White Matter Pathology as a Barrier to Gangliosidosis Gene Therapy.
White Matter Pathology as a Barrier to Gangliosidosis Gene Therapy.
复制标题
DOI：
10.3389/fncel.2021.682106
复制
发表时间：
2021
影响因子：
5.3
通讯作者：
Martin DR
中科院分区：
文献类型：
--
作者：
Maguire AS;Martin DR
神经节苷脂沉积症是一类神经退行性溶酶体贮积症，近期在基因治疗方面取得了有希望的进展。白质缺陷是神经节苷脂沉积症病理中已明确的组成部分，由于其对基因治疗的矫正部分具有抵抗性，现在受到了更多关注。在简要概述正常髓鞘形成之后，本综述概述了关于神经节苷脂沉积症中白质缺陷的起源以及通过基因治疗有效治疗它们的潜在障碍的当前观点。髓鞘形成不良（髓鞘未能正常形成）被认为是白质病理的主要原因，但确切的机制细节尚未完全了解。神经元贮积缺陷的影响可能超出继发性脱髓鞘（由于轴突缺失导致的髓鞘破坏），并导致髓鞘形成不良。在神经节苷脂沉积症动物模型中进行的临床前研究已大幅提高了寿命和生活质量，从而启动了几项临床试验。然而，白质病理的改善落后于其他指标，并且迄今为止很少有基于证据的解释被提出。鼓励该领域的研究小组在未来的基因治疗工作中纳入针对髓鞘的研究，以填补这一知识空白。
The gangliosidoses are a family of neurodegenerative lysosomal storage diseases that have recently seen promising advances in gene therapy. White matter deficits are well established components of gangliosidosis pathology that are now receiving more attention because they are partially refractory to correction by gene therapy. After a brief synopsis of normal myelinogenesis, this review outlines current viewpoints on the origin of white matter deficits in the gangliosidoses and potential obstacles to treating them effectively by gene therapy. Dysmyelinogenesis (failure of myelin sheaths to form properly) is proposed as the predominant contributor to white matter pathology, but precise mechanistic details are not well understood. The involvement of neuronal storage deficits may extend beyond secondary demyelination (destruction of myelin due to axonal loss) and contribute to dysmyelinogenesis. Preclinical studies in animal models of the gangliosidoses have substantially improved lifespan and quality of life, leading to the initiation of several clinical trials. However, improvement of white matter pathology has lagged behind other metrics and few evidence-based explanations have been proposed to date. Research groups in the field are encouraged to include myelin-specific investigations in future gene therapy work to address this gap in knowledge.
登录
查看更多内容
影响因子：
12.4
作者：
Gray-Edwards, Heather L.;Regier, Debra S.;Martin, Douglas R.
通讯作者：
Martin, Douglas R.
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：
5.1
作者：
Broekman, M. L. D.;Tierney, L. A.;Sena-Esteves, M.
通讯作者：
Sena-Esteves, M.
影响因子：
1.9
作者：
Baek, Rena C.;Martin, Douglas R.;Cox, Nancy R.;Seyfried, Thomas N.
通讯作者：
Seyfried, Thomas N.
影响因子：
1.9
作者：
Folkerth, RD;Alroy, J;Kaye, EM
通讯作者：
Kaye, EM