Krabbe disease successfully treated via monotherapy of intrathecal gene therapy
Krabbe disease successfully treated via monotherapy of intrathecal gene therapy
复制标题
DOI：
10.1172/jci133953
复制
发表时间：
2020-09-01
影响因子：
15.9
通讯作者：
Vite, Charles H.
中科院分区：
文献类型：
--
作者：
Bradbury, Allison M.;Bagel, Jessica H.;Vite, Charles H.
球样细胞脑白质营养不良（GLD;克拉伯病）是一种进行性、不可治愈的神经退行性疾病，由水解酶半乳糖神经酰胺酶（GALC）活性不足引起。精神病碱的随后细胞毒性积累导致弥漫性中枢和外周神经系统（CNS，PNS）脱髓鞘。症状前造血干细胞移植（HSCT）是治疗难治性GLD的唯一方法;然而，HSCT受者的临床结局通常较差，且手术相关的发病率较高。对于有症状的患者没有有效的治疗方法。在本文中，我们证明了在天然存在的GLD犬模型中，将编码犬GALC的鞘内AAV 9施用到小脑延髓池中的症状前单一疗法增加了CNS和PNS中的GALC酶活性，使精神病肽浓度正常化，改善了髓鞘形成并减弱了炎症。此外，AAV介导的治疗成功地预防了临床神经功能障碍，使治疗犬的寿命超过2.5岁，是未治疗犬的7倍多。此外，我们发现低5倍的剂量导致疾病的减弱形式，这表明足够的剂量是至关重要的。最后，使用高剂量AAV 9的症状后治疗也显著延长了寿命，这意味着HSCT不适用的患者的治疗选择。如果这些发现可以应用于患者，将改善术前或术后治疗患者的结局。
Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically.