Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease.
Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease.
复制标题
猫Sandhoff疾病中疾病进展和AAV治疗功效的生物标志物。
DOI：
10.1016/j.expneurol.2014.09.020
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发表时间：
2015-01
影响因子：
5.3
通讯作者：
Martin, Douglas R.
中科院分区：
文献类型：
--
作者：
Bradbury, Allison M.;Gray-Edwards, Heather L.;Shirley, Jamie L.;McCurdy, Victoria J.;Colaco, Alexandria N.;Randle, Ashley N.;Christopherson, Pete W.;Bird, Allison C.;Johnson, Aime K.;Wilson, Diane U.;Hudson, Judith A.;De Pompa, Nicholas L.;Sorjonen, Donald C.;Brunson, Brandon L.;Jeyakumar, Mylvaganam;Platt, Frances M.;Baker, Henry J.;Cox, Nancy R.;Sena-Esteves, Miguel;Martin, Douglas R.
关键词：
GM2 神经节苷脂病、泰-萨克斯病 (TSD) 和桑德霍夫病 (SD) 是进行性神经退行性疾病，由 β-N-乙酰己糖胺酶 (Hex) 突变引起。由于最近出现了新的实验性治疗方法，生物标志物的开发作为衡量治疗效果的客观手段，在 GM2 神经节苷脂沉积症中变得尤为重要。在这里，我们描述了用于评估猫 SD 模型中疾病进展的血液、脑脊液 (CSF)、磁共振成像 (MRI) 和电诊断方法，以及应用这些方法评估 AAV 介导的基因治疗。使用编码猫科动物 Hex 的 AAVrh8 载体，通过丘脑联合深部小脑核或单个侧脑室对 SD 猫进行颅内注射治疗。在未经治疗的 SD 猫中，基于血液和脑脊液的生物标志物在 AAV 基因治疗后出现显着变化。治疗后外周血单核细胞中溶酶体区室的扩张以及次级溶酶体酶活性的升高也有所减少。 SD 猫记录了神经节苷脂沉积症的 MRI 变化特征，并在 AAV 基因治疗后恢复正常。本文报道的微创生物标志物应该有助于评估未经治疗的 GM2 患者和未来临床试验中的患者的疾病进展。
The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated GM2 patients and those in future clinical trials.
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影响因子：
56.9
作者：
BUCHWALD, JS;HUANG, CM
通讯作者：
HUANG, CM
影响因子：
15.9
作者：
BALINT, JA;KYRIAKIDES, EC
通讯作者：
KYRIAKIDES, EC
DOI：
10.1016/s0195-5616(88)50051-7
发表时间：
1988-05-01
影响因子：
1.9
作者：
COOK, JR;DENICOLA, DB
通讯作者：
DENICOLA, DB
影响因子：
2.9
作者：
Huh, PW;Belayev, L;Ginsberg, MD
通讯作者：
Ginsberg, MD
影响因子：
12.4
作者：
Cachon-Gonzalez, M. Begona;Wang, Susan Z.;Cox, Timothy M.
通讯作者：
Cox, Timothy M.