Kev Txhim Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies Thiab Neurodegenerative Disorders Part 11
Mar 26, 2024
AAV-based micro-dystrophin (µDys) gene hloov
Kev kho mob rau DMD qhov zoo tshaj plaws yuav tsum rov qab kho dystrophin qhia hauv cov leeg pob txha. Hmoov tsis zoo, qhov ntev-ntev dystrophin noob loj dhau los ua kom tau ntim rau hauv cov khoom siv AAV.
Kev sib raug zoo ntawm kev noj zaub mov tsis txaus thiab kev nco tau nyiam heev. Tib neeg lub cev xav tau ntau yam vitamins, minerals, thiab lub zog kom lub cev noj qab haus huv thiab lub hlwb ua haujlwm zoo. Kev noj zaub mov tsis zoo tuaj yeem ua rau muaj teeb meem xws li kiv taub hau, qaug zog, ua haujlwm qeeb, thiab tsis muaj peev xwm mloog tau, uas tuaj yeem cuam tshuam rau tib neeg txoj kev kawm thiab kev ua neej nyob txhua hnub.
Tib neeg lub hlwb yog ib qho tseem ceeb tshaj plaws ntawm tib neeg lub cev thiab xav tau ntau lub zog thiab cov khoom noj kom ua haujlwm. Yog tias lub cev tsis muaj cov vitamins thiab minerals uas tsim nyog, nws tuaj yeem cuam tshuam rau lub hlwb kev loj hlob, ua rau txo qis kev txawj ntse thiab kev nco. Tib lub sijhawm, kev noj zaub mov tsis txaus kuj tuaj yeem cuam tshuam kev ua haujlwm ntawm lub paj hlwb thiab cuam tshuam kev xav thiab kev xav.
Yog li ntawd, kev noj zaub mov zoo yog qhov tseem ceeb heev rau lub hlwb noj qab haus huv. Cov kws tshawb fawb tau tshawb fawb ntau yam khoom noj thiab khoom noj uas zoo rau lub hlwb, xws li ntses roj, walnuts, txiv laum huab xeeb, blueberries, qe, txiv lws suav, thiab zaub tsaus. Cov zaub mov no tuaj yeem ua rau cov ntshav khiav hauv lub hlwb thiab txhim kho kev nco thiab kev txawj ntse.
Hauv cov ntsiab lus, kev noj zaub mov tsis zoo tuaj yeem cuam tshuam tsis zoo rau peb lub cev thiab lub hlwb, yog li peb yuav tsum tsom mus rau peb cov zaub mov kom tau txais cov as-ham txaus thiab lub zog. Los ntawm kev tswj hwm txoj kev noj qab haus huv, peb tuaj yeem txhim kho peb lub cim xeeb, txhim kho kev txawj ntse, thiab paub peb lub peev xwm tag nrho. 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 cov tshuaj ntxiv los txhawb kev nco
Cov tswv yim tam sim no sim hla lub fwj dej no los ntawm kev siv cov ntaub ntawv dystrophin truncated nrog ib qho kev ua haujlwm seem uas yog txaus rau kev tiv thaiv kab mob [56]. Tsob ntoo-yooj yim soj ntsuam kev sim, siv cov noob kev kho mob nrog xws li micro-dystrophinconstructs tam sim no tsis tu ncua (cov ntsiab lus hauv [52].
Cov txiaj ntsig thawj zaug los ntawm ib qho ntawm cov kev sim tshuaj tsis tu ncua nrog μDys pom tias ntau dua 80% ntawm cov leeg nqaij yog micro-dystrophin zoo nrog cov ntsiab lus tseem ceeb ntawm μDys hauv kev kho mob tom qab kho (95.8% piv rau li qub) (Sarepta Therapeutics Tshaj Tawm Pom Zoo Hloov Kho Tshiab Cov txiaj ntsig los ntawm Micro- Kev sim kho cov neeg mob nrog DMD https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-23rd-internationalcongress-world), thiab sau los ntawm [75, 306 ].
Tsis tas li ntawd, kev kho mob ntev nrog μDys muaj txiaj ntsig zoo hauv tus qauv canine [165]. MicroDys tsis muaj tag nrho cov functionallements ntawm tag nrho-ntev dystrophin uas yog ib qho tseem ceeb rau kev sib cuam tshuam nrog rau lwm cov proteins kom xa cov rog oncontractile actin.
Rau lub hom phiaj no, cov kev hloov tshiab ntawm μDyswith hloov lub hauv paus rod domains, uas xav tias yuav muaj ntau dua cellular cawm kev ua ub no, tau tsim [240, 241] thiab tam sim no tau sim hauv kev sim tshuaj [178].
Lwm qhov kev xaiv uas tau ua raws li tam sim no yog kev siv cov miniaturized utrophin (μUtro), luv luv codon-optimized version ntawm utrophin uas txawv ntawm qee cov protein-protein kev sib cuam tshuam los ntawm dystrophin. Nws tiv thaiv cov leeg nqaij pathology thiab tshwm nyob rau hauv ib qho tsis-immunogenicmanner hauv cov qauv dev loj. Txawm li cas los xij, qhov txiaj ntsig zoo ntawm tus kab mob phenotype tsis tau lees paub [280].
Kev tshaj tawm ntawm b1,4-N-acetylgalactosaminyltransferase (GALGT2) yog qhov ua tau thib peb. GALGT2 txhawb kev txhim kho ntawm qhov tseem ceeb cytoskeletal binding proteins uas tuaj yeem ua raws li tus neeg sawv cev ntawm dystrophin [43, 328].
Tom qab ua kom pom kev nyab xeeb hauv cov qauv ua ntej kho mob, qhov kev kho no tam sim no tau sim hauv theem I / IIa sim los ntsuas nws txoj kev nyab xeeb hauv tib neeg. (Gene Transfer Clinical Trial to deliverrAAVrh74.MCK. GALGT2 for Duchenne MuscularDystrophy-NCT03333590. https://clinicaltrials.gov/ct2/show/NCT03333590 48).
AAV gene transfer in Parkinson's disease (PD)
Parkinson tus kab mob yog ib tug ntev lub sij hawm degenerative teeb meem uas cuam tshuam rau ntau yam neuronal systems, tshwj xeeb tshaj yog themotor system. Cov tsos mob tshwm sim feem ntau suav nrog kev tshee, kev nruj, qeeb ntawm kev txav mus los ua ke nrog kev taug kev nyuaj.
Raws li tus kab mob loj zuj zus tuaj, cov tsos mob uas tsis yog lub cev muaj zog xws li kev paub thiab kev coj tus cwj pwm hloov kuj tshwm sim. Cov tsos mob ntawm lub cev yog tshwm sim los ntawm degeneration ntawm dopaminergic neurons hauv substantia nigra. Kev poob ntawm cov dopaminergic neurons no ua rau tsis txaus siab ntawm subthalamic nucleus (STN) ua rau muaj zog inhibition ntawm thalamus [203].
Yog li, Parkinson cov neeg mob raug kev txom nyem los ntawm qhov tsis xws luag hauv kev pib txav. Sib sib zog nqus lub hlwb stimulation ntawm subthalamic nucleusappears raws li ib tug txaus nyiam kev kho mob kev xaiv vim hais tias Levodopa [80] thiab lwm yam pharmacological kev kho mob tsis tuaj yeem cuam tshuam cov txheej txheem degenerative hauv tus kab mob no. Yog li, cov tswv yim noob siv AAV vectors tshwm sim raws li kev xaiv rau kev kho mob ntawm PD, kuj tseem ua ke nrog kev sib sib zog nqus hlwb.
Tam sim no, muaj ntau qhov kev sim nrog PD thiab cov tshuaj kho noob tau teev nyob rau hauv clinicaltrials.gov. Txhua txoj hauv kev ntawm kev kho noob rau PD yog los khaws cov dopamine ntau lawm hauv cov hlwb neuronal uas tsis muaj kev cuam tshuam, ua haujlwm tswj lub voj voog ntawm cov kab mob basal ganglia.
Rau lub hom phiaj no, kev xa ncaj qha hauv intraparenchymal los ntawm MRI-coj kev tswj hwm ntawm AAV2 encoding cDNA rau aromatic L-amino aciddecarboxylase (VY-AADC01) tau tsim [46].
Kaum tsib cov kev kawm uas muaj qib siab ntawm PD thiab kev hloov pauv ntawm cov tshuaj tiv thaiv lub cev muaj zog tau txais VY-AADC01.MRI-kev coj noj coj ua tau ua tiav cov kev pab cuam putaminal ntawm 20-40% los ntawm kev nce enzyme kev soj ntsuam los ntawm PET thiab koob tshuaj cuam tshuam txog kev kho mob.
Ib txhij txo cov tshuaj antiparkinsonian kom txo cov tsos mob ntawm dyskinesia [46]. Ib txoj hauv kev zoo sib xws yog MRI-guided AAV2-GAD (Glutamatdecarboxylase) xa mus rau hauv STN kom nce GABA inhibition hauv zos thiab kho cov kab mob hyperactivity hauv lub hlwb no. Theem 1 thiab 2 kev sim tau ua nrog AAV2-GAD xa ntawm Convection-enhanced delivery (CED) rau STN ntawm cov neeg mob PD[146, 171].
Cov neeg mob no tau nthuav tawm kev txhim kho hauv lawv cov tsos mob, tab sis tsis yog li ntawd raws li ua tiav los ntawm kev sib sib zog nqus hlwb ntawm STN [171].
Gene therapy txoj hauv kev hauv Alzheimer's disease (AD)
Lub cim ntawm pathological amyloid- (A ) peptide ntseeg tau tias yog thawj zaug tshwm sim hauv AD txheej txheem.Txij li ob peb qhov kev sim tshuaj yav dhau los suav nrog kev tiv thaiv kab mob kom txo tau cov load nrog amyloid plaquesfailed lossis pom tsuas yog cov teebmeem me me [228], FDA tau pom zoo tam sim no Aducanumab ua lag luam nyob rau hauv lub npe Aduhelm ™ raws li A-directed antibody.
Cov teebmeem ntawm qhov kev kho no zoo li tsawg dua li qhov xav tau, thiab qhov kev xav no rov qab mus rau cov kev kho noob caj noob ces uas cuam tshuam nrog kev ua haujlwm tsis zoo ntawm lub cev thiab degeneration.
Cov kev sib tw technical rau txoj hauv kev no zoo ib yam li cov hauv PD. Interventional MRI-guided convection-enhanced delivery is not particularly cuam tshuam rau kev kho mob ntawm PD cov neeg mob. Ib yam li ntawd, cov neeg mob AD tuaj yeem tau txais txiaj ntsig los ntawm cov kab mob sib kis thiab cov txheej txheem no. Qee qhov kev txhim kho kho mob tsom rau cov protein tau [49, 329]. Pathological tau nyob rau hauv lub hlwb AD yog muaj nyob rau hauv lub xeev hyperphosphorylated (piv txwv li phosphorylated ntawm ntau qhov chaw hauv cov tau protein). Qhov kev hloov pauv tom qab kev hloov pauv no sib raug rau tau sib sau ua ke thiab neurofibrillary tangleformation [133].
AAV-mediated gene hloov ntawm lub constitutively activetau kinase-p38 tau pom tias yuav txo tau-relateddementia nyob rau hauv pre-clinical dementia nas qauv txawm tias muaj kev txawj ntse tsis xws luag tam sim no [136]. Cov tswv yim no tseem tsis tau nkag mus rau theem ntawm kev sim tshuaj rau cov neeg mob AD. Txawm li cas los xij, nws yuav dhau los ua tau txij li kev hloov pauv noob ntawm BDNF tau nkag mus rau hauv tsev kho mob.
Qhov kev sim no yog ua raws li kev tshawb fawb ua ntej qhia tias BDNFdelivery (ntawm transgenic qhia lossis infusions) hauv rodentmodels thim rov qab synaptic poob tom qab muaj kab mob sib xws rau kev txhim kho kev kawm thiab kev txawj ntse. BDNF kuj tseem tiv thaiv qhov mob tshwm sim los ntawm cov kab mob endorhinalneuronal tuag hauv cov qauv primate. Hauv cov laus laus, BDNF tau txhim kho kev ua yeeb yam hauv visuospatial kev ntxub ntxaug cov hauj lwm uas sib haum mus rau qhov nce ntxiv ntawm qhov nruab nrab ntawm lub paj hlwb [216]. Raws li cov ntaub ntawv no, kev sim tshuaj theem 1 tau pib thaum Lub Ob Hlis 2021.
Qhov kev sim no ntsuas qhov cuam tshuam ntawm kev txhaj tshuaj ncaj qha ntawm AAV2-BDNFinto lub hlwb ntawm cov neeg mob AD lossis cov neeg mob uas muaj kev paub tsis meej (MCI) (Scott LaFee, Thawj-hauv-Humanclinical sim tshuaj ntsuam xyuas cov tshuaj kho noob rau Alzheimer's Disease, UC San Diego Xov Xwm Center Lub Ob Hlis 18th, 2021).
Cov lus xaus
Childhood proximal SMA yog homogenous kab mob tshwm sim los ntawm kev ploj lossis hloov pauv SMN1 thiab hloov kho los ntawm cov ntawv SMN2 sib txawv. Qhov no yog ib qho kev mob zoo tshaj plaws los txheeb xyuas cov teeb meem hauv cellular thiab txhim kho cov tswv yim kho mob uas them nyiaj rau qhov tsis muaj SMN protein, uas yog tus yuam sij rau SMA pathophysiology. Kev tshawb fawb dav dav ntawm tus mob no tso cai rau kev qhia txog kev kho mob nrog oligonucleotides thiab molecules uas hloov kho ua ntej mRNA splicing.
Tsis tas li ntawd, AAV-based gene therapy tau nkag mus rau theem kho mob rau kev kho cov kab mob neurodegenerative. Txij li feem ntau ntawm SMA raug kuaj pom thaum ntxov hauv lub neej thiab kev kho mob feem ntau pib tam sim tom qab kuaj mob, kev tiv thaiv kab mob tiv thaiv AAVs tsis tshua muaj teeb meem piv rau cov neeg mob hnub nyoog siab dhau los raug cov kab mob hauv lawv lub neej.
Kev kho mob nrog cov ntawv thov no tuaj yeem pab tsim thiab ua kom zoo dua analogousapproaches dhau SMA. Tam sim no, kev txhim kho ntawm cov tswv yim kho mob tseem tab tom ua thiab cia siab tias yuav ua rau muaj qhov sib txawv hauv kev kho mob ntawm lwm cov kab mob neurodegenerative xws li amyotrophic lateral sclerosis, Parkinson's, thiab Alzheimer's disease thiab musculardystrophies.
Cov ntawv luv
3,4-DAP: 3,4-Diaminopyridine; 4-AP: 4-Aminopyridine; AAV: Adeno related virus; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ASO: Antisense oligonucleotide; ATXN2: Ataxin 2; ATP: Adenosine triphosphate; BBB: Ntshav-hlwb barrier; BDNF: Lub hlwb-derived neurotrophic yam; BMD: Beckermuscular dystrophy; bp :paj paab; CED: Convection-enhanced delivery; CHIP1: Calcineurin-zoo li EF-tes Protein 1; KEV PAB CUAM: Cov me nyuam lub tsev kho mob ntawm Philadelphia me nyuam mos kuaj mob neuromuscular; CMAP: Cov leeg nqaij muaj peev xwm; CNTF: Ciliary neurotrophic yam; CSF: Cerebrospinal fuid; DMD: Duchenne muscular dystrophy; DPRs: Homopolymeric dipeptide repeatproteins; DSB: Ob chav hlua tawg; DSMA: Distal spinal muscular atrophy; E: Embryonic hnub; EAP: Cov kev pab cuam nthuav dav; EMA: European MedicinesAgency; FALS: Tsev neeg amyotrophic lateral sclerosis; FDA: Khoom noj khoom haus thiab tshuaj noj; GABA: Gamma aminobutyric acid; GAD: Glutamate decarboxylase; GDNF: Glial cell-derived neurotrophic yam; GOF: Tau txais kev ua haujlwm; gRNA:guide-RNA; HFMSE: Hammersmith ua haujlwm lub cev muaj zog nthuav dav; hIGF-1:Complexed nrog rhIGFBP-3; HINE-2: Hammersmith infant neurological test-2; IGF1: Insulin zoo li kev loj hlob 1; iPSC: Induced pluripotent qia cell; ISS: Intronic splice silencer; JNKs: C-Jun N-terminal kinases; kb: luj;. LOF: poob haujlwm; LTFU: Ua raws li lub sijhawm ntev; MCI: Kev puas hlwb me me; MMD: Microcystoid macular degeneration; MRI: Sib Nqus Resonance Imaging; NCALD: Neurocalcin delta; NMJ: Neuromuscular hlws ris; OLE: Qhib-labelextension; ORF: Qhib-nyeem ntawv ncej; P: Hnub yug; PD: Parkinson tus kab mob; PLS3: Plastin 3; PMO: Phosphorodiamidate morpholino oligomer; Ran: Repeatassociated non-AUG txhais; RBP: RNA khi cov protein; RULM: RevisedUpper Limb Module; SALS: Sporadic amyotrophic lateral sclerosis; scAAV: Selfcomplementary AAV; SMA: Spinal muscular atrophy; SMARD1: Spinal muscularatrophy nrog ua pa nyuaj hom 1; SMN: Ciaj sia taus lub cev muaj zog Neuron; SNP: Ib leeg nucleotide polymorphism; SnRNP: Me me nuclear ribonuclear particle; SOD1: Superoxid dismutase 1; STN: Subthalamic nucleus; TrkB: Tropomyosinrelated kinase.
Kev lees paub
Peb ua tsaug rau Dr. Michael Briese rau qhov kev xav tseem ceeb ntawm cov ntawv sau.
Cov sau phau ntawv pab
SJ thiab MS tau xeeb thiab sau qhov kev tshuaj xyuas. LH pab txhawb kom xeeb muaj kev pom thiab tsim cov duab. LH siv Servier kev kho mob kos duab rau cov duab kos (https://smart.servier.com). Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv kawg.
Nyiaj txiag
Kev ua haujlwm hauv cov kws sau ntawv 'lab tau txais kev txhawb nqa los ntawm Deutsche Forschungsgemeinschaft (DFG), Grants JA 1823/3-1, 2-1 rau SJ thiab SE 697/6-1, 4-2, { {6}}, thiab 7-1 toMS, los ntawm kev pab nyiaj los ntawm Picoquant, BMBF los ntawm CalsER Network, thiab kev txhawb nqa los ntawm Hermann thiab Lilly Schilling Stiftung im Stifterverband derDeutschen Wissenschaft thiab los ntawm Cure SMA (JAB1920) rau SJ.
Muaj cov ntaub ntawv thiab cov ntaub ntawv
Tsis siv tau.
Cov lus tshaj tawm
Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom
Tsis siv tau.
Tso cai rau kev tshaj tawm
Tsis siv tau.
Kev nyiam sib tw
Cov kws sau ntawv tshaj tawm tsis muaj kev sib tw nyiam.
Cov ntaub ntawv
1. Aartsma-Rus, A., Straub, V., Hemmings, R., Haas, M., Schlosser-Weber, G., Stoyanova-Beninska, V., Mercuri, E., Muntoni, F., Sepodes, B., Vroom, E., & Balabanov, P. (2017). Kev txhim kho ntawm exon hla kev kho mob rau Duchenne leeg nqaij dystrophy: Kev tshuaj xyuas tseem ceeb thiab kev pom ntawm cov teeb meem zoo tshaj [Tshawb xyuas]. Nucleic Acid Therapeutics, 27(5), 251–259.https://doi.org/10.1089/nat.2017.0682
2. Ahn, AH, & Kunkel, LM (1993). Cov txheej txheem thiab kev ua haujlwm ntau yam ntawm dystrophin. Nature Genetics, 3(4), 283–291.https://doi.org/10.1038/ng0493-283
3. Al-Zaidy, SA, & Mendell, JR (2019). Los ntawm kev sim tshuaj mus rau kev kho mob: Cov tswv yim xav txog kev hloov pauv noob hauv SMA Type1. Pediatric Neurology, 100, 3–11.https://doi.org/10.1016/j.pediatrneurol.2019.06.007
4. Alami, NH, Smith, RB, Carrasco, MA, Williams, LA, Winborn, CS, Han, SSW, Kiskinis, E., Winborn, B., Freibaum, BD, Kanagaraj, A., Clare, AJ, Badders , NM, Bilican, B., Chaum, E., Chandran, S., Shaw, CE, Eggan, KC, Maniatis, T., & Taylor, JP (2014). Axonal kev thauj mus los ntawm TDP-43mRNA granules raug cuam tshuam los ntawm ALS-ua rau kev hloov pauv [Kev Txhawb Kev Tshawb Fawb, NIH, Kev Txhawb Kev Tshawb Fawb Ntxiv, Tsis yog-US Gov't]. Neuron, 81(3), 536–543.https://doi.org/10.1016/j.neuron.2013.12.018
5. Alrafah, A., Karyka, E., Coldicott, I., Iremonger, K., Lewis, KE, Ning, K., & Azzouz, M. (2018). Plastin 3 txhawb nqa lub cev muaj zog neuron axonal kev loj hlob thiab txuas ntxiv kev muaj sia nyob hauv tus qauv nas ntawm tus txha nqaj qaum atrophy.Molecular Therapy-Methods & Clinical Development, 9, 81–89.https://doi.org/10.1016/j.omtm.2018.01.007
6. Andersen, PM, Forsgren, L., Binzer, M., Nilsson, P., Ala-Hurula, V., Keranen, ML, Bergmark, L., Saarinen, A., Haltia, T., Tarvainen, I. ., Kinnunen, E., Udd, B., & Marklund, SL (1996). Autosomal recessive neeg laus-onsetamyotrophic lateral sclerosis txuam nrog homozygosity rauAsp90Ala CuZn-superoxide dismutase kev hloov. Kev tshawb fawb soj ntsuam thiab noob caj noob ces ntawm 36 tus neeg mob [Kev Txhawb Kev Tshawb Fawb, Tsis yog-US Gov't]. Brain, 119(Pt 4), 1153–1172.https://doi.org/10.1093/brain/119.4.1153
7. Andersen, PM, Nilsson, P., Ala Hurula, V., Keranen, ML, Tarvainen, I., Haltia, T., Nilsson, L., Binzer, M., Forsgren, L., & Marklund, SL (1995). Amyotrophic lateral sclerosis txuam nrog homozygosity rau anAsp90Ala mutation hauv CuZn-superoxide dismutase. Nature Genetics, 10,61–66.
For more information:1950477648nn@gmail.com
