本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2307952

摘要内容如下：

背景

巨轴索神经病是一种罕见的常染色体隐性遗传、儿童、多症状、神经退行性疾病，由GAN（编码Gigaxonin的基因）的双等位基因功能缺失变异引起。

方法

我们在患有巨大轴突神经病的儿童中进行了scAAV9/Jet-GAN（一种基于自身互补腺相关病毒的基因疗法，含有GAN转基因）的鞘内剂量递增研究。安全性是主要终点。关键的次要临床终点是，与治疗前的斜率相比，治疗后1年的32项运动功能测量总百分比评分的变化率（即斜率）至少有95%的后验概率变慢。

结果

对14名参与者（3.5×1013总载体基因组（VG）（2名参与者）、1.2×1014 VG（4名参与者）、1.8×1014 VG（5名参与者）和3.5×1014 VG（3名参与者））给予四种鞘内剂量中的一种scAAV9/Jet-GAN。在68.7个月（范围8.6至90.5个月）的中位观察期内，发生的48例严重不良事件中，1例（发热）可能与治疗有关；682例不良事件中有129例可能与治疗有关。整个队列的平均治疗前斜率为每年-7.17个百分点（95%可信区间，-8.36至-5.97）。治疗后1年，3.5×1013-VG剂量的后验平均斜率变化为-0.54个百分点（95%可信区间，-7.48至6.28），1.2×1014-VG剂量的后验平均斜率变化为3.23个百分点（95%可信区间，-1.27至7.65），1.8×1014-VG剂量的后验平均斜率变化为5.32个百分点（95%可信区间，1.07至9.57），3.43个百分点（95%可信区间，-1.89至8.82），剂量为3.5×1014-VG。减缓斜率的相应后验概率为44%（95%可信区间，43至44）；92%（95%可信区间，92至93）；99%（95%可信区间，99至99），高于疗效阈值；和90%（95%可信区间，89至90）。在基因转移后6至24个月之间，6名参与者的感觉神经动作电位振幅增加、停止下降或在缺失后变得可记录，但8名参与者仍然缺失。

结论

鞘内基因转移和scAAV9/Jet-Gan治疗巨大轴索神经病与不良事件相关，并且在一年内的某些载体剂量下，可能在运动功能评分和其他指标方面产生益处。需要进一步的研究来确定鞘内AAV介导的基因治疗这种疾病的安全性和有效性。（由国家神经疾病和中风研究所等资助；ClinicalTrials.gov编号，NCT02362438。）

英文原文如下：

Abstracts

BACKGROUND  Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin.

METHODS  We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope.

RESULTS  One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8.

CONCLUSIONS  Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

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