Adrenoleukodystrophy (ALD) is an X-linked, potentially fatal peroxisome disease, characterized by three main clinical phenotypes: adrenomyeloneuropathy (AMN), cerebral adrenoleukodystrophy (CALD), and primary adrenal insufficiency. The clinical phenotypes of ALD are unpredictable, with no genotype-phenotype correlation, and disease progression cannot be predicted based on very long chain fatty acid (VLCFA) levels in plasma. Additionally, the phenotypes can exhibit significant variability. Currently, no definitive treatment for this disease exists, and treatment options vary depending on the specific phenotypes. For AMN, only symptomatic supportive treatment is available. However, early CALD can be stabilized through allogeneic hematopoietic stem cell transplantation (allo-HSCT) and transgenic autologous hematopoietic stem cell transplantation (trans-ASCT), and primary adrenal insufficiency can be treated through hormone replacement therapy. Allo-HSCT and trans-ASCT can prevent the progression of early CALD, but cannot reverse the changes of AMN or halt the progression of adrenal insufficiency. Furthermore, they cannot prevent neurological dysfunction or death in terminal CALD. In recent years, multiple clinical trials of drugs targeting ALD have demonstrated therapeutic potential for ALD. Trans-ASCT and gene editing therapy have also made breakthroughs in animal models and clinical trials, providing alternative options for ALD patients ineligible for allo-HSCT treatment. This paper reviews the latest therapeutic research results of ALD and provides a basis for clinical practice.
LIU Xiaoli, CAO Li. Advances in the treatment of adrenoleukodystrophy. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2025, 45(1): 95-100 doi:10.3969/j.issn.1674-8115.2025.01.011
肾上腺脑白质营养不良（adrenoleukodystrophy，ALD）呈X连锁遗传，因ATP结合盒转运蛋白亚家族D成员1（ATP-binding cassette transporters sub-family D member 1，ABCD1）基因突变后导致器官和血浆中极长链脂肪酸（very long chain fatty acid，VLCFA）累积并引起一系列表型，主要包括脑型肾上腺脑白质营养不良（cerebral adrenoleukodystrophy，CALD）、肾上腺脊髓神经病（adrenomyeloneuropathy，AMN）和原发性肾上腺功能不全（primary adrenal insufficiency），出生发病率为1/14 700［1］。
虽然allo-HSCT治疗早期CALD可以稳定患者的神经功能并提高其生存率，但也有相关风险。接受allo-HSCT治疗后的总体死亡率在儿童中约为20%，成人中约为40%［14］。死亡可能与疾病进展相关，但主要是移植相关并发症，如机会性感染、移植失败和移植物抗宿主病（graft versus host disease，GVHD）［5］。移植手术后脑脱髓鞘通常会继续延长12~18个月，然后停止进展。获益的延迟与从骨髓来源的细胞缓慢替代脑小胶质细胞有关。移植后神经系统功能障碍的进展取决于治疗前头颅MRI表现和症状［5，15］。移植相关的安全性结果也受到移植相关特征的影响，包括供体类型、来源和预处理方案等。HLA相合无关供者造血干细胞移植的移植失败发生率显著高于匹配的同胞供体［15］。
由于慢病毒的感染，在转基因治疗后存在发生插入突变的风险和诱发肿瘤事件，因此，安全性仍是体外慢病毒转基因治疗的一个主要问题［21］。2021年，美国食品与药品监督管理局（Food and Drug Administration，FDA）因患者出现了骨髓增生异常综合征而暂停了一项评估离体慢病毒trans-ASCT治疗（NCT03852498）效果和安全性的临床试验［22］。另一项评估自灭活慢病毒载体TYF-ABCD1纠正ALD相关ABCD1基因缺陷的安全性和效率的临床试验（NCT03727555）正在进行。较新的载体重组腺相关病毒（recombinant adeno-associated virus，rAAV）也在体外和体内成功地实现了Abcd1基因递送，使小鼠模型中大脑和脊椎的VLCFA比率正常化［23］。综上，trans-ASCT可能具有与allo-HSCT相似的潜在效果，但需要更长时间的随访和更大的样本量来证实慢病毒载体基因治疗的有效性和长期安全性。
PXL770是一种变构单磷酸腺苷激活蛋白激酶（AMP-activated protein kinase，AMPK）激活剂，可直接激活AMPK，改善Abcd1敲除小鼠的坐骨神经轴突形态［42］。2022年2月，美国FDA已授予PXL770（NCT03886103）药物研发与审评快速通道资格［43］，用于AMN患者的治疗。
LIU Xiaoli was responsible for drafting the initial version of the paper, while CAO Li reviewed it and provided guidance for the revision. Both authors have read the final version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
Both authors declare no relevant conflict of interests.
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... 由于慢病毒的感染，在转基因治疗后存在发生插入突变的风险和诱发肿瘤事件，因此，安全性仍是体外慢病毒转基因治疗的一个主要问题［21］.2021年，美国食品与药品监督管理局（Food and Drug Administration，FDA）因患者出现了骨髓增生异常综合征而暂停了一项评估离体慢病毒trans-ASCT治疗（NCT03852498）效果和安全性的临床试验［22］.另一项评估自灭活慢病毒载体TYF-ABCD1纠正ALD相关ABCD1基因缺陷的安全性和效率的临床试验（NCT03727555）正在进行.较新的载体重组腺相关病毒（recombinant adeno-associated virus，rAAV）也在体外和体内成功地实现了Abcd1基因递送，使小鼠模型中大脑和脊椎的VLCFA比率正常化［23］.综上，trans-ASCT可能具有与allo-HSCT相似的潜在效果，但需要更长时间的随访和更大的样本量来证实慢病毒载体基因治疗的有效性和长期安全性. ...
1
... 由于慢病毒的感染，在转基因治疗后存在发生插入突变的风险和诱发肿瘤事件，因此，安全性仍是体外慢病毒转基因治疗的一个主要问题［21］.2021年，美国食品与药品监督管理局（Food and Drug Administration，FDA）因患者出现了骨髓增生异常综合征而暂停了一项评估离体慢病毒trans-ASCT治疗（NCT03852498）效果和安全性的临床试验［22］.另一项评估自灭活慢病毒载体TYF-ABCD1纠正ALD相关ABCD1基因缺陷的安全性和效率的临床试验（NCT03727555）正在进行.较新的载体重组腺相关病毒（recombinant adeno-associated virus，rAAV）也在体外和体内成功地实现了Abcd1基因递送，使小鼠模型中大脑和脊椎的VLCFA比率正常化［23］.综上，trans-ASCT可能具有与allo-HSCT相似的潜在效果，但需要更长时间的随访和更大的样本量来证实慢病毒载体基因治疗的有效性和长期安全性. ...
1
... 由于慢病毒的感染，在转基因治疗后存在发生插入突变的风险和诱发肿瘤事件，因此，安全性仍是体外慢病毒转基因治疗的一个主要问题［21］.2021年，美国食品与药品监督管理局（Food and Drug Administration，FDA）因患者出现了骨髓增生异常综合征而暂停了一项评估离体慢病毒trans-ASCT治疗（NCT03852498）效果和安全性的临床试验［22］.另一项评估自灭活慢病毒载体TYF-ABCD1纠正ALD相关ABCD1基因缺陷的安全性和效率的临床试验（NCT03727555）正在进行.较新的载体重组腺相关病毒（recombinant adeno-associated virus，rAAV）也在体外和体内成功地实现了Abcd1基因递送，使小鼠模型中大脑和脊椎的VLCFA比率正常化［23］.综上，trans-ASCT可能具有与allo-HSCT相似的潜在效果，但需要更长时间的随访和更大的样本量来证实慢病毒载体基因治疗的有效性和长期安全性. ...
... PXL770是一种变构单磷酸腺苷激活蛋白激酶（AMP-activated protein kinase，AMPK）激活剂，可直接激活AMPK，改善Abcd1敲除小鼠的坐骨神经轴突形态［42］.2022年2月，美国FDA已授予PXL770（NCT03886103）药物研发与审评快速通道资格［43］，用于AMN患者的治疗. ...
1
... PXL770是一种变构单磷酸腺苷激活蛋白激酶（AMP-activated protein kinase，AMPK）激活剂，可直接激活AMPK，改善Abcd1敲除小鼠的坐骨神经轴突形态［42］.2022年2月，美国FDA已授予PXL770（NCT03886103）药物研发与审评快速通道资格［43］，用于AMN患者的治疗. ...
