Kev Txhim Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies Thiab Neurodegenerative Disorders Part 10

ASO kev kho mob rau cov leeg nqaij dystrophies

Duchenne's muscular dystrophy (DMD) thiab Becker's muscular dystrophy (BMD), ob hom X-txuas mus rau cov leeg nqaij dystrophy yog tshwm sim los ntawm kev hloov pauv hauv Dystrophin noob. DMD tshwm sim nrog qhov tshwm sim ntawm kwv yees li 1: 5000, qhov BMD cuam tshuam rau cov menyuam yaus uas muaj qhov tshwm sim ntawm 1: 30,000 [155].

Duchenne muscular dystrophy yog ib yam kab mob tsis tshua muaj caj ces uas ua rau cov leeg tsis muaj zog, qaug zog, txhav, thiab lwm yam tsos mob. Txawm li cas los xij, feem ntau cov neeg mob tseem tuaj yeem tswj hwm lawv lub neej thiab siv lub peev xwm los ntawm kev kho tshuaj thiab kev cob qhia kev kho mob, thiab lawv txoj kev sib raug zoo nrog kev nco yuav tsis cuam tshuam loj heev.

Ntau tus neeg uas muaj Duchenne cov leeg nqaij dystrophy tuaj yeem ua rau pom kev nco zoo hauv tsev kawm ntawv, kev ua haujlwm, thiab lub neej. Kev tshawb fawb qhia tau hais tias qhov no muaj ntau yam ua rau lawv tus kheej muaj peev xwm tswj hwm tus kheej thiab cov tswv yim daws teeb meem. Vim tias tus kab mob no ua rau cov leeg nqaij qaug zog thiab tsis muaj zog, cov neeg mob feem ntau yuav tsum tau npaj ntau dua txog lawv lub sijhawm thiab kev ua ub ua no kom ua tau zoo tshaj plaws ntawm lawv cov sijhawm ua haujlwm. Qhov kev muaj peev xwm no tseem siv lawv cov kev tswj tus kheej thiab kev tswj tus kheej, uas ua rau pab txhim kho lawv txoj kev nco thiab kev txawj ntse.

Yog li ntawd, txawm hais tias Duchenne cov leeg nqaij dystrophy yuav muaj qee yam cuam tshuam rau tib neeg lub cev kev noj qab haus huv, nws tsis tau txhais hais tias cov neeg mob yuav inevitably poob qab cov neeg zoo tib yam hais txog kev nco thiab kev kawm muaj peev xwm. Ntawm qhov tsis sib xws, lawv nyiam muaj qhov zoo dua qub hauv kev tswj tus kheej thiab cov tswv yim daws teeb meem, uas tseem pab lawv ua tiav cov txiaj ntsig zoo hauv kev kawm thiab kev sib tw ua haujlwm. Yog li ntawd, peb yuav tsum kho tus kab mob no thiab cov neeg mob kom muaj tus cwj pwm zoo, thiab muab kev txhawb nqa thiab kev txhawb zog rau lawv, kom lawv muaj kev noj qab haus huv thiab ua tiav lub neej. 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 txhawm rau txhim kho lub cim xeeb luv luv

Daim ntawv hnyav, DMD, feem ntau pib ua ntej 4 xyoos. Cov menyuam yaus uas raug kev txom nyem poob ambulation nyob ib ncig ntawm 12 xyoos thiab tau txais qhov cua thaum muaj hnub nyoog 18 xyoo [119].Lub neej nruab nrab hnub no yog 20-30 xyoo vim yog kev kho mob plawv thiab ua pa.

Nyob rau hauv sib piv rau SMA, lub spectrum ntawm kev hloov nyob rau hauv DMD yog dav thiab ntau yam los ntawm kev hloov pauv mus rau deletions nrog rau me me insertions tolarge duplications [24]. dystrophin noob yog ib qho ntawm cov noob loj tshaj plaws ntawm tib neeg uas muaj 79 exons thiab kwv yees li 2.4 lab lub hauv paus khub [2, 24, 41]. Lub luag haujlwm tseem ceeb ntawm dystrophin protein yog los txuas cov actin-cytoskeleton nrog rau cov cellular matrix hauv plawv thiab pob txha pob txha los ntawm kev sib cuam tshuam nrog subsarcolemmalactin thiab loj oligomeric dystrophin-glycoproteincomplex (DPG).

Qhov no tswj kev ua haujlwm zoo ntawm cov leeg nqaij fibers. Qhov tsis xws luag ntawm DPG ua rau cov leeg tsis muaj zog vim yog kev cog lus-vim kev puas tsuaj, necrosis, thiab mob, thiab hloov pauv ntawm myofibers ua haujlwm los ntawm cov ntaub so ntswg fibrous thiab fatty connective [29].

Cov kab mob nyob ntawm ntau yam ntawm cov haujlwm seem ntawm cov dystrophin protein, uas yog muab los ntawm cov noob caj noob ces. Interestingly, cov ntaub ntawv me me ntawm tus kab mob tsis tau tsuas yog kuaj pom nyob rau hauv cov neeg mob uas muaj qhov hloov pauv uas tsuas muaj qhov tshwm sim me me rau cov qauv ntawm cov protein thiab kev ua haujlwm tab sis kuj nyob rau hauv cov neeg mob BMD uas ntau qhov exon-encoded domains tsis tau sau tseg, uas ua rau muaj kev cuam tshuam loj heev dystrophin mRNA ntawm tsuas yog 8.8. kb79 ib.

Qhov kev soj ntsuam no tau ua txoj hauv kev los tiv thaiv qhov tseem ceeb subdomains hauv dystrophin protein thiab exons nrog rau cov ntawv sau tseg uas yog qhov tseem ceeb thiab yuav tsum muaj nyob rau hauv kev txo cov kab mob hnyav. Ib yam li ntawd, cov kev tshawb pom no yog lub hauv paus rau kev tsim cov noob caj noob ces artificialmini-dystrophin uas tuaj yeem siv rau kev kho noob los ntawm cov kab mob kab mob uas tuaj yeem nqa tau cDNAs ntawm qhov ntev [52].

Exon swb

Kev tuav pov hwm lossis kev khaws cia ntawm qhov qhib kev nyeem ntawv (ORF) yog ib qho kev xaiv los txwv lub cev qhov tshwm sim ntawm dystrophin poob hauv DMD cov neeg mob uas muaj kev hloov pauv tsis zoo. Kev tuav pov hwm ntawm ORF tuaj yeem kho tau los ntawm kev xa tawm ASO.

Kev khi ntawm ASOs rau dystrophin pre-mRNA cov ntawv sau tseg ua rau muaj kev tshem tawm / hla ntawm qee qhov exon(s) thiab tuaj yeem rov qab ORF [72]. Theresulting luv luv ORF ua ib tug phenotype zoo ib yam li piav rau cov me me daim ntawv ntawm DMD-the BMD.Tree ASOs nrog phosphorodiamidate morpholinooligomer (PMO) qaum qaum uas yog siv rau exon skipping-elegize (exon 51), Goodison (exon 53), thiab exonto. 53)-tau pom zoo los ntawm FDA.

Txawm li cas los xij, ASOs kuj qhia qee qhov kev txwv [75,306] [1]. Txij li cov neeg mob DMD muaj ntau qhov sib txawv hauv ntau qhov sib txawv uas ua rau ntau qhov kev nyeem ntawv cuam tshuam, xws li kev kho ib leeg-exon tsuas yog siv tau rau cov neeg mob DMD.

Multi-exon skipping tau raug npaj kom kov yeej qhov kev txwv ntawm ib leeg-exonskipping los ntawm kev tsom mus rau DMD cov neeg mob nrog ntau yam exons[16]. Ib qho dej cawv ntawm ASOs tsom rau qhov sib txawv hotspotsof exons 45-55 tuaj yeem hla cov exons hauv ob qho tib si DMD cov neeg mob cov leeg nqaij thiab cov qauv nas [73, 167].

Txawm li cas los xij, kev sib xyaw ntawm ob peb ASOs kuj tseem muaj kev pheej hmoo siab dua rau cov teeb meem tawm tsam. Qhov no yuav tsum tau kuaj hauv kev sim tshuaj. Yog tias cov nyiaj no tau muab txhais ua tiav rau lub tsev kho mob, nws tuaj yeem muaj txiaj ntsig zoo rau ntau dua 65% ntawm cov neeg mob DMD [74].

Genome kho

Genome kho nrog CRISPR-Cas9 zoo nkaus li yog ib qho kev xaiv zoo nkauj rau ORF kev kho dua tshiab ntawm dystrophin gene.Kev thov ntawm CRISPR-Cas9 tsis tas yuav rov txhaj tshuaj vim DNA hloov ua ntej mRNA yog tsom. Txoj kev no kuj tseem yuav pab tau rau kev kho cov neeg mob uas muaj qhov sib txawv hauv qee qhov exons ntawm DMD noob txij li nws tso cai rau kev tshem tawm cov exons ntxiv thiab lwm cov noob ntxiv.

Kev siv cov lus qhia multiplexed-RNA (gRNA) tsom rau qhov sib txawv ntawm cov exons 45–55 lossis 47–58, tau pom tias torestore dystrophin qhia [306] hauv cov neeg mob uas tau los ntawm myoblasts. Thaum cov myoblasts tau cog rau hauv nas, kev qhia tau khaws cia [226].
Txawm li cas los xij, vim tias Cas9 induces ob-strand breaks (DSBs) los ntawm gRNA nyob rau hauv lub hom phiaj, ntawm-target DNA-txiav tseem yog ib qho teeb meem. Tam sim no, tsis muaj kev sim tshuaj ntsuam xyuas siv genome kho txoj hauv kev rau DMD [75].

Kev pom ntawm AAV-raws li kev kho noob caj ces dhau SMA

Nyob rau hauv cov ntaub ntawv ntawm kev hloov pauv-raws li LOF, cov kev kho mob cuam tshuam yuav tsum tau rov tsim cov noob muaj nuj nqi. Nyob rau hauv rooj plaub ntawm SMA, scAAV9-SMN1 gene therapy muab pov thawj tias txoj hauv kev no ua tau rau kev kho mob ntawm cov kab mob neurodegenerative.

Qhov koob tshuaj ntawm 1.1 × 1014 vg / kgbody qhov hnyav tau tshwm sim txaus los hloov cov noob rau hauv cov chaw kho mob muaj feem cuam tshuam ntawm motoneurons thiab ua rau muaj kev cuam tshuam tsis zoo xws li mob siab mob siab rau qib qis.

Kev nce qib hauv siab transaminase tau tham txog vim qhov tshwm sim ntawm kev tiv thaiv kab mob loj heev tiv thaiv kab mob sib kis [195]. Hmoov tsis zoo, nyob rau hauv rooj plaub ntawm lwm yam kab mob neuromuscular-X-linkedmyotubular myopathy-qhov kev xa tawm ntawm highdose ntawm AAV8 cov khoom uas muaj cDNA rau myotubularin -1 tau tuag. Ob ntawm rau tus neeg mob uas tau txais koob tshuaj ntawm 2 × 1014 mg / kg lossis ntau dua tau tuag los ntawm kev ua haujlwm siab ua haujlwm raws li sepsis; Nws tau xav tias AAVs ncaj qha ua rau lub siab ua rau lub siab [117].

Tus, AAVs yog nyob rau ntawm ib sab zoo gene hloov tsheb tab sis nyob rau lwm qhov chaw muaj qhov tsis zoo ntawm cov tshuaj tiv thaiv mob hnyav, tshwj xeeb tshaj yog nyob rau hauv kev kho mob nrog cov koob tshuaj siab. Cov tswv yim tau npaj los txheeb xyuas cov neeg mob atrisk rau cov kev mob tshwm sim hnyav [57, 58], thiab rau kov yeej qhov teeb meem no los ntawm kev hloov kho lub cev tiv thaiv kab mob rau cov lus teb dampened.

Qhov no tuaj yeem ua tiav los ntawm depleting immunoglobulins ntawm plasmapheresis; lossis tshwj xeeb tshaj yog, los ntawm kev siv IgG cleaving metalloproteases IdeS lossis IdeZ [63]. Xws li txoj hauv kev los txo AAV-autoantibodies tuaj yeem pab txo qis cov kev mob tshwm sim ntawm AAV-raws li kev kho noob rau cov kab mob xws li DMD qhov chaw kho mob nrog cov kab mob loj heev yog qhov tsim nyog.
Tsis tas li ntawd, nws tuaj yeem muaj txiaj ntsig zoo rau kev kho mob rau cov neeg laus-pib tsis zoo thaum cov neeg mob xav tias yuav tau tsim cov kab mob AAV-antibody titersdue rau ntau qhov kev kis tus kab mob yav dhau los.Lwm lub tswv yim tuaj yeem yog kev txhaj tshuaj hauv zos, los ntawm kev siv byintrathecal ntawm cov kab mob recombinant los txhaj rau hauv cisterna manga. .

Txoj hauv kev no tam sim no tau ua raws nrog AAV1-raws li kev kho noob trial kom nce qhov kev qhia ntawm Progranulin hauv cov neeg mob nrog frontotemporal dementia nrog granulin mutations [120](Xovxwm tso tawm Lub Ib Hlis 28th, 2021: Passage Bio-Passage Bio Tau txais FDA Clearance ntawm IND Daim ntawv thov rau PBFT02 Gene Therapy Candidate rau Kev Kho Mob ntawm Cov Neeg Mob Frontotemporal Dementia nrog GranulinMutations).

Nws yuav qhia tias yuav ua li cas lub cev tiv thaiv kab mob tshwm sim thaum AAV cov kab lus raug txhaj rau hauv CSF, muaj pes tsawg lub hlwb tuaj yeem nqa cov kab mob mus rau cov khoom hloov pauv, thiab theem twg ntawm cov transgene qhia yog qhov tsim nyog rau kev kho mob cuam tshuam.

Hauv kev tshawb fawb qhia los ntawm Mueller li al., ob tus neeg mob ALS tau kho nrog ib qho intrathecal infusion ntawm AAVrh10 uas muaj microRNAs rau lub hom phiaj SOD1. Kev txo qis ntawm SOD1 cov ntawv teev lus thiab cov protein tau pom nyob rau hauv kev kuaj mob txha caj qaum ntawm Western blot inone ntawm cov neeg mob no.

Tib tus neeg mob tau pom kev txhim kho nyob rau hauv lub zog ntawm nws sab xis sab xis tab sis tsis muaj kev hloov pauv ntawm lub peev xwm tseem ceeb, thaum tus neeg mob thib ob tau tuav lub peev xwm tseem ceeb hauv lub sijhawm 12-monthobservation lub sij hawm [214].

Cov kws sau ntawv tau hais tias intrathecal infusion ntawm AAV-xa microRNAs rau SOD1 tuaj yeem muaj peev xwm ua rau muaj txiaj ntsig zoo, tab sis tej zaum yuav xav tau kev tiv thaiv kab mob.

For more information:1950477648nn@gmail.com