Geard Amy F, Massaro Giulia, Hughes Michael P, Arbuthnot Patrick, Waddington Simon N, Rahim Ahad A
Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
Pharmaceutics. 2025 May 15;17(5):650. doi: 10.3390/pharmaceutics17050650.
: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the 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. : The novel AAV-GD1 model was created through intracerebroventricular injection of AAV9 containing the human gene under control of the neuron-specific synapsin promoter (AAV9.hSynI.h) to the pre-existing acute K14-lnl/lnl model of type 2 GD. Administration of AAV9.hSynI.h 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 (AAV9.CAG.h) was administered to post-symptomatic mice. Animals were aged for 2 and 4 months post-treatment with AAV9.CAG.h, and immunohistochemistry and enzymatic activity were assessed to investigate therapeutic efficacy. : 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 transiently ameliorated the lung pathology and rescued the spleen pathology up to 4 months post-administration. : 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 represents a potential therapeutic option for all forms of Gaucher disease.
戈谢病（GD）是一种常染色体隐性溶酶体贮积症，由该基因的突变引起。1型戈谢病的特征是在内脏器官中底物蓄积，同时分别伴有区分2型和3型戈谢病的急性和慢性神经退行性变。我们之前已证明新生儿AAV9基因疗法治疗2型戈谢病的疗效，并旨在研究对1型疾病模型进行症状出现后给药的情况。目前1型疾病的小鼠模型在重现早期发病表型表现方面存在局限性，因此我们旨在创建一种新型1型模型，以测试成人基因疗法的疗效。：通过将含有在神经元特异性突触素启动子（AAV9.hSynI.h）控制下的人基因的AAV9脑室内注射到预先存在的2型戈谢病急性K14-lnl/lnl模型中，创建了新型AAV-GD1模型。给予AAV9.hSynI.h旨在恢复大脑中的葡糖脑苷脂酶表达，并将寿命延长至14天以上，使内脏病理进一步发展。在不同时间点通过免疫组织化学对器官病理进行表征。一旦确认内脏疾病，就对出现症状后的小鼠静脉注射含有驱动h的普遍活性CAG启动子的AAV9（AAV9.CAG.h）。在用AAV9.CAG.h治疗后，让动物存活2个月和4个月，并评估免疫组织化学和酶活性以研究治疗效果。：AAV-GD1模型在2月龄时在脾脏、肺和肝脏中显示出内脏病理。这使我们能够验证成人基因疗法的疗效；静脉注射AAV9.CAG.h可暂时改善肺部病理，并在给药后长达4个月挽救脾脏病理。：具有更严重内脏病理的新型AAV-GD1模型的创建为研究治疗1型戈谢病的新疗法提供了独特机会。AAV9.CAG.h代表了治疗所有形式戈谢病的一种潜在治疗选择。
