Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy
<b>Background/Objectives</b>: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the <i>GBA1</i> gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acut...
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| author | Amy F. Geard Giulia Massaro Michael P. Hughes Patrick Arbuthnot Simon N. Waddington Ahad A. Rahim |
| author_facet | Amy F. Geard Giulia Massaro Michael P. Hughes Patrick Arbuthnot Simon N. Waddington Ahad A. Rahim |
| author_sort | Amy F. Geard |
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| description | <b>Background/Objectives</b>: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the <i>GBA1</i> gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acute and chronic neurodegeneration that distinguish type 2 and type 3 GD, respectively. We have previously shown the efficacy of neonatal AAV9 gene therapy for treating type 2 GD and aimed to investigate post-symptomatic administration into a model of type 1 disease. Current murine models of type 1 disease are limited in their recapitulation of early onset phenotypic manifestation and thus we aimed to create a novel model of type 1 in which to test the efficacy of adult gene therapy. <b>Methods</b>: The novel AAV-GD1 model was created through intracerebroventricular injection of AAV9 containing the human <i>GBA1</i> gene under control of the neuron-specific synapsin promoter (AAV9.hSynI.h<i>GBA1</i>) to the pre-existing acute K14-lnl/lnl model of type 2 GD. Administration of AAV9.hSynI.h<i>GBA1</i> aimed to restore glucocerebrosidase expression in the brain and extend the lifespan beyond 14 days, allowing the visceral pathology to develop further. The organ pathology was characterised by immunohistochemistry at various time points. Once visceral disease was confirmed, an intravenous injection of AAV9 containing a ubiquitously active CAG promoter driving h<i>GBA1</i> (AAV9.CAG.h<i>GBA1</i>) was administered to post-symptomatic mice. Animals were aged for 2 and 4 months post-treatment with AAV9.CAG.h<i>GBA1</i>, and immunohistochemistry and enzymatic activity were assessed to investigate therapeutic efficacy. <b>Results</b>: The AAV-GD1 model displayed visceral pathology in the spleen, lung, and liver from 2 months of age. This allowed us to validate the efficacy of adult gene therapy; intravenous administration of AAV9.CAG.h<i>GBA1</i> transiently ameliorated the lung pathology and rescued the spleen pathology up to 4 months post-administration. <b>Conclusions</b>: The creation of the novel AAV-GD1 model with more aggressive visceral pathology presents a unique opportunity for investigation of new therapies to treat type 1 GD. AAV9.CAG.h<i>GBA1</i> represents a potential therapeutic option for all forms of Gaucher disease. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-beeba53efe574b5580dfb7296ec8d2b62025-08-20T03:47:54ZengMDPI AGPharmaceutics1999-49232025-05-0117565010.3390/pharmaceutics17050650Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic TherapyAmy F. Geard0Giulia Massaro1Michael P. Hughes2Patrick Arbuthnot3Simon N. Waddington4Ahad A. Rahim5Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UKDepartment of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UKDepartment of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UKWits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaWits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South AfricaDepartment of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK<b>Background/Objectives</b>: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the <i>GBA1</i> gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acute and chronic neurodegeneration that distinguish type 2 and type 3 GD, respectively. We have previously shown the efficacy of neonatal AAV9 gene therapy for treating type 2 GD and aimed to investigate post-symptomatic administration into a model of type 1 disease. Current murine models of type 1 disease are limited in their recapitulation of early onset phenotypic manifestation and thus we aimed to create a novel model of type 1 in which to test the efficacy of adult gene therapy. <b>Methods</b>: The novel AAV-GD1 model was created through intracerebroventricular injection of AAV9 containing the human <i>GBA1</i> gene under control of the neuron-specific synapsin promoter (AAV9.hSynI.h<i>GBA1</i>) to the pre-existing acute K14-lnl/lnl model of type 2 GD. Administration of AAV9.hSynI.h<i>GBA1</i> aimed to restore glucocerebrosidase expression in the brain and extend the lifespan beyond 14 days, allowing the visceral pathology to develop further. The organ pathology was characterised by immunohistochemistry at various time points. Once visceral disease was confirmed, an intravenous injection of AAV9 containing a ubiquitously active CAG promoter driving h<i>GBA1</i> (AAV9.CAG.h<i>GBA1</i>) was administered to post-symptomatic mice. Animals were aged for 2 and 4 months post-treatment with AAV9.CAG.h<i>GBA1</i>, and immunohistochemistry and enzymatic activity were assessed to investigate therapeutic efficacy. <b>Results</b>: The AAV-GD1 model displayed visceral pathology in the spleen, lung, and liver from 2 months of age. This allowed us to validate the efficacy of adult gene therapy; intravenous administration of AAV9.CAG.h<i>GBA1</i> transiently ameliorated the lung pathology and rescued the spleen pathology up to 4 months post-administration. <b>Conclusions</b>: The creation of the novel AAV-GD1 model with more aggressive visceral pathology presents a unique opportunity for investigation of new therapies to treat type 1 GD. AAV9.CAG.h<i>GBA1</i> represents a potential therapeutic option for all forms of Gaucher disease.https://www.mdpi.com/1999-4923/17/5/650Gaucher diseaseAAVgene therapymouse modelGD Type 1 |
| spellingShingle | Amy F. Geard Giulia Massaro Michael P. Hughes Patrick Arbuthnot Simon N. Waddington Ahad A. Rahim Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy Pharmaceutics Gaucher disease AAV gene therapy mouse model GD Type 1 |
| title | Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy |
| title_full | Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy |
| title_fullStr | Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy |
| title_full_unstemmed | Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy |
| title_short | Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy |
| title_sort | generation and treatment of a novel severe model of visceral gaucher disease by genetic therapy |
| topic | Gaucher disease AAV gene therapy mouse model GD Type 1 |
| url | https://www.mdpi.com/1999-4923/17/5/650 |
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