Kev Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Kev Pom Zoo Rau Cov Muscular Dystrophies Thiab Neurodegenerative Disorders Part 4

Antisense oligonucleotide cov tswv yimNusinersen / Spinraza ™: ib qho ASO-txoj hauv kev

ASOs yog luv luv ntawm cov hluavtaws nucleic acids uas khi lub hom phiaj-RNA los ntawm kev sib txuas ntawm lub hauv paus ua ke tomodulate RNA stability, qauv, thiab kev ua haujlwm [247].Nusinersen yog ib qho 18-mer ASO hloov los ntawm 2'-O-2-methoxyethyl phosphorothioate tiv thaiv nws los ntawm kev puas tsuaj sai.

Nrog kev txhim kho txuas ntxiv ntawm tib neeg kev ua neej nyob, ntau thiab ntau tus neeg tau pib mob siab rau lawv cov teeb meem kev noj qab haus huv. Ib qho tseem ceeb yog kev nco. Ntau tus neeg pom tias lawv qhov kev nco tau maj mam poob qis, thiab yuav ua li cas txhim kho lawv lub cim xeeb tau dhau los ua ib qho tseem ceeb heev.

Nyob rau hauv xyoo tas los no, kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm cov saw luv ntawm nucleic acids thiab nco. Cov saw luv ntawm nucleic acid yog cov khoom siv roj ntsha uas tswj hwm lub paj hlwb thiab lub cev tsis muaj zog. Thiab kev nco yog ib qho tseem ceeb tshaj plaws ntawm peb lub hlwb.

Cov saw luv luv ntawm nucleic acids tuaj yeem txhim kho qhov tseem ceeb ntawm lub paj hlwb los ntawm kev txhawb nqa kev kho thiab kev tswj hwm ntawm lub paj hlwb, ua rau lub hlwb nrawm dua thiab txhim kho kev nco. Tsis tas li ntawd, luv luv chains ntawm nucleic acids kuj tuaj yeem txo cov ntshav lipids thiab ntshav siab, thiab txhawb kev noj qab haus huv ntawm cov hlab plawv, yog li txhim kho lub cev metabolic muaj peev xwm thiab ua rau lub cev noj qab haus huv.

Txawm hais tias qhov poob ntawm lub paj hlwb ua haujlwm yog ib qho tshwm sim, peb tuaj yeem khaws peb lub cim xeeb hauv qee txoj hauv kev, xws li los ntawm kev noj cov khoom noj luv luv uas muaj cov nucleic acids, xws li seaweed, kelp, taum paj, thiab lwm yam. Tib lub sijhawm, tsis tu ncua. kev tawm dag zog lub cev thiab tswj kev ua neej zoo kuj tuaj yeem pab txhim kho peb lub cim xeeb.

Hauv lub neej niaj hnub no, kev nco tseem ceeb heev rau txhua tus. Peb yuav tsum xyuam xim rau kev sib raug zoo ntawm cov saw luv ntawm nucleic acids thiab kev nco, thiab siv ntau txoj hauv kev los txhim kho peb lub cim xeeb thiab ua rau peb lub neej muaj zog thiab muaj zog. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv cov kab mob. kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv kev loj hlob ntawm kev paub tsis meej thiab kab mob neurodegenerative.

Nyem paub cov tshuaj ntxiv los txhawb kev nco

Nws tau tsim los thaiv kev khi ntawm hnRNPA1 rau intronic splicing silencer N1-(ISS-N1) motif inintron 7 ntawm SMN2 noob. Qhov thaiv ntawm hnRNP A1 khi rau qhov chaw no ua rau cuam tshuam qhov chaw sib txuas inhibitor thiab yog li txhawb nqa exon 7 suav nrog hauv pre-mRNA uas yog muab los ntawm SMN2 noob [128].

Vim lawv qhov loj me, ASOs tsis tuaj yeem hla cov ntshav-hlwb teeb meem (BBB) ​​thiab yuav tsum tau thov los ntawm kev tswj hwm intrathecal kom lawv tuaj yeem raug coj los ntawm motoneurons los ntawm cov kua cerebrospinal (CSF).

Nusinersen yog thawj cov tshuaj uas tau pom zoo rau kev kho mob SMA los ntawm FDA thaum lub Kaum Ob Hlis 2016 thiab los ntawm EMA thaum Lub Rau Hli 2017. Tam sim no, 31 qhov chaw kho mob trialshave tau tshaj tawm los ntawm https://clinicaltrials.gov. Ntawm no peb tshaj tawm cov kev xaiv ntawm cov kev tshawb fawb tsom rau kev tshawb pom koob tshuaj nrog cov ntaub ntawv tau tshaj tawm. Thawj theem 1 kev soj ntsuam nrog Nusinersen (CS1, NCT01494701 thiab CS10, NCT01780246) tau ua nrog 28 tus neeg mob (2 txog 14 xyoos) nrog SMA hom 2 thiab hom 3.

Qhov kev tshawb fawb no tau muab pov thawj tias kev xa tawm intrathecal ntawm ib koob ntawm Nusinersen (1 mg, 3 mg, 6 mg, lossis 9 mg) muaj kev nyab xeeb thiab zam tau zoo. Nusinersen ntau dua ob npaug ntawm SMNprotein qib hauv CSF hauv pawg kho mob 6 mg thiab 9 mg.

Qhov no tau nrog los ntawm qhov tseem ceeb ntawm lub cev muaj zog ua haujlwm tau piav qhia los ntawm Hammersmith Functional Motor Scale Expanded (HFMSE) cov qhab nia hauv 9 mg pawg [44]. Ib theem tom ntej 2, qhib-labelstudy (CS3A; NCT01839656) nrog SMA hom 1 cov neeg mob nrog 2-3 SMN2 daim ntawv (3 lub lis piam mus rau 6 lub hlis ntawm hnub nyoog) tau ua nrog ntau koob tshuaj Nusinersen. Plaub tus neeg mob tau txais koob tshuaj nce ntxiv ntawm 6 txog 12 mg thiab 16 tus neeg mob tau txhaj tshuaj intrathecal 12 mg.

Cov neeg mob hauv pawg 12 mg tau nthuav tawm qhov ua tau zoo ntxiv hauv kev loj hlob lub cev muaj zog tseem ceeb ntawm Hammersmith Infant Neurological Examination-2 (HINE-2) cov qhab nia (los ntawm lub hauv paus mus rau zaum kawg p<0.0001), improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scores (p=0.0013) and significantly increased CMAP for abductor digit minimus and tibialis anterior via stimulation of the ulnar nerve or the peroneal nerve. 

Qhov tshwm sim ntawm qhov cua tsis muaj sia nyob mus tas li kuj tau nce ntxiv.

Kev soj ntsuam ntawm cov ntaub so ntswg tom qab tau nthuav tawm ib qho kev faib tawm ntawm Nusinersen thoob plaws hauv tus txha caj qaum, suav nrog motoneurons thiab lub paj hlwb uas tau sib koom nrog kev txhim kho exon 7 suav nrog hauv SMN2 thiab nce ntawm SMN protein [88]. Cov kev tshawb fawb tom qab nrog Nusinersen kev kho mob hauv 28 tus neeg mob nrog SMAtype 2 thiab hom 3 (hnub nyoog 2-5 xyoo) rau kwv yees li 3 xyoos tau pom tias muaj txiaj ntsig ntev (CS2; NCT01703988and CS12; NCT02052791).

Cov neeg mob pib nrog cov koob tshuaj nce ntxiv (3, 6, 9, 12 mg tshaj 253 hnub) ua raws li kev kho mob nrog 12 mg txhua 6 lub hlis rau ntau tshaj ob xyoos (CS12) [54]. Qhov no tau ua raws los ntawm SHINE txoj kev tshawb fawb (NCT02594124) los ntawm kev txuas ntxiv 12 mgNusinersen daim ntawv thov los soj ntsuam cov txiaj ntsig mus sij hawm ntev ntawm Nusinersen.

Kev kho mob dhau thawj peb xyoos tau ua rau muaj kev txhim kho lub cev muaj zog thiab kev ua haujlwm ntawm cov kab mob stabilization uas txawv heev ntawm keeb kwm kab mob. Cov neeg koom nrog tom qab-onsetSMA hauv CS2 / CS12 / SHINE tau nthuav tawm qhov nce hauv kev taug kev deb uas tsis tau pom nyob rau hauv cov keeb kwm keeb kwm yav dhau los [210] nrog kev ruaj khov hauv kev qaug zog thiab kev txhim kho ntawm kev ua haujlwm thoob plaws hauv kev kho mob Nusinersen (~ 5.5 xyoo) [209].

Theem 1/2 tau txhawb nqa kev tsim ntawm ob qhov loj, multicenter, randomized, sham-tswj, theem 3 kev tshawb fawb nrog Nusinersen: ENDEAR (NCT02193074) hauv SMA hom 1 cov neeg mob thiab CHERISH (NCT02292537) hauv SMA hom 2 cov neeg mob (NCT024) ) suav nrog 122 SMAtype 1 cov neeg mob thaum muaj hnub nyoog 7 hli lossis qis dua. Lawv raug randomized kom tau txais ntau yam tshuaj intrathecal ntawm Nusinersen lossis tus txheej txheem sham ntawm qhov sib piv ntawm 2 mus rau 1 [89].Nyob rau hauv txoj kev tshawb fawb CHERISH (NCT02292537) 126 tus menyuam raug muab tso rau hauv qhov sib piv 2: 1, kom tau txais ntau qhov koob tshuaj ntawm 12 mg Nusinersen. los yog kev txaj muag.

Lub hnub nyoog nruab nrab ntawm qhov pib kawm yog 4 xyoos (2–9 xyoos) hauv pawg Nusinersen thiab 3 xyoos (2–7 xyoos) hauv pawg tswj hwm [196]. Hauv ob qho kev tshawb fawb, cov menyuam kho tau pom tias muaj kev txhim kho tseem ceeb hauv lub cev muaj zog piv rau cov pab pawg tswj. Nyob rau hauv txoj kev tshawb fawb ENDEAR, qhov kev ciaj sia tag nrho yog siab dua hauv Nusinersen-kho pab pawg dua li hauv pawg tswj hwm.

Kev soj ntsuam zoo heev tau ua, vim tias cov menyuam mos uas muaj kab mob luv luv ntawm qhov kev tshawb fawb pib muaj feem yuav tau txais txiaj ntsig los ntawm Nusinersen ntau dua li cov neeg mob ntev dua. Lub sijhawm tseem ceeb ntawm kev pib ntawm Nusinersen kev kho mob cov txiaj ntsig kho mob yog tam sim no nyob rau hauv kev tshawb fawb hauv theem 2 txoj kev tshawb fawb ntawm cov neeg mob ua ntej cov tsos mob (NURTURE, NCT02386553).

25 tus neeg mob suav nrog tseem muaj sia nyob thiab tsis xav tau qhov cua mus tas li.Txhua tus neeg mob tuaj yeem zaum yam tsis muaj kev txhawb nqa thiab taug kev nrog lossis tsis muaj kev pabcuam thiab tseem tsis muaj qhov cua txhawb nqa [59]. Nyob rau lub Kaum Ob Hlis 2016 Nusinersen / Spinraza ™ tau los ntawm kev pom zoo koob tshuaj 12 mg rau ib qho kev kho mob rau txhua tus neeg mob. Tam sim no, kev nyab xeeb thiab kev ua tau zoo ntawm cov koob tshuaj ntau dua yog qhov tseem ceeb ntawm DEVOTEstudy (NCT04089566). DEVOTE tau muab faib ua ntu A, B, thiab C.

Ntu A yog ib qho kev kawm qhib-label tsom rau kev nyab xeeb thiab kev zam ntawm Nusinersen (3 × 28 mg loading dosesand 2 × 28 mg noj koob tshuaj). Tshooj B yuav tsum ua kom pom tias koob tshuaj ntau dua txhim kho cov neeg koom nrog cov txiaj ntsig tau ntsuas los ntawm CHOP INTEND thiab lub peev xwm ntawm lub cev muaj zog.

Qhov no yog tsim los ua ib qho randomized, ob-dig muag, ua haujlwm-tswj kev kawm nrog cov menyuam mos thiab tom qab pib SMApatients. Cov neeg mob yuav tau txais 4 × 12 mg loading koob tshuaj, ua raws li 2 × 12 mg noj tshuaj lossis 2 × 50 mgloading koob tshuaj thiab 2 × 28 mg noj tshuaj.

Cov neeg koom nrog tau txais FDA pom zoo 12 mg ntawm Nusinersen yuav ua raws li kev tswj hwm. Qhov qhib-daim ntawv lo ntu C yuav ntsuas kev nyab xeeb thiab kev zam ntawm kev hloov pauv cov neeg mob uas twb tau kho nrog Nusinersen tsawg kawg ib xyoos.

Lawv yuav tau txais ib koob tshuaj thawj zaug 20 mg tom qab los ntawm ob koob tshuaj 28 mg rau plaub thiab yim hli tom qab pib kho. Qhov kev sim DEVOTE yuav ua raws li qhov qhib-daim ntawv txuas ntxiv kawm ONWARD (NCT04729907) raws li kev txuas mus ntev.

Cov kev pab cuam nthuav dav (EAPs) rau Nusinersen tau pib hauv ntau lub tebchaws los txheeb xyuas cov txiaj ntsig kho mob nrog kev txhim kho lub cev muaj zog [10, 83,100, 199, 232]. Ob qhov kev tshawb fawb ntawm SMA cov neeg mob uas muaj neeg laus (txhais tau tias muaj hnub nyoog 16-65 thiab 18-72) tau tshaj tawm los ntawm Hagenacker li al., thiab Maggi li al. [111, 184].Qhov txiaj ntsig tseem ceeb hauv ob txoj kev tshawb fawb yog qhov nce hauv HFMSE tus qhab nia.

Maggi et al. Tsis tas li ntawd tau tshaj tawm tias RULM (Revised Upper Limb Module) tau qhab nia zoo dua qub hauv cov neeg zaum [184]. Ob qhov kev tshawb fawb muab pov thawj ntawm Nusinersen txoj kev nyab xeeb thiab kev ua tau zoo hauv SMA hom 2 thiab hom 3 cov neeg mob.

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