Login Register Cart 0
Research Article

AAV9-coGLB1 Improves Lysosomal Storage and Rescues Central Nervous System Inflammation in a Mutant Mouse Model of GM1 Gangliosidosis

Author(s): Sichi Liu, Wenhao Ma, Yuyu Feng, Yan Zhang, Xuefang Jia, Chengfang Tang, Fang Tang, Xiaobing Wu* and Yonglan Huang*

Volume 22, Issue 4, 2022

Published on: 01 April, 2022

Page: [352 - 365] Pages: 14

DOI: 10.2174/1566523222666220304092732

Price: $65

Abstract

Background: GM1 gangliosidosis (GM1) is an autosomal recessive disorder characterized by the deficiency of beta-galactosidase (β-gal), a ubiquitous lysosomal enzyme that catalyzes the hydrolysis of GM1 ganglioside.

Objective: The study aims to explore the application of the AAV9-coGLB1 for effective treatment in a GM1 gangliosidosis mutant mouse model.

Methods: We designed a novel adeno-associated virus 9 (AAV9) vector expressing β-gal (AAV9- coGLB1) to treat GM1 gangliosidosis. The vector, injected via the caudal vein at 4 weeks of age, drove the widespread and sustained expression of β-gal for up to 32 weeks in the Glb1G455R/G455R mutant mice (GM1 mice).

Results: The increased levels of β-gal reduced the pathological damage occurring in GM1 mice. Histological analyses showed that myelin deficits and neuron-specific pathology were reduced in the cerebral cortex region of AAV9-coGLB1-treated mice. Immunohistochemical staining showed that the accumulation of GM1 ganglioside was also reduced after gene therapy. The reduction of the storage in these regions was accompanied by a decrease in activated microglia. In addition, AAV9 treatment reversed the blockade of autophagic flux in GM1 mice.

Conclusion: These results show that AAV9-coGLB1 reduces the pathological signs of GM1 gangliosidosis in a mouse model.

Keywords: GM1 gangliosidosis, mouse model, gene therapy, AAV9, central nervous system inflammation, autophagic flux.

« Previous
Graphical Abstract

[1]
Lang FM, Korner P, Harnett M, Karunakara A, Tifft CJ. The natural history of Type 1 infantile GM1 gangliosidosis: A literature-based meta-analysis. Mol Genet Metab 2020; 129(3): 228-35.
[http://dx.doi.org/10.1016/j.ymgme.2019.12.012] [PMID: 31937438]
[2]
Priyanka K, Madhana Priya N, Magesh R. A computational approach to analyse the amino acid variants of GLB1 protein causing GM1 Gangliosidosis. Metab Brain Dis 2021; 36(3): 499-508.
[http://dx.doi.org/10.1007/s11011-020-00650-y] [PMID: 33394287]
[3]
Ou L, Kim S, Whitley CB, Jarnes-Utz JR. Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. Mol Genet Metab Rep 2019; 20: 100495.
[4]
Chen JC, Luu AR, Wise N, et al. Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice. J Biol Chem 2020; 295(39): 13532-55.
[http://dx.doi.org/10.1074/jbc.RA119.009811] [PMID: 31481471]
[5]
Kajihara R, Numakawa T, Odaka H, et al. Novel drug candidates improve ganglioside accumulation and neural dysfunction in GM1 gangliosidosis models with autophagy activation. Stem Cell Reports 2020; 14(5): 909-23.
[http://dx.doi.org/10.1016/j.stemcr.2020.03.012] [PMID: 32302553]
[6]
Ortolano S, Spuch C, Navarro C. Present and future of adeno associated virus based gene therapy approaches. Recent Pat Endocr Metab Immune Drug Discov 2012; 6(1): 47-66.
[http://dx.doi.org/10.2174/187221412799015245] [PMID: 22264214]
[7]
Ryckman AE, Brockhausen I, Walia JS. Metabolism of glycosphingolipids and their role in the pathophysiology of lysosomal storage disorders. Int J Mol Sci 2020; 21(18): E6881.
[http://dx.doi.org/10.3390/ijms21186881] [PMID: 32961778]
[8]
Monaco A, Fraldi A. Protein aggregation and dysfunction of autophagy- lysosomal pathway: A vicious cycle in lysosomal storage diseases. Front Mol Neurosci 2020; 13: 37.
[9]
Heckmann BL, Teubner BJW, Tummers B, et al. LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease. Cell 2020; 183(6): 1733-4.
[http://dx.doi.org/10.1016/j.cell.2020.11.033] [PMID: 33306957]
[10]
Karunakaran I, Alam S, Jayagopi S, et al. Neural sphingosine 1-phosphate accumulation activates microglia and links impaired autophagy and inflammation. Glia 2019; 67(10): 1859-72.
[http://dx.doi.org/10.1002/glia.23663] [PMID: 31231866]
[11]
Stavoe AKH, Holzbaur ELF. Autophagy in neurons. Annu Rev Cell Dev Biol 2019; 35: 477-500.
[12]
Biferi MG, Cohen-Tannoudji M, Garcia-Silva A, et al. Systemic treatment of Fabry Disease using a novel aav9 vector expressing alpha-galactosidase A. Mol Ther Methods Clin Dev 2021; 20: 1-17.
[13]
Kielian T. Lysosomal storage disorders: Pathology within the lysosome and beyond. J Neurochem 2019; 148(5): 568-72.
[http://dx.doi.org/10.1111/jnc.14672] [PMID: 30697734]
[14]
Vitner EB. The role of brain innate immune response in lysosomal storage disorders: Fundamental process or evolutionary side effect? FEBS Lett 2020; 594(22): 3619-31.
[http://dx.doi.org/10.1002/1873-3468.13980] [PMID: 33131047]
[15]
Jeyakumar M, Thomas R, Elliot-Smith E, et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 2003; 126(Pt 4): 974-87.
[http://dx.doi.org/10.1093/brain/awg089] [PMID: 12615653]
[16]
Liu S, Feng Y, Huang Y, et al. A GM1 gangliosidosis mutant mouse model exhibits activated microglia and disturbed autophagy. Exp Biol Med (Maywood) 2021; 246(11): 1330-41.
[http://dx.doi.org/10.1177/1535370221993052] [PMID: 33583210]
[17]
Lin S, Mei X. Role of NLRP3 inflammasomes in neuroinflammation diseases. Eur Neurol 2020; 83(6): 576-80.
[http://dx.doi.org/10.1159/000509798] [PMID: 33202405]
[18]
Wang Z, Meng S, Cao L, Chen Y, Zuo Z, Peng S. Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment. J Neuroinflammation 2018; 15(1): 109.
[http://dx.doi.org/10.1186/s12974-018-1137-1] [PMID: 29665808]
[19]
Feather-Schussler DN, Ferguson TS. A battery of motor tests in a neonatal mouse model of cerebral palsy. J Vis Exp 2016; 117: 53569.
[20]
Weismann CM, Ferreira J, Keeler AM, et al. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum Mol Genet 2015; 24(15): 4353-64.
[http://dx.doi.org/10.1093/hmg/ddv168] [PMID: 25964428]
[21]
Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140(6): 821-32.
[http://dx.doi.org/10.1016/j.cell.2010.01.040] [PMID: 20303873]
[22]
Hinderer C, Nosratbakhsh B, Katz N, Wilson JM. A single injection of an optimized adeno-associated viral vector into cerebrospinal fluid corrects neurological disease in a murine model of GM1 gangliosidosis. Hum Gene Ther 2020; 31(21-22): 1169-77.
[http://dx.doi.org/10.1089/hum.2018.206] [PMID: 33045869]
[23]
Gray-Edwards HL, Maguire AS, Salibi N. 7T MRI predicts amelioration of neurodegeneration in the brain after AAV gene therapy. Mol Ther Methods Clin Dev 2020; 17: 258-70.
[24]
Ren H, Wang G. Autophagy and lysosome storage disorders. Adv Exp Med Biol 2020; 1207: 87-102.
[25]
Takamura A, Higaki K, Kajimaki K, et al. Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis. Biochem Biophys Res Commun 2008; 367(3): 616-22.
[http://dx.doi.org/10.1016/j.bbrc.2007.12.187] [PMID: 18190792]
[26]
Zheng T, Zhao C, Zhao B, et al. Impairment of the autophagylysosomal pathway and activation of pyroptosis in macular corneal dystrophy. Cell Death Discov 2020; 6: 85.
[27]
Zatyka M, Sarkar S, Barrett T. Autophagy in rare (nonlysosomal) neurodegenerative diseases. J Mol Biol 2020; 432(8): 2735-53.
[http://dx.doi.org/10.1016/j.jmb.2020.02.012] [PMID: 32087199]
[28]
Aflaki E, Moaven N, Borger DK, et al. Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell 2016; 15(1): 77-88.
[http://dx.doi.org/10.1111/acel.12409] [PMID: 26486234]

Rights & Permissions Print Cite
Article Metrics
25
1
© 2024 Bentham Science Publishers | Privacy Policy