异染性白质营养不良
白质营养不良
医学
遗传增强
肾上腺脑白质营养不良
移植
造血干细胞移植
白质脑病
疾病
儿科
生物信息学
重症监护医学
内科学
病理
生物
遗传学
基因
受体
过氧化物酶体
作者
Allison M. Bradbury,Margie Ream
标识
DOI:10.1016/j.spen.2021.100876
摘要
Leukodystrophies and genetic leukoencephalopathies comprise a growing group of inherited white matter disorders. Diagnostic rates have improved with increased utilization of next generation sequencing. As treatment options continue to advance for leukodystrophies, so will candidacy for inclusion in the United States' newborn Recommended Universal Screening Panel as was achieved for X-linked adrenoleukodystrophy. Stem cell therapies have become standard of care for selected leukodystrophies. However, transplantation-related risks remain high and outcomes are not fully satisfactory. Transduction of autologous hematopoietic stem cells with lentiviral vectors, referred to as ex vivo gene therapy, circumvents some, but not all, of the risks of traditional transplantation and has recently been demonstrated to be safe and efficective in clinical studies of X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Gene therapy, through direct infusion of adeno-associated virus vectors, has emerged as a safer alternative for many monogenetic pediatric neurological disorders. Numerous preclinical studies have shown safety and efficacy of adeno-associated virus gene therapy in leukodystrophies allowing expanded access treatment for Canavan disease prior to initiation of a clinical trial. For inherited white matter disorders resulting from overexpression of a protein, such as Pelizaeus-Merzbacher disease, emerging RNA therapies have shown success in preclinical studies and promise for rapid translation to the clinic. Lastly, small molecule and protein therapies remain a long-term treatment option for a number of leukodystrophies, including intrathecal enzyme replacement therapy for metachromatic leukodystrophy. Herein we review recent advances in diagnosis and treatment of inherited white matter disorders.
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