Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel and University of Basel, Petersgraben 4, 4031, Basel, Switzerland.
School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK.
Orphanet J Rare Dis. 2021 Jan 6;16(1):19. doi: 10.1186/s13023-020-01655-7.
Rett syndrome (RS) is a severe neurodevelopmental disorder for which there is no approved therapy. This study aimed to assess safety and efficacy of oral fingolimod in children with RS using a pre-post and case-control design.
At the University of Basel Children's Hospital, Basel, Switzerland, children with RS were included if they were older than 6 years and met the established diagnostic criteria of RS, including a positive MeCP2 mutation. Participants were observed 6 months before and after treatment and received 12 months of fingolimod treatment. Serum samples of 50 children without RS served as reference for brain-derived neurotrophic factor (BDNF) measurements. Primary outcome measures were safety and efficacy, the latter measured by change in levels of BDNF in serum/CSF (cerebrospinal fluid) and change in deep gray matter volumes measured by magnetic resonance imaging (MRI). Secondary outcome measure was efficacy measured by change in clinical scores [Vineland Adaptive Behaviour Scale (VABS), Rett Severity Scale (RSSS) and Hand Apraxia Scale (HAS)].
Six children with RS (all girls, mean and SD age 11.3 ± 3.1 years) were included. Serum samples of 50 children without RS (25 females, mean and SD age 13.5 ± 3.9 years) served as reference for BDNF measurements. No serious adverse events occurred. Primary and secondary outcome measures were not met. CSF BDNF levels were associated with all clinical scores: RSSS (estimate - 0.04, mult.effect 0.96, CI [0.94; 0.98], p = 0.03), HAS (estimate - 0.09, mult.effect 0.91, CI [0.89; 0.94], p < 0.01) and VABS (communication: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/daily living: estimate 0.03, mult.effect 1.03, CI [1.02; 1.04], p < 0.01/social skills: estimate 0.07, mult.effect 1.08, CI [1.05; 1.11], p < 0.01/motoric skills: estimate 0.04, mult.effect 1.04, CI [1.03; 1.06], p = 0.02).
In children with RS, treatment with fingolimod was safe. The study did not provide supportive evidence for an effect of fingolimod on clinical, laboratory, and imaging measures. CSF BDNF levels were associated with clinical scores, indicating a need to further evaluate its potential as a biomarker for RS. This finding should be further validated in independent patient groups.
Clinical Trials.gov NCT02061137, registered on August 27th 2013, https://clinicaltrials.gov/ct2/show/study/NCT02061137 .
雷特综合征（RS）是一种严重的神经发育障碍，目前尚无批准的治疗方法。本研究旨在采用前后对照和病例对照设计评估口服芬戈莫德在 RS 儿童中的安全性和疗效。
在瑞士巴塞尔大学儿童医院，纳入年龄大于 6 岁且符合 RS 既定诊断标准（包括 MeCP2 突变阳性）的 RS 儿童。在治疗前和治疗后 6 个月对患者进行观察，并接受 12 个月的芬戈莫德治疗。50 名无 RS 儿童的血清样本作为脑源性神经营养因子（BDNF）测量的参考。主要终点是安全性和疗效，后者通过血清/脑脊液（CSF）中 BDNF 水平的变化和磁共振成像（MRI）测量的深部灰质体积的变化来衡量。次要终点是通过临床评分的变化来衡量疗效[适应行为量表（VABS）、雷特严重程度量表（RSSS）和手部失用症量表（HAS）]。
纳入了 6 名 RS 儿童（均为女性，平均年龄 11.3 ± 3.1 岁）。50 名无 RS 儿童（25 名女性，平均年龄 13.5 ± 3.9 岁）的血清样本用于 BDNF 测量。未发生严重不良事件。主要和次要终点均未达到。CSF BDNF 水平与所有临床评分相关：RSSS（估计值-0.04，多元效应 0.96，CI [0.94；0.98]，p=0.03）、HAS（估计值-0.09，多元效应 0.91，CI [0.89；0.94]，p<0.01）和 VABS（沟通：估计值 0.03，多元效应 1.03，CI [1.02；1.04]，p<0.01/日常生活：估计值 0.03，多元效应 1.03，CI [1.02；1.04]，p<0.01/社交技能：估计值 0.07，多元效应 1.08，CI [1.05；1.11]，p<0.01/运动技能：估计值 0.04，多元效应 1.04，CI [1.03；1.06]，p=0.02）。
在 RS 儿童中，芬戈莫德治疗是安全的。该研究未提供芬戈莫德对临床、实验室和影像学测量有疗效的支持证据。CSF BDNF 水平与临床评分相关，表明需要进一步评估其作为 RS 潜在生物标志物的潜力。这一发现应在独立的患者群体中进一步验证。
ClinicalTrials.gov NCT02061137，于 2013 年 8 月 27 日注册，https://clinicaltrials.gov/ct2/show/study/NCT02061137。
