Dragana Protic, Elizabeth Breeze, Guadalupe Mendoza, Marwa Zafarullah, Leonard Abbeduto, Randi Hagerman, Christopher Coffey, Merit Cudkowicz, Blythe Durbin-Johnson, Paul Ashwood, Elizabeth Berry-Kravis, Craig A Erickson, Robin Filipink, Andrea Gropman, Lenora Lehwald, Angela Maxwell-Horn, Stephanie Morris, Amanda Palladino Bennett, Lisa Prock, Amy Talboy, Nicole Tartaglia, Jeremy Veenstra-VanderWeele, Flora Tassone
{"title":"用 mGluR5 负性异位调节剂 AFQ056 治疗对脆性 X 综合征年轻患者血液生物标志物的负面影响。","authors":"Dragana Protic, Elizabeth Breeze, Guadalupe Mendoza, Marwa Zafarullah, Leonard Abbeduto, Randi Hagerman, Christopher Coffey, Merit Cudkowicz, Blythe Durbin-Johnson, Paul Ashwood, Elizabeth Berry-Kravis, Craig A Erickson, Robin Filipink, Andrea Gropman, Lenora Lehwald, Angela Maxwell-Horn, Stephanie Morris, Amanda Palladino Bennett, Lisa Prock, Amy Talboy, Nicole Tartaglia, Jeremy Veenstra-VanderWeele, Flora Tassone","doi":"10.1177/20503121241282401","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Design: </strong>A double-blind placebo-controlled parallel-group flexible-dose forced titration design.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Registration: </strong>ClincalTrials.gov NCT02920892.</p>","PeriodicalId":21398,"journal":{"name":"SAGE Open Medicine","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526204/pdf/","citationCount":"0","resultStr":"{\"title\":\"Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome.\",\"authors\":\"Dragana Protic, Elizabeth Breeze, Guadalupe Mendoza, Marwa Zafarullah, Leonard Abbeduto, Randi Hagerman, Christopher Coffey, Merit Cudkowicz, Blythe Durbin-Johnson, Paul Ashwood, Elizabeth Berry-Kravis, Craig A Erickson, Robin Filipink, Andrea Gropman, Lenora Lehwald, Angela Maxwell-Horn, Stephanie Morris, Amanda Palladino Bennett, Lisa Prock, Amy Talboy, Nicole Tartaglia, Jeremy Veenstra-VanderWeele, Flora Tassone\",\"doi\":\"10.1177/20503121241282401\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Design: </strong>A double-blind placebo-controlled parallel-group flexible-dose forced titration design.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome.</p><p><strong>Conclusion: </strong>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. 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引用次数: 0
摘要
背景：脆性 X 综合征（Fragile X Syndrome）的发病率约为每 4000 名男性中 1 例，每 8000 名女性中 1 例，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 基因的全突变以 CGG 三核苷酸重复序列（>200 CGG 重复序列）的扩增为特征，会导致脆性 X 综合征。目前，还没有针对脆性 X 综合征的靶向治疗方法。在最近进行的一项名为FXLEARN的大型多点试验中，研究人员调查了mGluR5负异osteric调节剂AFQ056（mavoglurant）的效果，但并未发现AFQ056对3-6岁脆性X综合征儿童的语言发育有显著影响：目前对FXLEARN研究中收集的生物样本进行的分析旨在确定AFQ056是否会影响脆性X综合征患儿体内与Akt/mTOR和基质金属蛋白酶9信号转导相关的潜在生物标志物的水平。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着至关重要的作用：双盲安慰剂对照平行组灵活剂量强制滴定设计：方法：在FXLEARN期间，收集基线和后续访问（1个月和8个月访问）的血液样本以检测生物标志物。生物标志物分析包括通过 Southern 印迹和 PCR 方法进行脆性 X 信使核糖核蛋白-1 基因分型、通过 PCR 确定脆性 X 信使核糖核蛋白-1 mRNA 水平、使用磁珠面板检测基质金属蛋白酶 9 水平以及检测 Akt/mTOR 信号通路靶点的磷酸化水平：研究结果表明，服用AFQ056不会影响脆性X综合征患儿血液生物标志物的表达水平：结论：我们的研究结果表明，治疗组的临床改善与生物标志物水平之间缺乏关联，这与 FXLEARN 研究中观察到的治疗效果不一致。这些结果表明，根据主要或次要终点评估，AFQ056并不能带来益处：注册：ClincalTrials.gov NCT02920892。
Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome.
Background: 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.
Objectives: 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.
Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design.
Methods: 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.
Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome.
Conclusion: 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.
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