Abstract：
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder that leads to progressive neurodegeneration in brain and spinal cord. The most devastating phenotype of childhood cerebral ALD can be halted by allogeneic hematopoietic stem cell transplantation but the procedure remains cumbersome and limited by engraftment problems and graft versus host disease. This is particularly difficult for boys with more advanced brain lesions and neurologic impairment. Fortunately, newborn screening has led to regular monitoring and increased detection of cerebral ALD in early symptomatic or asymptomatic stages. Adults with ALD can also develop cerebral ALD but here implementation of HSCT is more challenging due to vulnerabilities not seen in childhood cerebral ALD. More recently the hematopoietic stem cell approach has given rise to a first ex vivo lentiviral gene therapy for this rare disorder. Over 60 boys with cerebral ALD have received ex vivo lentiviral gene therapy worldwide. While the approach is effective in halting progression of early-stage inflammatory demyelination in brain and prevents engraft problems and graft versus host disease, there have also been cases of myelodysplastic syndrome emerging. In September of 2022, the FDA granted accelerated approval of ex vivo lentiviral gene therapy to slow the progression of neurologic dysfunction in boys 4-17years of age with early, active cerebral ALD. We describe the history of these developments, outline the pathophysiology of the disorder and the corresponding rationale of hematopoietic stem cell therapy as well as current developments in the field.
摘要：
X连锁肾上腺脑白质营养不良（ALD）是一种过氧化物酶体疾病，可导致脑和脊髓进行性神经变性。儿童大脑ALD最具破坏性的表型可以通过异基因造血干细胞移植来停止，但该程序仍然繁琐且受移植问题和移植物抗宿主疾病的限制。对于患有更晚期脑损伤和神经系统损害的男孩来说，这尤其困难。幸运的是,新生儿筛查导致在早期有症状或无症状阶段进行定期监测并增加对脑ALD的检测.患有ALD的成年人也可以发展为脑ALD，但是由于儿童脑ALD中未发现的漏洞，因此HSCT的实施更具挑战性。最近，造血干细胞方法已经产生了针对这种罕见疾病的第一个离体慢病毒基因疗法。超过60名患有脑ALD的男孩在全球范围内接受了离体慢病毒基因疗法。虽然该方法可有效阻止大脑早期炎症性脱髓鞘的进展，并可预防移植问题和移植物抗宿主病，也有出现骨髓增生异常综合征的病例.2022年9月，FDA批准了体外慢病毒基因疗法的加速批准，以减缓4-17岁男孩的神经功能障碍的进展。活跃的大脑ALD。我们描述了这些发展的历史，概述该疾病的病理生理学和造血干细胞治疗的相应原理以及该领域的最新发展。
