Progress in gene therapy mechanism of amyotrophic lateral sclerosis

doi:10.16352/j.issn.1001-6325.2023.04.0674

Abstract

Abstract: Gene therapy research on amyotrophic lateral sclerosis (ALS) focuses on SOD1, C9ORF72, FUS and ATAX2, et al. According to the mechanism, the pathogenicity of variant genes is mostly acquired by the toxicity gain of function. Two strategies are adopted for the silencing and editing of disease causing genes, namely, naked injection of antisense oligonucleotides (ASO) to induce the degradation of mRNA mediated by RNase H or the silencing of disease causing gene mediated by adeno-associated virus (AAV) to delivery RNA interference (RNAi) to decrease toxicity protein. CRISPR/Cas9 edits and modifies the causing gene to decrease the expression of toxic protein. In addition, there has been much progress in decreasing the level of toxic protein through specific antibodies and metabolic regulators, as well as neuroprotective therapy.

Key words: amyotrophic lateral sclerosis, gene therapy, antisense oligonucleotides, RNA interference, CRISPR-Cas9

CLC Number:

R746.4

LI Xiaoguang, YANG Lu, LIU Xudong, JIA Xinmiao, YANG Xinzhuang, CUI Liying. Progress in gene therapy mechanism of amyotrophic lateral sclerosis[J]. Basic & Clinical Medicine, 2023, 43(4): 674-679.

References

[1]Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS[J]. N Engl J Med, 2022, 387:1099-1110.
[2] Provenzano F, Nyberg S, Giunti D, et al. Micro-RNAs shuttled by extracellular vesicles secreted from mesenchymal stem cells dampen astrocyte pathological activation and support neuroprotection in in-vitro models of ALS[J]. Cells, 2022, 11:3923. doi: 10.3390/cells11233923.
[3] Smith RA, Miller TM, Yamanaka K, et al. Antisense oligonucleotide therapy for neurodegenerative disease[J]. J Clin Invest, 2006, 116:2290-2296.
[4]Tran H, Moazami MP, Yang H, et al. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide[J]. Nat Med, 2022, 28:117-124.
[5] Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, et al Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis[J]. Nat Med, 2022, 28:104-116.
[6] Scoles DR, Meera P, Schneider MD, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2[J]. Nature, 2017,544:362-366.
[7] Paul S, Dansithong W, Figueroa KP, et al. Staufen1 in human neurodegeneration[J]. Ann Neurol, 2021, 89:1114-1128.
[8] Kumagai S, Nakajima T, Shimazaki K, et al. Early distribution of18 F-labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non-human primates[J]. J Gene Med, 2023, 25:e3457. doi: 10.1002/jgm.3457.
[9]Borel F, Gernoux G, Sun H, et al. Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques[J]. Sci Transl Med,2018,10:eaau6414. doi: 10.1126/scitranslmed.aau6414.
[10]Mueller C, Berry JD, McKenna-Yasek DM, et al. SOD1 suppression with adeno-associated virus and microRNA in familial ALS[J]. N Engl J Med, 2020, 383:151-158.
[11] Hordeaux J, Buza EL, Jeffrey B, et al. MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates[J]. Sci Transl Med, 2020, 12:eaba9188. doi: 10.1126/scitranslmed.aba9188.
[12] Bravo-Hernandez M, Tadokoro T, Navarro MR, et al. Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS[J]. Nat Med, 2020, 26:118-130.
[13] Rochat C, Bernard-Marissal N, Kállstig E, et al. Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis[J]. Glia, 2022,70:842-857.
[14] Chen YA, Kankel MW, Hana S, et al. In vivo genome editing using novel AAV-PHP variants rescues motor function deficits and extends survival in a SOD1-ALS mouse model[J]. Gene Ther, 2022, 1:1-12.
[15] Lim CKW, Gapinske M, Brooks AK, et al. Treatment of a mouse model of ALS by in vivo base editing[J]. Mol Ther, 2020, 28:1177-1189.
[16] Duan W, Guo M, Yi L, et al. The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model[J]. Gene Ther, 2020, 27:157-169.
[17]Meijboom KE, Abdallah A, Fordham NP, et al. CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitrol[J]. Nat Commun, 2022, 13:6286. doi: 10.1038/s41467-022-33332-7.
[18] Xia Y, Chen Z, Xu G, et al. Novel SOD1 monoclonal antibodies against the electrostatic loop preferentially detect misfolded SOD1 aggregates[J]. Neurosci Lett, 2021, 742:135553. doi: 10.1016/j.neulet.2020.135553.
[19] Licata NV, Cristofani R, Salomonsson S, et al. C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation[J]. EMBO J, 2022, 41:e105026. doi: 10.15252/embj.2020105026.
[20] Kim G, Nakayama L, Blum JA, et al. Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2[J]. Cell Rep, 2022, 41:111508. doi: 10.1016/j.celrep.2022.111508.
[21] Baloh RH, Johnson JP, Avalos P, et al. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial[J]. Nat Med, 2022, 28:1813-1822.
[22]Guttenplan KA, Weigel MK, Adler DI, et al. Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model[J]. Nat Commun, 2020, 11:3753. doi: 10.1038/s41467-020-17514-9.
[23]Wang S, Ichinomiya T, Savchenko P, et al. Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (AAV9-SynCav1) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1G93A mice[J]. Theranostics, 2022, 12:5389-5403.
[24] Oya R, Tsukamoto O, Hitsumoto T, et al. Gene transfer of skeletal muscle-type myosin light chain kinase via adeno-associated virus 6 Improves muscle functions in an amyotrophic lateral sclerosis mouse model[J]. Int J Mol Sci, 2022, 23:1747. doi: 10.3390/ijms23031747.