Kev Txhim Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies Thiab Neurodegenerative Disorders Part 1
Mar 25, 2024
Abstract
Keeb kwm: Cov kev siv zog loj tau ua nyob rau hauv kaum xyoo dhau los los tsim thiab txhim kho kev kho mob rau qhov sib thooj spinalmuscular atrophy (SMA). Kev taw qhia ntawm Nusinersen / Spinraza ™ raws li kev kho tshuaj tiv thaiv oligonucleotide, Onasemnogene abeparvovec / Zolgensma ™ raws li AAV9-raws li kev kho noob, thiab Risdiplam / Evrysdi™ ua ib qho me me moleculemodifier ntawm pre-mRNA splicing rau kev cuam tshuam cov qauv tshiab nrog neurodegeneration.
Proximal spinal muscular atrophy (SMA) yog ib hom kab mob caj ces uas cuam tshuam rau lub cev lub paj hlwb, ua rau lub cev nqaij daim tawv maj mam atrophy thiab poob. Cov neeg uas muaj SMA feem ntau ntsib ntau yam teeb meem ntawm lub cev thiab lub neej, tab sis lawv lub cim xeeb zoo li cov neeg feem coob.
Tsis muaj pov thawj tias SMA cuam tshuam kev nco. Ntau tus neeg mob SMA nthuav qhia kev ua tau zoo ntawm kev nco, tej zaum vim tias lawv tau ntsib ntau yam teeb meem hauv lawv lub neej. SMA cov neeg mob yuav tsum nco ntsoov cov ntaub ntawv xws li cov ntaub ntawv kho mob, cov tshuaj noj, thiab contraindications kom muaj kev noj qab haus huv thiab lub neej zoo. Lawv kuj yuav tsum muaj lub siab ntshiab los daws cov teeb meem ntawm lub neej niaj hnub, xws li kev tswj cov sij hawm thiab tuav cov xwm txheej nyiaj txiag.
Txawm hais tias cov neeg uas muaj SMA yuav xav tau kev txhawb nqa thiab kev pab ntxiv los daws cov teeb meem hauv lub neej uas lawv ntsib, qhov no tsis txhais tau tias lawv lub peev xwm thiab kev nco yuav raug cuam tshuam. Lawv lub peev xwm xav, qib kev txawj ntse, thiab kev muaj peev xwm kawm tau zoo ib yam li cov pej xeem, thiab lawv tuaj yeem ua tiav ntau yam dej num thiab kev ua ub no los ntawm lawv cov kev siv zog thiab kev txhawb nqa tsim nyog.
Hauv cov tsev neeg thiab cov zej zog ntawm SMA cov neeg mob, peb yuav tsum tsom mus rau kev txhawb nqa thiab pab lawv xav tau los pab lawv daws cov teeb meem ntau yam. Nyob rau tib lub sijhawm, peb yuav tsum saib SMA cov neeg mob zoo, nkag siab lawv tus mob, thiab hwm lawv cov kev xav thiab kev xav. Cov neeg uas muaj SMA muaj zog sib npaug ntawm lub siab thiab kev nco, thiab lawv kuj yuav tsum tau txais kev hwm thiab qhuas kom paub lawv txoj kev npau suav thiab kev xav. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham 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
Lub cev tseem ceeb: Kev kho rau SMA yog tsim los cuam tshuam nrog lub hauv paus cellular ntawm tus kab mob los ntawm kev hloov kho pre-mRNA splicing thiab txhim kho qhov kev qhia ntawm Survival Motor Neuron (SMN) protein, uas tsuas yog qhia nyob rau theem qis hauv qhov teeb meem no.
e cov tswv yim sib raug zoo kuj tuaj yeem siv rau lwm yam kab mob uas tshwm sim los ntawm kev ua haujlwm tsis zoo lossis muaj tshuaj lom ntau ntawm kev hloov pauv. Txoj kev loj hlob ntawm kev kho mob rau SMA yog raws li kev siv cellculture systems thiab nas qauv, nrog rau cov kev soj ntsuam kev sim tshiab uas suav nrog cov nyeem ntawv uas tau xub qhia thiab ua kom zoo dua hauv cov kev tshawb fawb ua ntej.
Qhov no tau sau tseg hauv thawj ntu ntawm qhov kev tshuaj xyuas no. Qhov thib ob tham txog kev txhim kho tam sim no thiab kev pom ntawm amyotrophic lateral sclerosis, cov leeg nqaij dystrophy, Parkinson's, thiab Alzheimer's kab mob, nrog rau cov teeb meem uas yuav tsum tau kov yeej los qhia txog RNA-raws li kev kho mob thiab cov kev kho mob rau cov kab mob no.
Xaus: RNA-raws li kev kho mob muab txoj hauv kev rau kev kho kev txhim kho ntawm cov kab mob neurodegenerative nyuaj xws li amyotrophic lateral sclerosis, muscular dystrophy, Parkinson's, thiab Alzheimer's disease.
Cov kev paub dhau los nrog cov tshuaj tshiab no rau SMA, thiab cov kev paub dhau los hauv AAV noob kev kho mob tuaj yeem pab nthuav dav cov txheej txheem tam sim no los cuam tshuam nrog cov txheej txheem pathophysiological hauv neurodegeneration.
Keywords: Motoneuron disease, Neurodegenerative disease, Muscular disease, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Muscular dystrophy, Alzheimer's disease, Parkinson's disease, Clinical trial, Gene therapy.
Keeb kwm
Spinal muscular atrophy (SMA) yog qhov tshwm sim feem ntau ntawm kev ua rau neeg tuag taus neuromuscular teeb meem nrog autosomal recessive qub txeeg qub teg. Nws yog tshwm sim los ntawm homozygous poob kev ua haujlwm (LOF) kev hloov pauv ntawm SurvivalMotor Neuron 1 (SMN1) gene [170] ntawm tib neeg chromosome 5 (5q13.2).
Yog li, cov kev kho mob kom deb li deb tau tsom mus rau kev kho dua tshiab ntawm SMN qhia. Cov qauv tsim tshwj xeeb ntawm tib neeg chromosome 5 nrog cov noob thib ob SMN (SMN2) yog lub luag haujlwm rau kev tsim cov cellular ntawm cov qib qis ntawm SMN protein uas tsis txaus los tswj cov qauv thiab kev ua haujlwm ntawm motoneurons.SMN2 txawv ntawm SMN1 los ntawm ib qho C rau T transitionin exon 7. , ua rau nce kev hla ntawm exon 7 [180,206].
Yog li, txoj hauv kev los txwv lwm txoj kev sib txuas ntawm qhov exon no, thiab AAV9-raws li kev kho noob rau kev txhim kho ntawm SMN protein nyob rau hauv motoneurons tau ua rau muaj kev vam meej hauv kev kho degeneration ntawm motoneurons nyob rau hauv tus kab mob no.Kev kho cov protein qhia kuj tseem yog lub hauv paus rau kev kho mob. kev loj hlob hauv Duchenne-thiab Becker-typemuscular dystrophies [52, 72, 155].
Tus, oligonucleotide-raws li kev kho mob nrog rau kev kho noob tam sim no tau sim hauv cov teeb meem no. Kev paub txog kev kho mob zoo li no tau nce mus sai, thiab qhov no tseem muaj kev cuam tshuam txog kev kho mob rau lwm yam kab mob neurodegenerative xws li amyotrophic lateral sclerosis (ALS).
Kev kho Oligonucleotide tsis tsuas yog muab txoj hauv kev los txhawb kev nthuav tawm cov proteins xws li SMN, tab sis kuj tseem cuam tshuam qhov kev qhia ntawm mutant proteins nrog rau kev ua haujlwm pathological hauv lwm yam kab mob neurodegenerative.
Qhov no muaj ntau txoj hauv kev rau kev cuam tshuam nrog lwm cov txheej txheem neurodegenerative.Peb qhov kev tshuaj xyuas qhia txog kev txhim kho antisense oligonucleotide (ASO) thiab kev kho noob rau SMA, raws li cov ntaub ntawv tshawb fawb ntawm PubMed.gov thiab tso tawm cov ntaub ntawv los ntawm https://clinicaltrials.gov.
Qhov thib ob hais txog cov cib fim thiab cov teeb meem cuam tshuam nrog kev txhim kho ntxiv ntawm cov txheej txheem no rau kev kho mob ntawm lwm cov kab mob neurodegenerative thiab cov leeg nqaij dystrophies.
Spinal muscular atrophy (SMA): kab mob thiab kev txheeb xyuas cov hom phiaj rau kev kho mob
Kev nthuav qhia kab mob thiab kev faib tawm ntawm tus txha caj qaum muscularatrophy (SMA)
Daim ntawv mob hnyav ntawm cov leeg txha caj qaum atrophy, tseem hu ua Werdnig-Hofmann tus kab mob [122, 123, 316], yog qhov tshwm sim ntau tshaj plaws ntawm monogenetic lethal pediatric neuromuscular teeb meem.
Ib daim ntawv me me ntawm qhov sib thooj spinalmuscular atrophy kuj muaj nyob rau hauv keeb kwm uas tau raug suav tias yog ib qho kab mob sib txawv [160]. Txawm li cas los xij, tom qab kev txheeb xyuas cov kab mob hauv qab no tsis zoo [170], nws tau pom tseeb tias ob qho tib si kab mob tshwm sim los ntawm homozygous deletion ntawm Survival Motor Neuron 1 (SMN1) gene ntawm tib neeg chromosome 5q13.2.
Txhua hom 5q-SMA (hom 1–4) muaj qhov xwm txheej ntawm 1/6000–10,000 thoob ntiaj teb [77, 229, 231, 305].
SMA ua raws li autosomal recessive qub txeeg qub teg. Kev ua haujlwm tsis zoo thiab poob ntawm tus txha caj qaum motoneurons yog cov kab mob tseem ceeb tshaj plaws uas ua rau tsis muaj zog thiab atrophy, tshwj xeeb tshaj yog nyob rau hauv cov leeg nqaij sib xws, thiab ua pa tsis ua haujlwm.Raws li tus kab mob pib thiab mob hnyav, SMA tau muab faib ua plaub hom xws li hom mob hnyav tshaj plaws ntawm hom 1 mus rau nruab nrab hom 2 thiab mob me me. hom 3 thiab 4 (nrog rau cov neeg laus pib) [69, 70, 78, 230].
Qhov kev faib tawm no tsuas yog tsom mus rau qhov ua tiav lub cev muaj zog nrog qhov tsis zoo ntawm kev sib tshooj ntawm ntau hom. Yog li, ib qho kev faib tawm ntxiv tau qhia txog kev hloov pauv hloov pauv hauv qhov chaw kho mob phenotype tom qab kho thiab. Qhov kev faib tawm tshiab no cais cov tsis-sitters (hom 1–2), sitters (hom 2–3), thiab cov neeg taug kev (hom 3–4) [197], sau tseg hauv Table 1.
SMA noob caj noob ces
Ob tug ciaj sia taus lub cev muaj zog neuron noob: SMN1 thiab SMN2
Tib neeg muaj ob lub noob SMN (SMN1 thiab SMN2) nyob rau hauv thaj tsam duplicated ntawm chromosome 5q. Homozygousloss lossis kev hloov pauv ntawm SMN1 ua rau SMA, qhov poob ntawm SMN2 feem ntau tsis cuam tshuam nrog tus kabmob. Thaum lub sij hawm hloov pauv, qhov sib npaug ntawm SMN noob tshwm sim nyob rau theem ntawm cov tsis yog tib neeg primates [251]. Hauv kev kuaj sim thiab lwm cov nas tsuag, Smn gene tsis yog duplicated [263, 264].
SMN1 thiab SMN2 txawv tsuas yog nyob rau hauv ob peb nucleotides. Qhov tseem ceeb tshwj xeeb yog C rau T hloov pauv inexon 7 ntawm centromeric SMN2 uas ua rau lwm txoj kev sib txuas ntawm exon 7. Feem ntau cov ntawv sau los ntawm SMN2gene tsis muaj exon 7-encoded domains, uas ua rau tsuas yog 5-10% tag nrho-ntev SMN protein nyob rau hauv Kev sib piv rau 100% tag nrho-ntev SMN protein los ntawm SMN1 cov ntawv sau tseg (Daim duab 1).
Yog li ntawd, SMN2 tsuas tuaj yeem them nyiaj ib nrab rau SMN1 poob [180, 206, 207]. Cov neeg mob SMA feem ntau nqa 2-3SMN2 daim ntawv luam. Qhov no tso cai rau cov xov tooj ntawm tes ntawm kwv yees li 10-30% tag nrho-ntev SMN protein nyob rau hauv kev sib piv rau kev noj qab haus huv tswj nrog SMN1 cov ntawv luam ntawm cov noob. Yog li, SMN2 tus lej luam yog qhov tseem ceeb tshaj plaws geneticmodifier ntawm SMA kab mob hnyav [85, 319].
Feem ntau ntawm cov neeg mob SMA cuam tshuam loj heev bearhomozygous deletions ntawm SMN1 whereas feem ntau SMA type2 thiab 3 cov neeg mob qhia ib tug homozygous tsis tuaj ntawm SMN1vim rau ib tug noob hloov ntawm SMN1 rau hauv SMN2 [37, 318].
Gene hloov dua siab tshiab yog ib qho ua rau SMN2 gene copynumber variations, nce SMN2 gene copy number from 2 to 3 or 4 [40]. Plaub daim ntawv theej ntawm SMN2 feem ntau tsim cov protein ntau txaus rau SMN rau cov kab mob milderdisease phenotype [85, 185] hauv SMA hom 3 cov neeg mob.Nyob li ntawm 5% ntawm SMA cov neeg mob, taw tes hloov pauv tau kuaj pom hauv SMN1 noob feem ntau hauv exons 6 thiab 7 [320].
Cov xwm txheej zoo li no yog hu ua "compound heterozygotes"-witha deletion / hloov pauv hauv ib qho allele thiab ib qho kev hloov pauv hauv lwm qhov.
Sib nrug los ntawm 5q-SMA, lwm hom kab mob txha caj qaum muaj nyob uas tuaj yeem muab faib ua pawg raws li kab mob phenotype thiab geneticinheritance: autosomal recessive thiab autosomal dominant distal spinal muscular atrophies (DSMAs); autosomal dominant proximal spinal muscular atrophies; autosomal recessive non-5q spinal thiab bulbar muscularatrophies; X-txuas recessive SMAs.
Genetic modifers hauv SMA
Ib qho kev nthuav qhia dav dav ntawm qhov sib txawv ntawm tag nrho RNA los ntawm cov kab mob lymphoblastoid, muab los ntawm SMN1-cov kwv tij tsis muaj peev xwm nrog cov kab mob sib txawv, qhia txog kev sib koom ua ke tseem ceeb ntawm cov kab mob thiab Plastin 3 (PLS3) qhia [224].
PLS3 mapsto Xq23 [282]. Cov noob yog nyob rau ntawm X-chromosome thiab tshwm raws li kev sib deev tshwj xeeb hloov pauv ntawm SMA. Plastinsare evolutionarily txuag thiab ua haujlwm raws li kev hloov pauv ntawm actin cytoskeleton.
Tus plays lub luag haujlwm tseem ceeb hauv cell migration, adhesion, thiab exo- thiab endocytosis [321]. Ntxiv cov tshuaj genetic modifiers hauv SMA suav nrog Neurocalcin delta (NCALD) thiab Calcineurin-zoo li EF-handProtein 1 (CHP1).
Ob leeg proteins ua raws li Ca2+-sensors thiab Ca2+-binding proteins [124, 143, 246].
Tag nrho peb SMAprotective modifiers tsis ua haujlwm hauv kev sib dhos ntawm spliceosomal snRNPs. Txij li thaum lawv tau koom nrog hauv kev hloov pauv ntau yam txheej txheem ntawm tes nrog rau kev cawm ntawm kev tsis txaus ntseeg endocytosis hauv Smn-tsis muaj cov hlwb thiab cov tsiaj qauv [64, 124, 143, 246], cov kev hloov kho SMA no tau hloov mus rau cov hom phiaj kho mob.
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