Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease.
Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease.
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DOI：
10.1038/s41434-020-00190-1
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发表时间：
2021-04
期刊：
影响因子：
5.1
通讯作者：
Martin DR
中科院分区：
文献类型：
--
作者：
McCurdy VJ;Johnson AK;Gray-Edwards HL;Randle AN;Bradbury AM;Morrison NE;Hwang M;Baker HJ;Cox NR;Sena-Esteves M;Martin DR
桑德霍夫病（SD）是一种常染色体隐性溶酶体贮积病，由β-N-乙酰氨基己糖苷酶（Hex）的β-亚基缺陷引起，Hex是分解代谢GM 2神经节苷脂（GM 2）的酶。Hex缺乏会导致GM 2和相关糖缀合物的神经元储存，导致进行性神经变性和死亡，通常发生在婴儿期。对于人类患者没有有效的治疗方法。腺相关病毒（AAV）基因治疗改善了疾病症状发作前治疗的SD猫的临床结局和生存率。大多数人类患者在临床疾病发作后被诊断，因此必须在有症状的SD猫中测试AAV基因疗法，以提供在人类中可以预期的治疗益处的现实指示。在该研究中，将AAVrh 8载体注射到有症状的SD猫的丘脑和小脑深部核中导致广泛的中枢神经系统酶分布，尽管仍然存在大量的储存物质负担。在早期症状阶段接受治疗的猫显示出延迟的疾病进展，并且与未接受治疗的猫相比，存活率显著增加。在病程后期给药时，治疗效果较差，但仍有可能获得治疗获益。结果对于人类患者的治疗是令人鼓舞的，并为人类SD的AAV基因治疗的发展提供支持。
Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by defects in the β-subunit of β-N-acetylhexosaminidase (Hex), the enzyme that catabolizes GM2 ganglioside (GM2). Hex deficiency causes neuronal storage of GM2 and related glycoconjugates, resulting in progressive neurodegeneration and death, typically in infancy. No effective treatment exists for human patients. Adeno-associated virus (AAV) gene therapy led to improved clinical outcome and survival of SD cats treated before the onset of disease symptoms. Most human patients are diagnosed after clinical disease onset, so it is imperative to test AAV gene therapy in symptomatic SD cats to provide a realistic indication of therapeutic benefits that can be expected in humans. In this study, AAVrh8 vectors injected into the thalamus and deep cerebellar nuclei of symptomatic SD cats resulted in widespread central nervous system enzyme distribution, although a substantial burden of storage material remained. Cats treated in the early symptomatic phase showed delayed disease progression and a significant survival increase versus untreated cats. Treatment was less effective when administered later in the disease course, although therapeutic benefit was still possible. Results are encouraging for the treatment of human patients and provide support for the development AAV gene therapy for human SD.
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DOI：
10.1038/mt.2015.189
发表时间：
2016-02
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Gurda BL;De Guilhem De Lataillade A;Bell P;Zhu Y;Yu H;Wang P;Bagel J;Vite CH;Sikora T;Hinderer C;Calcedo R;Yox AD;Steet RA;Ruane T;O'Donnell P;Gao G;Wilson JM;Casal M;Ponder KP;Haskins ME
通讯作者：
Haskins ME
影响因子：
3.5
作者：
Cachon-Gonzalez, Maria-Begona;Wang, Susan Z.;Cox, Timothy M.
通讯作者：
Cox, Timothy M.
影响因子：
5.3
作者：
Cearley, Cassia N.;Wolfe, John H.
通讯作者：
Wolfe, John H.
影响因子：
5.3
作者：
Cressant, A;Desmaris, N;Heard, JM
通讯作者：
Heard, JM
影响因子：
5.1
作者：
Broekman, M. L. D.;Tierney, L. A.;Sena-Esteves, M.
通讯作者：
Sena-Esteves, M.