脑肾上腺白质营养不良症(CALD)是一种罕见的进行性遗传性脑部疾病，主要发生在男孩身上，可导致神经功能丧失，最终导致早期死亡。

Cerebral adrenoleukodystrophy (CALD) is a rare progressive, genetic brain disease that primarily presents in boys, causing loss of neurological function and ultimately leading to early death.

麻省总医院(Massachusetts General Hospital)和波士顿儿童医院(Boston Children’s Hospital)的研究人员报道，在接受首个批准用于CALD的基因疗法治疗6年后，94%的患者神经功能没有下降，超过80%的患者没有出现重大残疾。

Researchers from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, Boston Children's Hospital, and collaborators have shown that six years after treatment with the first gene therapy approved for CALD, 94 percent of patients have had no decline in neurological functioning, with over 80 percent remaining free of major disability.

发表在《新英格兰医学杂志》(New England Journal of Medicine)上的两篇文章描述了接受这种基因疗法的患者的长期疗效，同时也强调了治疗后出现白血病的安全性问题。

Findings, published in two articles in the New England Journal of Medicine, describe long-term outcomes in those treated with the eli-cel gene therapy, while also highlighting safety concerns about the emergence of blood cancers post-treatment.

“大脑肾上腺白质营养不良症是一种毁灭性的脑部疾病，会在儿童的童年和发育的黄金时期累及儿童，”马萨诸塞州总医院神经内科白质营养不良症诊所主任、这篇关于长期结果的论文的第一作者Florian Eichler医学博士说。

"Cerebral adrenoleukodystrophy is a devastating brain disease that strikes children in the prime of their childhood and development," said Florian Eichler, MD, director of the Leukodystrophy Clinic in the Department of Neurology at Massachusetts General Hospital, first author of the paper on long-term outcomes.

“当我最初开始治疗CALD患者时，80%来到我们诊所的患儿面临死亡，而现在这个比例已经翻转了。

"When I initially began treating patients with CALD, 80 percent came into our clinic on death's door, and now the ratio has flipped.

我们谨慎地庆祝我们已经能够稳定这种神经系统疾病并让这些男孩重新过上充实的生活，但是我们在这些病人的一部分中看到了恶性肿瘤，这一事实又使我们的快乐大打折扣。

We cautiously celebrate that we have been able to stabilize this neurologic disease and give these boys back a fulfilling life, but that jubilation is dampened by the fact that we see malignancy in a subset of these patients.

这是我们正在积极尝试弄清和解决的问题。”

This is something that we are actively trying to understand and address."

2022年，美国食品和药物管理局批准了首个治疗CALD的基因疗法elivaldogene autotemcel (eli-cel)，由麻省总医院和波士顿儿童医院的研究人员进行了临床评估。

In 2022, the U.S. Food and Drug Administration approved the first gene therapy for CALD, elivaldogene autotemcel (eli-cel), which was clinically evaluated by the researchers from Mass General and Boston Children's Hospital.

在这项新研究中，32名患有早期CALD的3至13岁男孩接受了作为ALD-102试验的一部分的细胞治疗，该试验由开发该疗法的bluebird bio, Inc.公司发起。

In the new study, 32 boys aged 3 to 13 years with early-stage CALD received eli-cel as part of the ALD-102 trial, which was sponsored by bluebird bio, Inc., the company that developed the therapy.

该疗法使用Lenti-D慢病毒载体，向从患者体内取出的血液干细胞中添加ABCD1基因的健康拷贝，这种基因在CALD患者中是有缺陷的。

The therapy uses a Lenti-D lentiviral vector to add a healthy copy of the ABCD1 gene, which is faulty in those with CALD, to blood stem cells that have been removed from the patient.

然后通过自体造血干细胞移植(HSCT)将这些干细胞重新引入患者体内。

These stem cells are then reintroduced to the patient via an autologous hematopoietic stem cell transplantation (HSCT).

使用患者自身的细胞大大降低了移植物抗宿主病的风险，这是其他形式的治疗所带来的风险。

Using a patient's own cells substantially reduces the risk of graft-versus host disease-;a risk posed by other forms of treatment.

在ALD-102试验中，一名患者出现了骨髓增生异常综合征(MDS)，并伴有过多的原细胞，这是一种血液恶性肿瘤，似乎是由用于携带基因的Lenti-D慢病毒载体引发的。

In the ALD-102 trial, one patient developed a condition known as myelodysplastic syndrome (MDS) with excess blasts, a hematologic malignancy that appears to have been triggered by the Lenti-D lentiviral vector used to deliver the gene therapy.

在第二项更近期的细胞疗法(ALD-104)试验中，35名患者中有6名出现血液恶性肿瘤(5名MDS患者和1名急性髓系白血病患者)，这似乎也是由载体引起的。

In a second, more recent trial of the eli-cel therapy (ALD-104), six of 35 patients have developed a hematologic malignancy (MDS in five patients and acute myeloid leukemia in one) which appear to be also caused by the vector.

这些结果同期发表在该杂志。

These results were reported in a second paper published in the same volume of the journal.

第二个试验ALD-104的方案与第一个试验的不同之处是，它在HSCT期间使用了不同的化疗药物(氟达拉滨代替环磷酰胺)，以及其他可能导致第二个试验中白血病风险明显增加的变化。

The protocol for the second trial, ALD-104, differed from the first in that it uses a different chemotherapy drug during HSCT (fludarabine instead of cytoxan) and other changes that may have contributed to the apparent increase risk of leukemia in this second trial.

研究人员将继续研究血液恶性肿瘤的潜在原因，这是复杂的，尚未完全阐明。

The researchers will continue to study the potential causes of hematologic malignancy, which are complex and not yet fully elucidated.

改进慢病毒载体和改进CALD的造血干细胞移植方案是当务之急。

Improving lentiviral vectors and refining HSCT regimens for CALD are a high priority.

新生儿肾上腺脑白质营养不良筛查提高了早期发现CALD的可能性，这可能会增加识别可能受益于基因治疗的患者的机会，特别是那些缺乏匹配供体进行同种异体造血干细胞移植的患者。

With newborn screening for adrenoleukodystrophy improving the possibility of early detection of CALD, there may be expanded opportunities to identify patients who may benefit from gene therapy, especially those lacking matched donors for allogeneic HSCT.

波士顿儿童医院血液学/肿瘤学主任David a . Williams医学博士说:“作为一名临床医生和高级研究人员，见证我们在过去十年中与CALD的斗争中取得的重大进展确实令人鼓舞。”

"As both a clinician and senior investigator, it's truly inspiring to witness the significant strides we've made over the past decade in the fight against CALD," said David A. Williams, MD, chief of the Division of Hematology/Oncology at Boston Children's Hospital.

“虽然与基因疗法和载体技术相关的风险是真实存在的，但我们取得的进展为面临有限选择的家庭带来了希望。

"While the risks associated with gene therapy and vector technology are real, the progress we've made offers a source of hope for families facing limited options.

每一次进步都让我们更接近这些家庭迫切需要的答案。

Every advancement brings us closer to the answers these families desperately need.

我们致力于通过持续的研究来改进和提高载体的安全性，这一承诺坚定不移，因为我们不知疲倦地工作，以确保基因疗法治疗这种毁灭性疾病的长期安全性和有效性。

Our commitment to refining and improving the vector's safety by continued research remains unwavering, as we work tirelessly to ensure the long-term safety and efficacy of gene therapy treatments for this devasting disease.

这些努力包括世界各地的研究者，目前正在进行中。”

These efforts include multiple investigators world-wide and are underway."

Journal references:

Eichler, F., et al. (2024) Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy. New England Journal of Medicine. DOI: 10.1056/NEJMoa2400442

Duncan, C. N., et al. (2024) Hematologic Malignancy After Gene Therapy for Cerebral Adrenoleukodystrophy. New England Journal of Medicine. DOI: 10.1056/NEJMoa2405541