Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease
Pathological mutations in GBA, encoding lysosomal glucocerebrosidase (GCase), cause Gaucher disease (GD). GD is a multi-system disease with great phenotypic variation between individuals. It has been classified into type 1 with primarily peripheral involvement and types 2 and 3 with varying degrees...
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doaj-0769db607a724ad29cd26439e03603a12021-03-22T12:48:21ZengElsevierNeurobiology of Disease1095-953X2019-10-01130104513Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher diseaseKasey L. Jackson0Catherine Viel1Jennifer Clarke2Jie Bu3Monyrath Chan4Bing Wang5Lamya S. Shihabuddin6S. Pablo Sardi7Rare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of AmericaRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of AmericaRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of AmericaRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of AmericaRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of AmericaAnalytical R&D, Sanofi, Waltham, MA 02451, United States of AmericaRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of AmericaRare and Neurologic Diseases Research Therapeutic Area, Sanofi, Framingham, MA 01701, United States of America; Corresponding author at: 49 New York Ave, Framingham, MA 01701, United States of America.Pathological mutations in GBA, encoding lysosomal glucocerebrosidase (GCase), cause Gaucher disease (GD). GD is a multi-system disease with great phenotypic variation between individuals. It has been classified into type 1 with primarily peripheral involvement and types 2 and 3 with varying degrees of neurological involvement. GD is characterized by decreased GCase activity and subsequent accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Current murine models of neuronopathic GD mostly replicate the severe aspects of the neurological symptoms developing rapid progression and early lethality, thus presenting a short window for therapeutic testing. In order to develop a model of chronic neuronopathic GD, we reduced GCase in the central nervous system (CNS) of a mild GD mouse model (GbaD409V/D409V) via intracerebroventricular administration of an adeno-associated virus encoding a microRNA to Gba (AAV-GFP-miR-Gba). GbaD409V/D409V mice have significantly reduced GCase activity and increased substrate accumulation in the CNS. Phenotypically, these mice partially recapitulate features of mild type 1 GD. Their neurological examination reveals cognitive impairment with normal motor features. Administration of AAV-GFP-miR-Gba into GbaD409V/D409V pups in the CNS caused progressive lipid substrate accumulation. Phenotypically, AAV1-GFP-miR-Gba-treated mice were indistinguishable from their littermates until 10 weeks of age, when they started developing progressive neurological impairments, including hyperactivity, abnormal gait, and head retroflexion. Importantly, these impairments can be prevented by simultaneous administration of a miR-resistant GBA, demonstrating that the pathological effects are specifically due to Gba mRNA reduction. This novel model of neuronopathic GD offers several advantages over current models including slower progression of neurological complications and an increased lifespan, which make it more amenable for therapeutic testing.http://www.sciencedirect.com/science/article/pii/S096999611930172XNeuronopathic Gaucher diseaseGbaAtaxiaAAV-mediated microRNA reduction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kasey L. Jackson Catherine Viel Jennifer Clarke Jie Bu Monyrath Chan Bing Wang Lamya S. Shihabuddin S. Pablo Sardi |
spellingShingle |
Kasey L. Jackson Catherine Viel Jennifer Clarke Jie Bu Monyrath Chan Bing Wang Lamya S. Shihabuddin S. Pablo Sardi Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease Neurobiology of Disease Neuronopathic Gaucher disease Gba Ataxia AAV-mediated microRNA reduction |
author_facet |
Kasey L. Jackson Catherine Viel Jennifer Clarke Jie Bu Monyrath Chan Bing Wang Lamya S. Shihabuddin S. Pablo Sardi |
author_sort |
Kasey L. Jackson |
title |
Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease |
title_short |
Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease |
title_full |
Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease |
title_fullStr |
Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease |
title_full_unstemmed |
Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease |
title_sort |
viral delivery of a microrna to gba to the mouse central nervous system models neuronopathic gaucher disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2019-10-01 |
description |
Pathological mutations in GBA, encoding lysosomal glucocerebrosidase (GCase), cause Gaucher disease (GD). GD is a multi-system disease with great phenotypic variation between individuals. It has been classified into type 1 with primarily peripheral involvement and types 2 and 3 with varying degrees of neurological involvement. GD is characterized by decreased GCase activity and subsequent accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Current murine models of neuronopathic GD mostly replicate the severe aspects of the neurological symptoms developing rapid progression and early lethality, thus presenting a short window for therapeutic testing. In order to develop a model of chronic neuronopathic GD, we reduced GCase in the central nervous system (CNS) of a mild GD mouse model (GbaD409V/D409V) via intracerebroventricular administration of an adeno-associated virus encoding a microRNA to Gba (AAV-GFP-miR-Gba). GbaD409V/D409V mice have significantly reduced GCase activity and increased substrate accumulation in the CNS. Phenotypically, these mice partially recapitulate features of mild type 1 GD. Their neurological examination reveals cognitive impairment with normal motor features. Administration of AAV-GFP-miR-Gba into GbaD409V/D409V pups in the CNS caused progressive lipid substrate accumulation. Phenotypically, AAV1-GFP-miR-Gba-treated mice were indistinguishable from their littermates until 10 weeks of age, when they started developing progressive neurological impairments, including hyperactivity, abnormal gait, and head retroflexion. Importantly, these impairments can be prevented by simultaneous administration of a miR-resistant GBA, demonstrating that the pathological effects are specifically due to Gba mRNA reduction. This novel model of neuronopathic GD offers several advantages over current models including slower progression of neurological complications and an increased lifespan, which make it more amenable for therapeutic testing. |
topic |
Neuronopathic Gaucher disease Gba Ataxia AAV-mediated microRNA reduction |
url |
http://www.sciencedirect.com/science/article/pii/S096999611930172X |
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