Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, Building 35A, Room 1E623, 35A Convent Drive, MSC 3708, Bethesda, MD 20892-3708, USA.
Genes (Basel). 2024 Mar 15;15(3):364. doi: 10.3390/genes15030364.
Gaucher disease, an autosomal recessively inherited lysosomal storage disorder, results from biallelic mutations in the gene resulting in deficient activity of the enzyme glucocerebrosidase. In Gaucher disease, the reduced levels and activity of glucocerebrosidase lead to a disparity in the rates of formation and breakdown of glucocerebroside and glucosylsphingosine, resulting in the accumulation of these lipid substrates in the lysosome. This gives rise to the development of Gaucher cells, engorged macrophages with a characteristic wrinkled tissue paper appearance. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease, associated with varying degrees of severity. The visceral and hematologic manifestations of Gaucher disease respond well to both enzyme replacement therapy and substrate reduction therapy. However, these therapies do not improve the neuronopathic manifestations, as they cannot cross the blood-brain barrier. There is now an established precedent for treating lysosomal storage disorders with gene therapy strategies, as many have the potential to cross into the brain. The range of the gene therapies being employed is broad, but this review aimed to discuss the progress, advances, and challenges in developing viral gene therapy as a treatment for Gaucher disease.
戈谢病是一种常染色体隐性遗传的溶酶体贮积病，由 基因的双等位基因突变引起，导致葡糖脑苷脂酶活性降低。在戈谢病中，葡糖脑苷脂酶的水平和活性降低，导致葡糖脑苷脂和葡萄糖神经酰胺的形成和分解速度不一致，导致这些脂质底物在溶酶体中积累。这导致戈谢细胞的发育，充满了特征性的皱纸外观的巨噬细胞。戈谢病有非神经病变（1 型）和神经病变（2 型和 3 型）两种形式，与不同的严重程度相关。戈谢病的内脏和血液学表现对酶替代疗法和底物减少疗法都有很好的反应。然而，这些疗法并不能改善神经病变表现，因为它们不能穿过血脑屏障。现在已经有了用基因治疗策略治疗溶酶体贮积病的既定先例，因为许多基因治疗策略都有可能进入大脑。所采用的基因治疗方法范围很广，但本综述旨在讨论开发病毒基因治疗作为戈谢病治疗方法的进展、进展和挑战。
