Cerebral adrenoleukodystrophy (CALD) is a rare metabolic disorder in which rapid and progressive inflammatory demyelination leads to irreversible loss of neurologic function and death. There is no approved treatment for CALD, although Lenti-D Drug Product (DP) is in development as an autologous hematopoietic stem cell (HSC) gene therapy. We have previously shown promising results from the ALD-102 clinical study of the safety and efficacy of Lenti-D DP in boys ≤17 years old with CALD; based on data from 29 patients, Lenti-D DP was generally safe and led to stabilization of disease progression.

The primary efficacy endpoint in ALD-102 is the proportion of patients who are alive and free of major functional disabilities (MFD) at Month 24. The primary safety endpoint is the proportion of patients who experience acute (≥Grade 2) or chronic graft-versus-host disease (GVHD) by Month 24.

ALD-102 has completed enrollment, with 32 boys having received Lenti-D DP as of April 2019. The median DP cell dose was 11.4 (min - max, 5.0 - 20.1) × 10⁶ CD34 cells/kg; median DP vector copy number was 1.2 (min - max, 0.5 - 2.7) copies/diploid genome. Median day of neutrophil and platelet engraftment was 13.0 days (min-max, 11.0 - 41.0) and 32.0 days (min - max, 16.0 - 60.0), respectively. The median follow-up time for the cohort of 32 patients is 21.2 months (min - max, 0.0 – 60.2). Fifteen patients have completed 24 months of follow-up in ALD-102 and continue to be free of major functional disabilities (MFD) through their last follow-up in a long-term extension study. Fourteen patients remain in ALD-102; the longest follow-up among these patients is 20.4 months. Two patients were withdrawn and referred for allo-HSCT before their Month 24 visit; another experienced early and rapid disease progression while on-study resulting in MFDs and death. All other Lenti-D DP-treated patients showed stabilization of neurologic function score at their last follow-up (stable NFS was defined as NFS ≤4 without a change of >3 from baseline). There have been no reports of graft failure, GVHD, or transplant-related mortality; recorded adverse events are consistent with myeloablative conditioning. There is no evidence of replication competent lentivirus or insertional oncogenesis.

Lenti-D DP appears to stabilize neurologic disease progression and continues to show favorable safety with the longest follow-up at 60.2 months. Additional follow-up is ongoing to assess durability of effects and long-term safety.

脑肾上腺白质营养不良（CALD）是一种罕见的代谢异常，其中快速和进行性炎症性脱髓鞘导致神经功能不可逆转的丧失和死亡。尽管Lenti-D药品（DP）作为一种自体造血干细胞（HSC）基因疗法正在开发中，但尚未批准CALD的治疗方法。先前我们从ALD-102临床研究中获得了关于Lenti-D DP在CALD≤17岁的男孩中的安全性和有效性的令人鼓舞的结果；根据来自29位患者的数据，Lenti-D DP通常是安全的，可稳定疾病进展。

ALD-102的主要疗效终点是在第24个月活着且没有重大功能障碍（MFD）的患者比例。主要安全终点是经历了急性（≥2级）或慢性移植-对宿主疾病（GVHD）在第24个月之前。

ALD-102已完成注册，截至2019年4月，已有32名男孩接受了Lenti-DDP。DP细胞的中位剂量为11.4（min-max，5.0-20.1）×10 ⁶CD34细胞/ kg；DP载体拷贝数的中位数为1.2（最小-最大，0.5-2.7）拷贝/二倍体基因组。中性粒细胞和血小板植入的中位数天分别为13.0天（最小-最大，11.0-41.0）和32.0天（最小-最大，16.0-60.0）。该队列32位患者的中位随访时间为21.2个月（最小-最大，0.0-60.2）。15名患者在ALD-102中完成了24个月的随访，并且在他们的一项长期延伸研究中，通过最后一次随访，他们仍然没有重大功能障碍（MFD）。ALD-102中留有14例患者。这些患者中最长的随访时间为20.4个月。两名患者在第24个月就诊前退出并接受了allo-HSCT；另一位在研究过程中经历了疾病的快速早期发展，导致MFD和死亡。所有其他接受Lenti-D DP治疗的患者在最后一次随访时均显示神经功能评分稳定（稳定NFS定义为NFS≤4，与基线相比变化不大于3）。没有关于移植失败，GVHD或移植相关死亡率的报道；记录的不良事件与清髓条件一致。没有证据表明有复制能力的慢病毒或插入的肿瘤发生。

Lenti-D DP似乎可以稳定神经系统疾病的进展，并在持续最长的60.2个月随访中显示出良好的安全性。正在进行进一步的随访，以评估效果的持久性和长期安全性。