhawb nqa lub tswv yim no, txawm hais tias luam tawm cov txiaj ntsig kev kho mob tseem nyob tsis ntev. Cov kev tshawb fawb ua ntej txhawb nqa los ntawm AGTC tau soj ntsuam AAVRPGR (retinitis pigmentosa GTPase regulator) nyob rau hauv cov kab mob caninemodel ntawm RPGR X-txuas retinitis pigmentosa (XLRP).103 Efficacy (kev txhim kho hauv fundus autofluorescence) tau tshaj tawm ntawm dosesas 10 3 1. tsis raug soj ntsuam kom txog thaum koob tshuaj ntawm 4.5 1011 vg.103 Biogen's 6-hli AAV-RPGR theem I/II qhov kev sim tshuaj ntsuam xyuas tau nthuav tawm ntawm lub rooj sib tham ASGCT xyoo no.

Nws tau tshaj tawm txog kev txhim kho hauv qhov muag pom hauv rau rau tus neeg mob XLRP kho, "kev txhim kho qhov pom tshwj xeeb," thiab "cov pov thawj ntawm qhov ua tau zoo dua qub" hauv ib tus neeg mob tau kho ntawm qhov koob tshuaj siab (5 1011 vg). Kev tswj tau qhov mob tsuas yog pom nyob rau hauv pawg no siab.

Txawm hais tias tseem tsis tau nthuav tawm / tshaj tawm, AGTC cov xov xwm tshaj tawm 104 (hnub nkag mus rau 6-12-20) hais tias 9 ntawm 17 tus neeg kho mob tau ntsib kev txhim kho hauv qhov muag, raws li ntsuas los ntawm microperimetry thiab/lossis kho qhov muag pom kev zoo tshaj plaws (BCVA) ntawm 3 lub hlis tom qab txhaj tshuaj. Tsuas yog cov neeg mob uas txhaj tshuaj submacular pom qhov kev txhim kho no.

Thaum 6 lub hlis tom qab txhaj tshuaj, kev txhim kho hauv cov neeg mob cuaj no tau ruaj khov. Hauv plaub ntawm cov neeg mob no (4/8 kuaj), muaj kev txhim kho hauv qhov pom kev rhiab heev (piv txwv li, microperimetry).

Proteomic tsom xam qhia tias muaj kwv yees li 2,{1}} molecules ntawm RPGR ib PR sensory cilium (PSC), ua nws 1,087th feem ntau enriched protein nyob rau hauv rods.105 Nyob rau hauv sib piv, preclinical kev tshawb fawb soj ntsuam AAV-cyclic nucleotide-gated channel subunit beta 3 (CNGB3) nyob rau hauv adog qauv ntawm CNGB3 ACHM qhia tsuas yog kev txhim kho me ntsis hauv retinal muaj nuj nqi ntawm 5 1010 vg thiab o ntawm 5 1011 vg.

Phase I/II sim rau CNGB3 ACHM tau pib hauv 2016 los ntawm ob qho tib siAGTC thiab MeiraGtx, tab sis cov txiaj ntsig kho mob tseem tsis tau nthuav tawm / tshaj tawm. Cyclic nucleotide-gated channels tau nthuav tawm heev (61,000 molecules ib PSC), ua rau lawv ntau dua li RPGR.105

Cov kev tshawb fawb ua ntej hauv cov yaj qauv ntawm cyclicnucleotide-gated channel subunit alpha 3 (CNGA3) ACHM tau nthuav tawm kev txhim kho zoo hauv retinal muaj nuj nqi ntawm 1.8 1011 vg (tsawg dosetested) thiab mob ntawm 6.0 1011 vg.

Phase I/II kev soj ntsuam kev sim ua nyob rau hauv University Hospital Tuebingen thiab Ludwig Maximilian University of Munich (ClinicalTrials.gov: NCT02610582) kho cov neeg mob ntawm cov koob tshuaj nram qab no: 1 1010 vg, 5 1010 vg, or1 1011 vg.91

Tsis muaj qhov mob uas tsis tuaj yeem tswj tau, thiab kev txhim kho me ntsis hauv qhov pom kev pom, qhov sib txawv rhiab heev, thiab chromatic kev ntxub ntxaug tau raug soj ntsuam ntawm txhua qhov koob tshuaj, ua raws li kev ua haujlwm lom neeg los ntawm vector.92

Cov koob tshuaj uas xav tau rau kev kho mob hauv cov kev tshawb fawb preclinical tau siab dua hauv CNGA3-ACHM txheeb ze RPGR-XLRP, txawm hais tias CNGA3-ACHM cov txiaj ntsig tau pom zoo tias IRDs tshwm sim los ntawm qhov tsis xws ntawm cov noob caj noob ces tseem tuaj yeem ua tiav.

Qee qhov IRDs, xws li MYO7A-associated Usher syndrome thiab ABCA4-sociated Stargardt kab mob, yog tshwm sim los ntawm kev hloov pauv ingenes rau cov coding sequences loj heev kom haum rau hauv standardAAV vector ( ntim peev 5 kb).

Lentivirus, uas tuaj yeem ua kom muaj peev xwm loj dua (9.7 kb), yog li ntawd tau xaiv los kho cov IRDs hauv theem I / II kev sim tshuaj uas tau pib hauv 2011/2012. Tsis muaj ntawv tshaj tawm txog kev ua haujlwm lom neeg tau muab luam tawm rau hnub no rau ob qho kev sim.

Qhov no tau xav tias yog vim qhov tseeb tias lentivirus tsis zoo hloov pauv cov postmitotic PRs, 106,107 lub hom phiaj ntawm tes hauv USH1B thiab Stargardt. Kev siv zog tam sim no tab tom ua los ntawm ntau pab pawg los tsim dual AAV vector platforms uas yuav txhawb nqa kev xa cov noob loj rau PRs.108,109

Tshaj li tus kab mob monogenic, AAV kuj tau siv los vectorize antivascular endothelial growth factor (VEGF) reagents rau retina viaSRI los ua kev kho mob ib zaug rau daim ntawv neovascular ntawm AMD (ntub AMD).

Qhov no sawv cev rau qhov kev txhim kho ntawm tus qauv-ntawm-kev saib xyuas txhua hli intravitreal txhaj tshuaj (IVIs) ntawm VEGF inhibitors uas tuaj yeem raug kev txom nyem los ntawm kev ua tsis zoo. REGENXBIO tsis ntev los no tau ua tiav ib theem I / IIa sim uas cov neeg mob hla tsib cohortsreceived koob ntawm AAV8-anti VEGF fab ntawm 3 109 vg thiab 2.4 1011 vg ib lub qhov muag. Kev nce koob tshuaj ntawm cov protein qhia tau pom ntawm 1 lub hlis pi

Tsis muaj tshuaj AEs thiab tsis muaj cov tsos mob tshwm sim ntawm kev tiv thaiv kab mob los yog tshuaj tiv thaiv ocularinflammation. Txawm hais tias tsis muaj cov cim qhia tseeb ntawm kev txhim kho tau raug sau tseg hauv pawg 1 (3 109 vg / qhov muag) lossis pawg 2 (1 1010 vg / qhov muag), cov neeg mob hauv pawg 3 (6 1010 vg / qhov muag) pom kev txhim kho hauv meanBCVA thiab lub hauv nruab nrab ntawm cov retinal thickness. 50% ntawm cov neeg mob hauv pawg 3 tseem nyob twj ywm tsis pub txhaj tshuaj (piv txwv li, tsis muaj IVIs VEGF inhibitors) txog li 2 xyoos tom qab kho.

Tsis ntev los no, cov txiaj ntsig tau los ntawm pawg 5 (2.5 1011 vg / qhov muag) pom tias 73% ntawm cov neeg mob tseem txhaj tshuaj tsis pub tsawg kawg 9 lub hlis tom qab kho. REGENXBIO muaj cov phiaj xwm hloov kho nws txoj kev xa khoom.

Nws lub hom phiaj yog xa AAV mus rau subretinal spacevia microcannula uas nkag mus rau retina tom qab los ntawm qhov chaw suprachoroidal (saib nqe lus hauv qab no) thiab ua li ntawd, nce kev nkag mus rau kev kho mob (yuav tsis xav tau vitrectomy / full-blownsurgery). Lwm lub ncauj lus. Kev txaus siab nyob rau hauv IRD gene therapy teb yog qhov kev tshuaj ntsuam xyuas kev pheej hmoo kom tau txais txiaj ntsig rau txoj hauv kev subretinal.

Ib qho piv txwv yog seb qhov detachment ntawm lub cone-exclusive fovea ntawm SRIis pom zoo. Nyob rau hauv tej yam IRDs characterized los ntawm lub xub ntiag ntawm hnyav ua hauj lwm tsis txaus txawm hais tias retinal preservation (piv txwv li, GUCY2DLCA1), SRI ntawm macula poses ib tug txaus nyiam txaus ntshai-kev pab piv piv. muaj peev xwm kom tau txais txiaj ntsig raws li lawv qhov kev khaws cia ntawm cov retinal laminar architecture ua rau lawv (1) ntau dua yuav zam kev phais foveal detachment thiab (2) muaj peev xwm ntau dua kev kho mob.

Qhov no yog qhov sib piv nrog cov neeg mob uas khaws lub khob hliav qab ua haujlwm thiab muaj lub zog degenerating retina (piv txwv li, retinitis pigmentosa). Hauv qhov xwm txheej tom ntej, SRI ntawm AAVs muaj peev xwm kis tau tom qab dhau ntawm cov npoo ntawm kev tshem tawm tuaj yeem kho cov qib kev kho mob ntawm geneexpression hauv foveal cones thaum zam kev pheej hmoo cuam tshuam nrog foveal detachment.

Tseeb, ntxiv-foveal SRI ntawm cov vectors (AAV44.9 raws) txhawb 98% kev hloov pauv ntawm foveal cones hauv macaque yam tsis tas yuav tshem tawm fovea thaum phais.112

Tsis tas li ntawd, cov kab mob tshiab no uas kis tau tom qab los ntawm kev txhaj tshuaj blebmay kuj tseem tuaj yeem pab txhim kho kev ua haujlwm thoob plaws lub retina.112 Txawm tias muaj kev phais nyuaj, ntau yam zoo uas SRI muaj (cov noob muaj zog hauv cov hlwb sab nraud, xa mus rau lub cev tsis muaj zog- qhov chaw muaj cai, nws qhov kev ua tiav pov thawj hauv kev hais txog IRDs, thiab cov thev naus laus zis tshiab tab tom tshawb nrhiav los ua kom nws muaj kev nyab xeeb ntxiv) qhia tias qhov kev xa khoom no yuav txuas ntxiv siv rau qee lub sijhawm.

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