Protic Dragana, Breeze Elizabeth, Mendoza Guadalupe, Zafarullah Marwa, Abbeduto Leonard, Hagerman Randi, Coffey Christopher, Cudkowicz Merit, Durbin-Johnson Blythe, Ashwood Paul, Berry-Kravis Elizabeth, Erickson Craig A, Filipink Robin, Gropman Andrea, Lehwald Lenora, Maxwell-Horn Angela, Morris Stephanie, Bennett Amanda Palladino, Prock Lisa, Talboy Amy, Tartaglia Nicole, Veenstra-VanderWeele Jeremy, Tassone Flora
Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology, and Toxicology, University of Belgrade, Belgrade, Serbia.
Fragile X Clinic, Special Hospital for Cerebral Palsy and Developmental Neurology, Belgrade, Serbia.
SAGE Open Med. 2024 Sep 29;12:20503121241282401. doi: 10.1177/20503121241282401. eCollection 2024.
Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3-6 years.
The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome.
A double-blind placebo-controlled parallel-group flexible-dose forced titration design.
Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels' detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected.
This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome.
Our findings of the lack of association between clinical improvement and biomarkers' levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints.
ClincalTrials.gov NCT02920892.
脆性X综合征的发病率约为男性1/4000至女性1/8000，是遗传性智力障碍最常见的遗传病因，也是自闭症谱系障碍最常见的单基因病因。脆性X信使核糖核蛋白1基因的完全突变以CGG三核苷酸重复序列的扩增（>200个CGG重复序列）为特征，可导致脆性X综合征。目前，尚无针对脆性X综合征的靶向治疗方法。在最近一项大型多中心试验FXLEARN中，研究了代谢型谷氨酸受体5负变构调节剂AFQ056（玛伐谷氨酸）的效果，但未显示AFQ056对3至6岁脆性X综合征儿童的语言发育有显著影响。
对FXLEARN研究中收集的生物样本进行的当前分析旨在确定AFQ056是否会影响脆性X综合征年轻个体中与Akt/mTOR和基质金属蛋白酶9信号传导相关的潜在生物标志物水平。先前的研究表明，这些生物标志物在脆性X综合征的病理生理学中起关键作用。
双盲安慰剂对照平行组灵活剂量强制滴定设计。
在FXLEARN研究的基线及后续访视（第1个月和第8个月访视）期间采集用于生物标志物检测的血样。生物标志物分析包括通过Southern印迹法和PCR方法进行脆性X信使核糖核蛋白1基因分型、通过PCR测定脆性X信使核糖核蛋白1 mRNA水平、使用磁珠板检测基质金属蛋白酶9水平以及检测Akt/mTOR信号通路的靶点及其磷酸化水平。
本研究表明，给予AFQ056不会影响脆性X综合征幼儿中所研究血生物标志物的表达水平。
我们关于治疗组临床改善与生物标志物水平之间缺乏关联的研究结果与FXLEARN研究中观察到的未获益处相符。这些结果表明，按照主要或次要终点评估，AFQ056未带来益处。
ClinicalTrials.gov NCT02920892
