Kev Txhim Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies Thiab Neurodegenerative Disorders Part 6

SMN1 gene-therapy: Onasemnogene abeparvovec/Zolgensma ™

Lwm txoj hauv kev los ua kom SMN protein ntau ntau inmotoneurons thiab lwm hom cell yog SMN1 genetherapy.

Gene therapy yog ib txoj kev kho tshiab uas kho ntau yam kab mob los ntawm kev hloov DNA sib lawv liag. Nyob rau hauv xyoo tas los no, ntau thiab ntau cov kev tshawb fawb tau pom tias kev kho noob kuj tuaj yeem txhim kho kev nco thiab muaj peev xwm kho tau los cuam tshuam rau Alzheimer's kab mob, kev kawm tsis taus, thiab lwm yam.

Ua ntej, kev kho cov noob tuaj yeem tsom rau kev kho lossis kev tswj hwm ntawm qee cov noob ntsig txog kev nco. Piv txwv li, APOE gene plays lub luag haujlwm tseem ceeb hauv qhov tshwm sim ntawm Alzheimer's disease, thiab kev tshawb fawb tam sim no tau pom qhov sib txuas ntawm APOE gene variation thiab nws tshwm sim hauv Alzheimer's disease. Kev kho noob caj noob ces tuaj yeem ua rau lub hom phiaj hloov pauv hauv APOE noob thiab txo qhov tshwm sim ntawm Alzheimer's kab mob los ntawm qhov chaw.

Qhov thib ob, kev kho noob kuj tuaj yeem tsom cov noob muaj feem xyuam nrog cov neurons thiab synapses. Kev tshawb fawb qhia tau hais tias kev hloov pauv hauv neurotransmitters xws li dopamine thiab acetylcholine tuaj yeem cuam tshuam kev kawm thiab kev nco. Gene therapy tuaj yeem ua rau cov neurons los txhawb kev sib kis ntawm cov ntaub ntawv khaws cia thiab txhim kho kev nco.

Tsis tas li ntawd, kev tshawb fawb txog kev kho noob yuav tsum muab ntau txoj hauv kev los txhim kho kev nco. Cov kws tshawb fawb tau ua haujlwm nyuaj los kawm txog kev sib txuas ntawm qee cov noob thiab lub hlwb cov txheej txheem, vam tias yuav cuam tshuam ncaj qha rau hauv lub hlwb ua haujlwm los ntawm kev kho noob los txhawb kev txawj ntse thiab kev nco thaum laus.

Hauv luv luv, gene therapy tau siv dav hauv cov tshuaj niaj hnub no thiab muaj peev xwm ua tau zoo hauv kev txhim kho kev nco. Txawm hais tias kev kho noob rau tib neeg lub hlwb tseem nyob rau theem kev tshawb fawb, peb tuaj yeem ntseeg tau tias nrog kev txhim kho txuas ntxiv ntawm thev naus laus zis yav tom ntej, kev kho noob yuav coj tau txiaj ntsig ntau dua rau tib neeg kev noj qab haus huv thiab lub neej. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv hauv ntau txoj hauv kev.

Nyem paub txoj hauv kev los txhim kho koj lub cim xeeb

Txij li thaum SMA yog monogenetic autosomal recessive disorder uas yog tshwm sim los ntawm kev poob ntawm cov SMN protein, nws zoo nkaus li lub hom phiaj zoo heev rau genetherapies.

Qhov me me SMN1 cDNA tuaj yeem yooj yim ntim rau hauv ib qho tsis-replicating self-complementary (sc)AAV9vector thiab xa systemically. scAAV9 tsis tuaj yeem xa SMN1 cDNA rau cov leeg thiab lwm cov ntaub so ntswg, tab sis kuj hla BBB kom ncav cuag CNSand spinal motoneurons [92, 93, 195, 299].

Preclinicalstudies tau lees paub qhov siab SMN qhia los ntawm AAV-mediated gene hloov hauv motoneurons thiab peripheraltissues hauv tus qauv nas ntawm SMA [17, 93]. SMA micethat tau kho nrog scAAV9- kho SMN1 kev kho noob caj noob ces tau nthuav tawm qhov txuas ntxiv ntawm lub neej ntev dhau 250 hnub [93].

Qhov kev vam meej kab mob kis kab mob rau SMN1 tau hu ua Onasemnogene abeparvovec. Onasemnogene abeparvovec feem ntau hu ua AVXS-101 yog kev lag luam nyob rau hauv lub npe Zolgensma™. Onasemnogene abeparvovec tau los ua thawj hom kev kho mob uas tau pom zoo hauv Asmeskas rau kev kho mob SMA cov neeg mob (txog li ob xyoos) thiab los ntawm EMA.

Qhov pom zoo koob tshuaj ntawm 1.1 × 1014 vectorgenomes (vg) ib kilogram (kg) lub cev qhov hnyav yog xa tawm ntawm ib qho kev txhaj tshuaj rau hauv cov hlab ntsha. Nws tshwm sim tau zoo nyob rau hauv cov neeg mob nrog SMA hom 1 lossis 2 thiab ua ntej cov tsos mob SMA cov me nyuam mos [125].

Ob qhov kev sim tshuaj AVXS-101-CL-101 (START,NCT02122952) thiab CL-303 (STR1VE-US,NCT03306277; STR1VE-EU, NCT03461289; STR1VEAP, NCT0383718 ua tau zoo nrog Cov neeg mob nqa ob-allelic SMN1 kev hloov pauv thiab ob daim ntawv SMN2 [57, 58, 195, 198]. START yog qhov kev kawm qhib-daim ntawv lo nrog 15 SMA hom 1 cov menyuam mos uas tau kawm hauv ob pawg.

Tsob ntoo me nyuam mos tau txais ib koob tshuaj qis ntawm Onasemnogene abeparvovec (6.7 × 1013 mg / kg).Txhua tus neeg mob hauv pawg (n=15) tseem muaj sia nyob yam tsis muaj qhov cua mus tas li thaum muaj hnub nyoog 20 hli. Hauv cov neeg mob ntshav siab (12 tus neeg mob, 1.1 × 1014 mg / kg), nce los ntawm cov ntsiab lus ntawm 9.8 cov ntsiab lus ntawm 1 lub hlis thiab 15.4 cov ntsiab lus ntawm 3 lub hlis hauv CHOP INTEND qhab nia tau kuaj pom. Tsis tas li ntawd, 11 ntawm cov neeg mob uas tau koob tshuaj ntau zaum tsis tau txais kev pab, 9 dov dhau, 11 noj qhov ncauj thiab hais tau, thiab 2 taug kev ntawm nws tus kheej.

Kev nce qib hauv cov ntshav aminotransferase tshwm sim hauv 4 tus neeg mob uas tau kho nrog prednisolone [195]. Txoj kev tshawb fawb STR1VE-US yog ib qho qhib-daim ntawv sau npe, ib zaug koob tshuaj thib 3 mus sib hais. SMA cov neeg mob uas muaj biallelic SMN1 kev hloov pauv (kev rho tawm lossis taw tes hloov pauv) thiab ib rau ob daim ntawv SMN2 tau yau dua 6 lub hlis thiab cov tsos mob.

Lawv tau txais ib koob tshuajOnasemnogene abeparvovec ntawm 1.1 × 1014 vg / kgbody qhov hnyav rau 30-60 min. Kev saib xyuas ntawm 22SMA cov neeg mob tau pib teem sijhawm ib zaug hauv ib lub lis piam thiab tom qab 4 lub lis piam ib zaug hauv ib hlis. Txhua tus neeg mob tuaj yeem tos nws tus kheej rau 30 s. 20 tus neeg mob tsis muaj qhov cua mus tas li.

Tag nrho tab sis ib qho ntawm 12 tus neeg mob hauv cov neeg mob siab tau txais txiaj ntsig tseem ceeb ntawm lub cev muaj zog xws li kev zaum tsis muaj kev pab, thiab kev nce ntxiv ntawm CHOP INTEND qhab nia ntawm 50–60 cov ntsiab lus [57, 58]. Raws li cov ntaub ntawv uas tau sau tseg hauv cov kev sim no, qhov kev siv tau ntev ntev ntawm Onasemnogene abeparvovec ntawm lub cev muaj zog yuav tsum tau ua.

Cov teebmeem tsis zoo yog bronchiolitis, mob ntsws, thiab ua pa nyuaj. Tsuas yog ob tus neeg mob tau pom tias muaj cov aminotransferases. Cov txheej txheem ntawm kev tiv thaiv kab mob thiab tshwj xeeb tshaj yog cov kab mob siab tau pom nyob rau hauv cov kev tshawb fawb soj ntsuam no tseem tsis tau nkag siab tag nrho. Ib tus neeg mob tau tsim cov cim qhia ntawm hydrocephalus uas lub tshuab tsis meej.

CHOP INTEND cov txiaj ntsig tau piav qhia cov txiaj ntsig ntxov thiab sai. Cov neeg mob muaj peev xwm vam meej thiab nqos tau zoo yam tsis muaj kab mob plawv thaum kawg ntawm kev tshawb fawb [57, 58].

Lwm qhov kev sim tshuaj nrog Onasemnogeneabeparvovec yog txuas ntxiv raws li qhov qhib-label theem 1-2 sim nrog kev tswj hwm intrathecal hauv SMA hom 2 cov neeg mob (6 lub hlis txog 60 lub hlis) nrog peb daim ntawv SMN2 (STRONG, NCT03381729). Txoj kev tshawb fawb STRONG tau pom tias muaj txiaj ntsig zoo hauv lub cev muaj zog thiab kev nyab xeeb [90].

Kev tswj hwm intrathecal tuaj yeem hla qhov muaj peev xwm tiv thaiv kab mob hauv cov neeg mob uas tau kis tus kab mob ua ntej ua ntej kho. Thaum tus neeg raug tus kab mob AAV endogenous, kev tiv thaiv kab mob tuaj yeem pib. [27, 312] ib.

Thus a significant number of individuals produce neutralizing antibodies and block the gene transfer to cellular targets [3, 312]. The two studies by Day et al. [57, 58] revealed that 7.7% of the SMA patients and 14.8% of their biological mothers were positive for AAV9 reactive antibodies with exclusionary antibody titers>1:50 ntawm lawv qhov kev ntsuam xyuas thawj zaug. 5.6% tau pom cov titers siab ntawm lawv qhov kev tshuaj ntsuam zaum kawg thiab tsis suav nrog kev txais Onasemnogene abeparvovec hauv kev sim tshuaj.

Yog li, feem ntau ntawm SMA cov menyuam mos yuav tsum tau txais txiaj ntsig los ntawm kev tswj hwm Onasemnogeneabeparvovec thaum muab intrathecally [57,58]. Lwm theem 3 txoj kev kawm nrog cov tshuaj txhaj tshuaj hauv cov neeg mob ua ntej SMA hom 1 lossis 2 cov neeg mob nrog ob lossis peb daim ntawv luam ntawm SMN2 (SPR1NT, NCT03505099) tau pib. Cov ntaub ntawv ua ntej qhia tias Onasemnogene abeparvovec tau txais txiaj ntsig zoo thaum siv qhov siab siab (6.0 × 1013 mg / kg).

Ob qhov kev tshawb fawb mus sij hawm ntev (LTFU) tam sim no tau saib xyuas kom txog rau thaum Lub Kaum Ob Hlis 2033 thiab 2035. LT-001/NCT03421977 yog kev tshawb nrhiav kev nyab xeeb ntawm 13 tus neeg mob SMA hom 1 hauv theAVXS-101-CL{{10} } trial (2017–2033), whereas LT-002/NCT04042025 (2020–2035) tseem tso npe cov neeg mob los ntawmSTRONG, STR1VE thiab SPR1NT.

Txhua qhov kev sim tshuaj ntawmOnasemnogene abeparvovec/Zolgensma ™ raws li lawv lub sijhawm tau sau tseg hauv daim duab 3.

Kev txiav txim siab ib ntus rau kev kho SMA

Kev nce tus nqi ntawm SMN protein nyob rau hauv neurons thiab lwm hom cell tsis tsuas yog muaj qhov zoo tab sis kuj muaj kev pheej hmoo. Cov theem qhia ntawm SMN yog tswj tau zoo thaum lub sij hawm kev loj hlob ib txwm thiab tsis tuaj yeem hloov kho los ntawm txoj kev kho noob. Kev soj ntsuam hauv nas qauv sib cav hais tias tus kab mob overexpression tuaj yeem muaj kev cuam tshuam ntev ntev los ntawm kev cuam tshuam nrog txoj haujlwm RNA ua haujlwm.

Hauv kev tshawb fawb tsis ntev los no, nws tau raug tshaj tawm tias qhov kev nthuav dav ntev ntev ntawm AAV9-SMN1 ua rau cov tshuaj tiv thaiv kev puas tsuaj ntawm proprioceptive synapses thiab neurodegeneration hauv SMAmouse cov qauv cuam tshuam nrog kev poob ntawm qhov tseem ceeb ntawm lub cev muaj zog [301]. AAV9-SMN1 ua rau cytoplasmic SMN aggregation nyob rau hauv cov neurons uas sib haum mus rau snRNP biogenesis thiab dav transcriptionabnormalities nyob rau hauv DRG neurons [301].

Cov kev soj ntsuam no qhia tau hais tias cov hom phiaj kho mob ntxiv uas tsis yog SMN1 thiab SMN2 noob yuav tsum raug soj ntsuam thiab txiav txim siab (saib hauv qab no cov kev kho mob uas tsis yog SMN). Rau kev ua tiav kev kho mob ntev ntev ntawm SMA, nws zoo nkaus li tseem ceeb kom nkag siab txog lub sijhawm uas SMN proteinis xav tau los tiv thaiv kab mob kev loj hlob, thiab hom cell thiab kab mob twg xav tau SMN ntawm lub sijhawm rau homeostasis.

SMN deficiency yog embryonic tuag thiab SMA tsim nyob rau hauv thaum yau los yog prenatally nyob rau hauv lub sij hawm tseem ceeb lub qhov rais thaum neuromuscular synapses muaj zog thiab loj hlob. Thereconstitution ntawm SMN2 protein los ntawm ASO mus kom ze thaum lub sij hawm postnatal thaum ntxov nyob rau hauv ib tug hnyav SMA mousemodel (P 1-4) tau zoo los tiv thaiv qhov pib ntawm tus kab mob.

Qhov ciaj sia taus ntawm cov nas SMA kho tau ntev mus txog 250 hnub ntawm hnub nyoog [127] uas sib haum rau 16-fold nce. Pib nce SMN 10 hnub tom qab yug me nyuam ua tsis tau tej yam txiaj ntsig. Strikingly, tus kab mob phenotype yog thim rov qab hauv cov ntawv me me SMA. Inan intermediate SMA nas qauv, kev kho mob tom qab-symptomaticnon-SMN tau muaj txiaj ntsig zoo [86].

Txawm li cas los xij, ncua kev kho mob tsuas yog ib lossis ob peb hnub hauv cov nas hnyav SMA hom 1 tom qab cov tsos mob tshwm sim tau txo qis cov txiaj ntsig [93, 249] ntawm motoneuron poob, thiab kev hloov pauv ntawm morphological ntawm neuromuscular endplates tseem nyob [183]. SMN protein tsis txaus ua ntej cuam tshuam rau qhov kawg ntawm lub cev muaj zog [156, 208, 255]. Yog li ntawd, lub qhov rais zoo tshaj plaws rau kev rov ua dua ntawm SMN protein nyob rau hauv cov xwm txheej hnyav yog nyob ntawm qhov kev loj hlob ntawm cov kab mob neuromuscular endplates [147].

Cov kev tshawb fawb nrog cov qauv nas ntawm SMAindicate tias qhov kev kho mob zoo tshaj plaws hauv cov xwm txheej hnyav yog nyob ntawm cov ntawv thov tom qab thaum ntxov. Qhov no kuj tau tshwm sim rau SMN-kev ywj pheej kho cov qauv inmouse [291]. Hauv ob qhov kev sim tshuaj nrog cov neeg mob, cov kev soj ntsuam zoo sib xws tau ua.

Pib qhov kev kho mob ua ntej cov tsos mob hauv cov menyuam mos uas muaj ob lossis peb daim ntawv SMN2 tau muaj txiaj ntsig zoo dua li kev pib kho thaum thawj cov tsos mob tshwm sim. Thaum kho nrog Nusinersen / Spinraza ™ yog pib ntawm tsawg dua 2 lub hlis ntawm lub neej, thiab tom qab qhov nruab nrab ntawm 2.9 xyoo ntawm kev kho mob, 100% ntawm cov menyuam yaus tuaj yeem ncav cuag qhov tseem ceeb ntawm zaum ntawm nws tus kheej. Ntxiv mus, 88% ntawm cov neeg mob kuj tuaj yeem taug kev ntawm nws tus kheej [59].

Hauv qhov sib piv, qhov cuam tshuam ntawm kev kho tau tshwm sim tau txo qis hauv theem 3 sim nrog Nusinersen / Spinraza ™ qhov twg kev kho tau pib tom qab pib tshwm sim hauv cov menyuam yaus nrog 2 daim ntawv luam ntawm SMN2. Kev kho mob postymptomatic ua rau txo qis kev tuag, tab sis tsuas yog 51% ntawm cov neeg mob tau pom tias lub cev muaj zog ua haujlwm tau zoo thiab tsuas yog 8% tuaj yeem zaum ntawm nws tus kheej ntawm 13 lub hlis tom qab pib kho [89].

Hauv kev xaus, kev ncua ntawm SMNelevation los ntawm ob peb lub lis piam mus txog 5 lub hlis tuaj yeem txo qhov kev ua tiav ntawm lub cev muaj zog. Yog li, nws zoo nkaus li tseem ceeb uas kev kho mob hauv cov menyuam yaus nrog SMA pib tam sim tom qab kuaj mob. Cov kev soj ntsuam no tseem muab cov lus sib cav muaj zog rau kev tshuaj ntsuam xyuas menyuam mos, txhawm rau txheeb xyuas cov tsos mob ua ntej thiab cov tsos mob ntxov.

Ua ntej cov tsos mob tshwm sim thiab irreversible motoneuron degeneration pib, cov me nyuam mos uas pom los ntawm kev ntsuam xyuas tus me nyuam yuav tsum raug xa mus rau kev kho tam sim ntawd. Thaum SMN qib qis heev, motoneurons poob lawv txoj haujlwm nyob rau lub sijhawm luv luv thiab kev nce qib mus rau theem thaum kev kho dua tshiab tuaj yeem raug txwv, thiab lub sijhawm lub qhov rais rau kev rov ua tiav ntawm motoneuron muaj nuj nqi thiab / lossis cellular regeneration tuaj yeem ploj.

Cov nuj nqis rau daim ntawv thov Spinraza™ hauv thawj xyoo yog kwv yees li $400,000–500,000 (lossis€ 400,000–500,000). Nyob rau hauv tag nrho $250,000–300,{11}} (lossis€ 250,000–300,{15}}) ib xyoos yog xam rau tus neeg mob lub neej.

Ib daim ntawv thov ntawm Zolgensma ™ raug nqi $ 2 lab. Tsis ntev dhau los, cov tswv yim kho mob ntawm noob caj noob ces yuav tsum tau pom zoo los ntawm FDA thiab EMA. Cov nqi kho mob zoo li no tuaj yeem ua teeb meem rau cov kws kho mob.

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