Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice

Junling Liu; Mahmoud Bassal; Stefanie Schlichting; Ingke Braren; Alessandro Di Spiezio; Paul Saftig; Udo Bartsch

doi:10.1016/j.nbd.2022.105628

Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice

Standard

Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice. / Liu, Junling; Bassal, Mahmoud; Schlichting, Stefanie; Braren, Ingke; Di Spiezio, Alessandro; Saftig, Paul; Bartsch, Udo.

in: NEUROBIOL DIS, Jahrgang 164, 105628, 03.2022.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Liu, J, Bassal, M, Schlichting, S, Braren, I, Di Spiezio, A, Saftig, P & Bartsch, U 2022, 'Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice', NEUROBIOL DIS, Jg. 164, 105628. https://doi.org/10.1016/j.nbd.2022.105628

APA

Liu, J., Bassal, M., Schlichting, S., Braren, I., Di Spiezio, A., Saftig, P., & Bartsch, U. (2022). Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice. NEUROBIOL DIS, 164, [105628]. https://doi.org/10.1016/j.nbd.2022.105628

Vancouver

Liu J, Bassal M, Schlichting S, Braren I, Di Spiezio A, Saftig P et al. Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice. NEUROBIOL DIS. 2022 Mär;164. 105628. https://doi.org/10.1016/j.nbd.2022.105628

Bibtex

@article{182f999fc2f743feb7891290e0c52c6f,

title = "Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice",

abstract = "Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells.",

keywords = "Animals, Autophagy/physiology, Cathepsin D/genetics, Disease Models, Animal, Genetic Therapy, Lysosomes/physiology, Mice, Mice, Knockout, Retinal Degeneration/genetics",

author = "Junling Liu and Mahmoud Bassal and Stefanie Schlichting and Ingke Braren and {Di Spiezio}, Alessandro and Paul Saftig and Udo Bartsch",

year = "2022",

month = mar,

doi = "10.1016/j.nbd.2022.105628",

language = "English",

volume = "164",

journal = "NEUROBIOL DIS",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

RIS

TY - JOUR

T1 - Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice

AU - Liu, Junling

AU - Bassal, Mahmoud

AU - Schlichting, Stefanie

AU - Braren, Ingke

AU - Di Spiezio, Alessandro

AU - Saftig, Paul

AU - Bartsch, Udo

PY - 2022/3

Y1 - 2022/3

N2 - Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells.

AB - Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells.

KW - Animals

KW - Autophagy/physiology

KW - Cathepsin D/genetics

KW - Disease Models, Animal

KW - Genetic Therapy

KW - Lysosomes/physiology

KW - Mice

KW - Mice, Knockout

KW - Retinal Degeneration/genetics

U2 - 10.1016/j.nbd.2022.105628

DO - 10.1016/j.nbd.2022.105628

M3 - SCORING: Journal article

C2 - 35033660

VL - 164

JO - NEUROBIOL DIS

JF - NEUROBIOL DIS

SN - 0969-9961

M1 - 105628

ER -