Kev Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Kev Pom Zoo Rau Cov Muscular Dystrophies Thiab Neurodegenerative Disorders Part 9

SOD 1

Cov noob encoding Cu/Zn superoxide dismutase (SOD1) yog thawj qhov kev hloov pauv uas ua rau fALS [62,254].

Superoxide dismutase (SOD) yog ib qho tseem ceeb antioxidant enzyme uas ua lub luag haujlwm hauv kev tswj cov redox tshuav nyiaj li cas hauv cov hlwb. Kev tshawb fawb qhia tau tias muaj kev sib raug zoo ntawm SOD thiab kev nco.

Ua ntej tshaj plaws, SOD tuaj yeem tshem tawm cov dawb radicals hauv lub cev, txo oxidative kev puas tsuaj rau cell membranes, thiab tiv thaiv cov qauv thiab kev ua haujlwm ntawm neurons. Qhov no pab txhim kho kev nco, tshwj xeeb tshaj yog rau cov neeg laus. Ib txoj kev tshawb nrhiav pom tias qib SOD hauv cov neeg laus muaj feem cuam tshuam nrog lawv lub peev xwm kev txawj ntse, nrog rau qib siab ntawm SOD qhia tau cuam tshuam nrog kev txawj ntse zoo dua.

Qhov thib ob, SOD kuj tseem tuaj yeem txhawb kev tsim cov neurons thiab txhim kho lub hlwb plasticity. Qhov no yog qhov tseem ceeb heev rau kev khaws cia thiab txhim kho. Ib txoj kev tshawb fawb qhia tau hais tias SOD tuaj yeem txhawb kev loj hlob ntawm neural qia hlwb hauv thaj tsam hippocampus ntawm lub hlwb thiab txhim kho kev nco.

Tsis tas li ntawd, SOD kuj tuaj yeem txo cov lus teb inflammatory thiab inhibit neuronal tuag. Qhov no kuj muaj txiaj ntsig zoo rau kev tiv thaiv kev paub tsis meej thiab kab mob.

Txhawm rau ua kom tiav, muaj kev sib raug zoo ntawm SOD thiab nco. Nyob rau hauv lub neej niaj hnub, peb tuaj yeem tiv thaiv lub hlwb thiab txhim kho kev nco qab los ntawm kev ua kom tau txais SOD, xws li noj ntau cov khoom noj uas muaj SOD, xws li blueberries, broccoli, thiab lwm yam, tib lub sijhawm, tswj kev noj qab haus huv, xws li kev noj qab haus huv. kev tawm dag zog thiab kev ua haujlwm tsis tu ncua thiab so, kuj tseem muaj txiaj ntsig zoo los txhawb kev tsim thiab kev saib xyuas ntawm SOD. 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 los ntawm ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Feem ntau ntawm SOD1 kev hloov pauv (18.9%) sib haum rau fALS, thaum 1.2% sib npaug nrog sALS rooj plaub[334], ob qho tib si nthuav tawm cov qauv qub txeeg qub teg[6–8]. Feem ntau ntawm ALS-ua rau SOD1 kev hloov pauv tsis qhia txog kev sib raug zoo ntawm SOD1 enzymatic kev ua ub no thiab ALS kab mob hnyav [48, 221, 269].

Kev poob ntawm kev ua haujlwm rau Sod1 hauv Sod1 noob knockout nas tsis ua rau muaj qhov tsis xws luag hauv lub cev muaj zog axon elongation [142] lossis motoneurondegeneration [244]. Tsis tas li ntawd, lub xub ntiag los yog tsis muaj endogenous nas Sod1 tsis cuam tshuam rau kev muaj sia nyob ntawm mice qhia txog tib neeg SOD1G85R transgene [36].

Qhov no sib cav rau GOF lom txawm hais tias SOD1-LOF yuav tsis raug cais tag nrho. Hauv kev tshawb nrhiav qhov chaw kho mob tsis ntev los no ua tiav 1/2/3, SOD1 tau tsom los ntawm ASO Tofersen / BIIB067 (NCT02623699 Lub Kaum Ob Hlis 8th, 2015 txog Lub Peb Hlis 24, 2021) rau kev ntsiag to cov mutant nrog rau cov tsiaj qus-hom allele [2020] ].Qhov no yog ib qho kev kawm 3-ib feem (A, B, C) los tshuaj xyuas qhov ua tau zoo, kev nyab xeeb, thiab kev ua siab ntev ntawm BIIB067.

BIIB067 kev tswj hwm ua rau muaj kwv yees li 36% kev tawm tsam ntawm SOD1 hauv CSF uas zoo li muaj kev nyab xeeb rau SOD1-ALS cov neeg mob[201]. Nws tseem qhib, seb qhov no puas txaus rau lub sijhawm ntev ntawm kev cuam tshuam cov tshuaj lom ntawm mutant SOD1, txawm hais tias kev tswj hwm zoo li muaj kev nyab xeeb.

Tsuas yog qee qhov lumbar puncture-txog cov kev mob tshwm sim tau raug tshaj tawm [201]. Thawj ob ntu (theem 1/2) feem ntau tsis yog tsim los rau kev ntsuam xyuas ntawm lub cev muaj zog. Txawm li cas los xij, lawv tau qhia tias qhov kev kho mob no tuaj yeem ua rau muaj kab mob qeeb zuj zus thiab ua rau muaj kev ua tau zoo dua hauv kev muaj peev xwm tseem ceeb thiab kev ntsuas tes tuav dynamometry [201]. Cov txiaj ntsig no tau ua raws li theem 3 pib thaum lub Tsib Hlis 2019 los ntsuas qhov ua tau zoo ntawm kev kho mob.

Txhua hom kev hloov pauv SOD1 thiab qib hnyav ntawm cov neeg mob ALS tau suav nrog. Txhawm rau tshawb nrhiav cov teebmeem kev kho mob ntawm BIIB067 hauv cov neeg mob ALS ua ntej cov tsos mob, rov ua cov placebo-tswj theem 3 txoj kev tshawb fawb (uas tam sim no nyob rau hauv qhov kev pab cuam) tau pib rau lub Tsib Hlis 17, 2021 (NCT04856982). Lub hom phiaj tseem ceeb yog txhawm rau ntsuas qhov ua tau zoo ntawm BII067 hauv cov neeg mob ua ntej cov tsos mob ALS-SOD1 nrog rau qib siab neurofilament.

Lub hom phiaj thib ob suav nrog kev ntsuam xyuas kev nyab xeeb, pharmacodynamics, thiab kev kho- teb biomarkers. Lub sijhawm kwv yees kawm tiav yog hnub thib ob ntawm 2027.

C9ORF 72

Yam tsawg kawg hauv Tebchaws Europe thiab Asmeskas, feem ntau ntawm cov caj ces ntawm ALS thiab Frontotemporal Dementia (FTD) yog GGGGCC (G4C2) hexanucleotide rov nthuav dav hauv qhov qhib nyeem ntawv 72 (C9ORF72) gene localizedon chromosome 9.

Qhov kev hloov pauv yog kwv yees li 34% ntawm fALS thiab ze li 25% ntawm tsev neeg FTD mob (C9ALS/FTD) hauv cov neeg nyob sab Europe [302, 334]. Txog li 25 G4C2 rov ua dua tau pom nyob rau hauv cov tib neeg noj qab haus huv, thaum cov neeg mob C9ALS / FTD chaw nres nkoj ntau pua mus rau ntau txhiab qhov rov ua dua [60, 245, 253].

Qhov nthuav dav yog nyob rau hauv intron1 uas tseem muaj thaj tsam txhawb nqa ntawm cov ntawv sau thib ob rau C9ORF72 [161, 204, 205]. Yog li, txo qis cov lus qhia ntawm qhov sib txuas thib ob tau sau tseg kom txo qis C9ORF72 protein ntau hauv cov neeg mob.

Txawm li cas los xij, thaj chaw intronic nthuav dav no kuj tau txhais los ntawm ib daim ntawv uas tsis yog-canonical ntawm cov protein biosynthesis (repeat-associated non-AUG [RAN] translation) [15, 212, 335].Raws li kev soj ntsuam ntawm RNA-foci lossis aberrant RNAsas zoo li. Kev tsim cov tshuaj lom homopolymeric dipeptide rov ua cov proteins (DPRs) los ntawm kev txhais lus RAN [94,163, 205, 212, 286, 290, 315], GOF mechanism tshwm sim.

Antisense RNA-foci paub txog sequester RNA-binding proteins (RBPs), ua rau LOF ntawm RBPsin coj cov neurons [163, 168, 189]. Depletion ntawm C9orf72 nyob rau hauv cov nas motoneurons cais ua rau kev hloov pauv hauv axon kev loj hlob thiab kev sib txawv ntawm presynaptic [278].

Qhov phenotype no kuj tau pom nyob rau hauv C9ORF72 ALSpatients 'inducible pluripotent qia cell (iPSC)-derivedmotoneurons thiab zoo ib yam li qee qhov kev hloov pauv uas tau pom hauv cell kab lis kev cai qauv ntawm SMA. Raws li cov kev tshawb pom no, ib qho kev kho mob sib xyaw ua ke nrog kev ua kom tsis muaj zog ntawm G4C2- rov ua dua-muaj RNAs thiab nce ib txhij ntawm C9ORF72 qhia los ntawm cov noob kev kho mob tau raug npaj rau cov neeg mob C9ORF72 [101].

ASOBIIB078 uas tsom rau qhov kev nkag siab-strand ntawm C9ORF72 cov ntaub ntawv sau tseg uas muaj cov hexanucleotide G4C2 rov ua dua tau raug kuaj kom muaj kev nyab xeeb thiab ua kom ntev nyob rau theem 1 kev kho mob nrog cov neeg laus C9ORF72 ALS cov neeg mob (NCT03626012).

Txoj kev tshawb no tseem ua haujlwm nrog qhov kwv yees ua tiav qhov kawg ntawm 2021. Qhov kev sim tau pib ua raws li theem 1 kev tshawb fawb txuas ntxiv (NCT04288856) txhawm rau ntsuas kev nyab xeeb mus sij hawm ntev, kam rau ua, pharmacokinetics, thiab cuam tshuam txog kev mob ntawm BIIB078 daim ntawv thov rau yav dhau los C9ORF72 cov neeg mob. . Txoj kev tshawb fawb tseem tab tom sau npe nrog kev kwv yees ua tiav hauv nruab nrab ntawm 2023.

FUS

Kev hloov pauv hauv FUS / TLS (Fused hauv Sarcoma / Translocatedin Liposarcoma) yog ib qho kev tsim caj ces rau cov ntaub ntawv tsis tshua muaj offALS thiab FTD [35, 162, 303, 304]. FUS kev hloov pauv muaj nyob hauv 4% ntawm cov neeg mob fALS thiab tsawg dua 1% ntawm cov neeg mobALS [61, 334] nrog tus qauv autosomal dominantinheritance.

Lub ubiquitously nthuav qhia DNA-/RNA-binding protein FUS localizes feem ntau mus rau lub nucleus nyob rau hauv physiological mob [333]. FUS koom nrog hauv DNA kho [313] tab sis kuj ua raws li RNA-binding protein nyob rau hauv ntau yam ntawm RNA metabolism, nrog rau cov kev cai transcriptional [188, 288], lwm splicing [121, 135, 164, 252], mRNA thauj [96], mRNA stability [145, 297, 327], thiab microRNA biogenesis [105, 213].

Toxic GOF thiab LOF vim FUS aggregation thiab cytoplasmic mislocalization ua lub luag haujlwm hauv FUS-ALS / FTD pathogenesis [150]. Txoj kev kho ASO-raws li kev kho mob tau pib rau ALS tshwm sim los ntawm aspecific FUS kev hloov pauv (P525L) uas cuam tshuam nrog kev ua phem ntawm ALS nrog rau cov menyuam yaus hnub nyoog qis dua. Ib tsob ntoo ntawm cov neeg mob FUS-ALS tau txais Jacifusen, tus kheej ASO [13].

Tus neeg mob FUS-ALS uas twb tau tsim teeb meem ua pa tau txais kev kho mob ntawm tus kheej ASO thiab tuag ib xyoos tom qab [14]. Cov txiaj ntsig ua ntej los ntawm qhov teeb meem no cuam tshuam, qhov cuam tshuam tsis zoo kuj tuaj yeem tshwm sim los ntawm kev tsoo cov tsiaj qus-hom FUStranscript. FUS cuam tshuam raws li RNA-binding protein nrog cov ntawv sau los ntawm kwv yees li 5500 noob [164].

Yog li, khob FUS los ntawm ASO txoj hauv kev tuaj yeem cuam tshuam nrog kev hloov pauv ntawm RNAs nrog ntev introns, ntau qhov tshwj xeeb tshaj yog encode rau synaptic proteins [164]. Kev txo qis ntawm cov ntawv sau tseg thiab cov proteins sib raug zoo ua rau cov thawj cov neurons ua rau muaj kev hloov pauv ntawm morphological xws li kev loj hlob cones [225], luv dua neurites [134, 225], txawv txav dendritic spines [95, 327], thiab hloov pauv neurotransmission [297].
Nyob rau hauv vivo, knockdown ofFUS nyob rau hauv murine hippocampal neurons ua rau muaj zog phospho-tau accumulations nrog rau txo neurogenesis, thiab yog li ib tug FTD-zoo li phenotype [134, 297]. Cov ntaub ntawv no thaum kawg xav tau kev siv zog ntxiv rau hauv kev tshawb nrhiav cov kws kho mob uas tshwj xeeb rau FUS qhia.

Jacifusen tau teem sijhawm muab rau yim tus neeg mob ntxiv nrog FUS kev hloov pauv (Figueiredo, M. (2020)-Collaboration Funds Experimental Therapy for RareFUS-ALS, nkag mus rau 3.28.20. https://alsnewstoday.com/2020/03/16/jacifusen -collaboration-funds-experimentaltherapy-for-patients-with-rarefus-als/). Cov kev sim ntxiv tau npaj nrog ION3763-CS1 uas tseem tsom rau qhov kev hloov pauv FUS no.

Kev nrhiav neeg ua haujlwm rau qhov kev sim no yuav pib thaum Lub Rau Hli 2021, thiab txog tam sim no tsis muaj cov ntaub ntawv kho mob. Muaj kev kho cov noob rau SOD1-, C9ORF72-, thiab FUSALS tau piav qhia hauv daim duab 4.

Genetic modifiers hauv ALS

Ataxin-2 yog ib qho protein uas nkag los ntawm ATXN2 noob. Kev nthuav dav ntawm cov kab mob polyglutamine hauv tib neeg ATXN2gene ua rau spinocerebellar ataxia hom 2 (SCA2) [131,238, 262]. SCA2 yog tus cwj pwm los ntawm neuronal degeneration nyob rau hauv lub cerebellum thiab inferior txiv ntseej uas ua rau ataxia, parkinsonism, thiab dementia. Ntau tshaj li kaum xyoo dhau los, nws tau pom tias qhov kev nthuav dav CAG no yog txuam nrog kev pheej hmoo siab dua rau ALS [76].

Txij xyoo 2017, nws tau paub tias txo qis ntawm Ataxin-2 ntawm ASOapproaches ncua lub neej ncua sij hawm thiab txo qis kev coj tus cwj pwm tsis zoo hauv TDP-43-ALS tus qauv[21].

Thaum lub Cuaj Hlis 2020, kev nrhiav neeg ua haujlwm rau kev tshawb fawb ntawm ALSpatients nrog lossis tsis muaj CAG nthuav dav hauv ATXN2gene tau pib los ntsuas kev nyab xeeb, kev zam, thiab tshuaj tshuaj ntawm Ataxin-2 ASO hu ua BIIB105.Lub sijhawm kwv yees kawm tiav yog Lub Ob Hlis 2023. kev kawm muaj nyob rau ntawmhttps://clinicaltrials.gov.

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