Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.
Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.
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DOI：
10.1016/j.ymthe.2021.01.026
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发表时间：
2021-05-05
期刊：
影响因子：
--
通讯作者：
Bongarzone ER
中科院分区：
文献类型：
--
作者：
Heller GJ;Marshall MS;Issa Y;Marshall JN;Nguyen D;Rue E;Pathmasiri KC;Domowicz MS;van Breemen RB;Tai LM;Cologna SM;Crocker SJ;Givogri MI;Sands MS;Bongarzone ER
溶酶体酶半乳糖神经酰胺酶（GALC）的新生儿AAV 9基因治疗显著改善了Twitch小鼠的中枢和外周神经病理学、存活率，并在很大程度上使运动缺陷正常化。尽管有这些治疗里程碑，但新的观察发现，6-8个月后，大脑中存在多个小的局灶性脱髓鞘区域。这些病变与影响幼稚Twitch小鼠大脑的弥漫性、全局性脱髓鞘形成鲜明对比。迟发性病变表现出溶酶体改变，GALC表达减少，精神病碱水平升高。此外，我们发现病变与血浆纤维蛋白原外渗和纤维蛋白原-BMP-SMAD-GFAP胶质反应的激活密切相关。纤维蛋白原外渗与病变区域内血管紧密连接破坏相关。病变周围为正常外观的白色物质。我们的研究表明，治疗性GALC的失调可能是由病变内治疗性AAV附加体DNA的耗尽驱动的，与增殖的少突胶质细胞祖细胞和神经胶质细胞的存在平行。我们相信，这是第一次证明在溶酶体贮积病动物模型的脑中具有有害作用的AAV基因治疗载体的体内表达减少。这种表型的发展将GALC活性的局部丧失与经AAV基因治疗处理的Twitch小鼠的成年脑中的复发性神经病理学联系起来，鉴定并警告AAV功效可能的迟发性降低，并暗示其他遗传性脑白质营养不良。Heller及其同事证明了在新生儿AAV 9基因治疗GALC缺乏症后，Twitch小鼠成年脑中脱髓鞘病变的形成。病变缺乏治疗水平的AAV-GALC，并显示胶质溶酶体表型的复苏。他们的研究确定了使用AAV载体进行遗传性脑白质营养不良基因治疗的长期安全性，需要进一步改进。
Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6–8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice. Late-onset lesions exhibited lysosomal alterations with reduced expression of GALC and increased psychosine levels. Furthermore, we found that lesions were closely associated with the extravasation of plasma fibrinogen and activation of the fibrinogen-BMP-SMAD-GFAP gliotic response. Extravasation of fibrinogen correlated with tight junction disruptions of the vasculature within the lesioned areas. The lesions were surrounded by normal appearing white matter. Our study shows that the dysregulation of therapeutic GALC was likely driven by the exhaustion of therapeutic AAV episomal DNA within the lesions, paralleling the presence of proliferating oligodendrocyte progenitors and glia. We believe that this is the first demonstration of diminishing expression in vivo from an AAV gene therapy vector with detrimental effects in the brain of a lysosomal storage disease animal model. The development of this phenotype linking localized loss of GALC activity with relapsing neuropathology in the adult brain of neonatally AAV-gene therapy-treated Twitcher mice identifies and alerts to possible late-onset reductions of AAV efficacy, with implications to other genetic leukodystrophies. Heller and colleagues demonstrate the formation of demyelinating lesions in the adult brain of the Twitcher mouse, following neonatal AAV9 gene therapy for the treatment of GALC deficiency. Lesions lack therapeutic levels of AAV-GALC and show a resurgence of the gliotic lysosomal phenotype. Their study identifies long-term safety aspects of the use of AAV vectors for the gene therapy of genetic leukodystrophies in need of further improvement.
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影响因子：
6.4
作者：
Hu F;Ku MC;Markovic D;Dzaye O;Lehnardt S;Synowitz M;Wolf SA;Kettenmann H
通讯作者：
Kettenmann H
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
15.9
作者：
Bradbury, Allison M.;Bagel, Jessica H.;Vite, Charles H.
通讯作者：
Vite, Charles H.
DOI：
10.1073/pnas.1808064115
发表时间：
2018-12-11
影响因子：
11.1
作者：
Duncan, Ian D.;Radcliff, Abigail B.;Wierenga, Lauren A.
通讯作者：
Wierenga, Lauren A.
影响因子：
5.4
作者：
Afione, SA;Conrad, CK;Flotte, TR
通讯作者：
Flotte, TR