Comparison of different promoters to improve AAV vector-mediated gene therapy for neuronopathic Gaucher disease

被引：1

作者：

Massaro, Giulia ^{[1
]}

Geard, Amy F. ^{[1
,2
]}

Nelvagal, Hemanth R. ^{[1
]}

Gore, Katrina ^{[3
]}

Clemo, Nadine K. ^{[3
]}

Waddington, Simon N. ^{[2
,4
]}

Rahim, Ahad A. ^{[1
]}

机构：

[1] UCL, UCL Sch Pharm, 29 39 Brunswick Sq, London WC1N 1AX, England

[2] Univ Witwatersrand, Wits SAMRC Antiviral Gene Therapy Res Unit, Med Sch, Fac Hlth Sci, 7 York Rd, ZA-2193 Parktown, South Africa

[3] Apollo Therapeut, Stevenage Biosci Catalyst, 50 60 Stn Rd, Cambridge CB1 2JH, England

[4] UCL, UCL EGA Inst Womens Hlth, Med Sch Bldg,74 Huntley St, London WC1E 6AU, England

来源：

HUMAN MOLECULAR GENETICS | 2024年 / 33卷 / 17期

关键词：

gaucher disease; type; 2; gaucher; GBA1; AAV9; neonatal gene therapy; DELIVERY; PHENOTYPE; MODELS;

D O I：

10.1093/hmg/ddae081

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD. Graphical Abstract

引用

页码：1467 / 1480

页数：14

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