Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome.

AFQ056 Fragile X syndrome MMP-9 biomarkers mTOR pathway

Journal

SAGE open medicine
ISSN: 2050-3121
Titre abrégé: SAGE Open Med
Pays: England
ID NLM: 101624744

Informations de publication

Date de publication:
2024
Historique:
received: 30 04 2024
accepted: 22 08 2024
medline: 1 11 2024
pubmed: 1 11 2024
entrez: 1 11 2024
Statut: epublish

Résumé

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.

Sections du résumé

Background UNASSIGNED
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 UNASSIGNED
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 UNASSIGNED
A double-blind placebo-controlled parallel-group flexible-dose forced titration design.
Methods UNASSIGNED
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 UNASSIGNED
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 UNASSIGNED
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.
Registration UNASSIGNED
ClincalTrials.gov NCT02920892.

Identifiants

DOI: 10.1177/20503121241282401 PMID: 39483619 PMC: PMC11526204
pubmed: 39483619
doi: 10.1177/20503121241282401
pii: 10.1177_20503121241282401
pmc: PMC11526204
doi:

Banques de données

ClinicalTrials.gov
['NCT02920892']

Types de publication

Journal Article

Langues

eng

Pagination

20503121241282401

Informations de copyright

© The Author(s) 2024.

Déclaration de conflit d'intérêts

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dragana Protic has received funding from The Science Fund of the Republic of Serbia and the FRAXA Research Foundation for carrying out studies on Fragile X Syndrome. Flora Tassone has received funding from Zynerba and Azrieli Foundation for carrying out studies on Fragile X Syndrome. Elizabeth Berry-Kravis has received funding from Acadia, Biogen, BioMarin, Erydel, GeneTx/Ultragenyx, Ionis, Jaguar, Kisbee, Neuren, Neurogene, Orphazyme/Kempharm/Zevra, PTC Therapeutics, Roche, Taysha, Tetra/Shionogi, Yamo, Zynerba, and Mallinckrodt Pharmaceuticals, for consulting or on clinical trials in genetic neurological disorders, all funds directed to Rush University Medical Center. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Auteurs

Dragana Protic (D)

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.
ORCID: 0000-0002-2137-5405

Elizabeth Breeze (E)

Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA.
MIND Institute, University of California Davis, Sacramento, CA, USA.

Guadalupe Mendoza (G)

Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, USA.

Marwa Zafarullah (M)

Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, USA.

Leonard Abbeduto (L)

MIND Institute, University of California Davis, Sacramento, CA, USA.
Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, CA, USA.

Randi Hagerman (R)

MIND Institute, University of California Davis, Sacramento, CA, USA.
Department of Pediatrics, University of California Davis, Sacramento, CA, USA.

Christopher Coffey (C)

Department of Biostatistics, University of Iowa, Iowa City, IA, USA.

Merit Cudkowicz (M)

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Blythe Durbin-Johnson (B)

Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, USA.

Paul Ashwood (P)

Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA.

Elizabeth Berry-Kravis (E)

Department of Pediatrics, Neurological Sciences, Anatomy, and Cell Biology, Rush University Medical Center, Chicago, IL, USA.

Craig A Erickson (CA)

Cincinnati Hospital and Medical Center, Cincinnati, OH, USA.

Robin Filipink (R)

Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Andrea Gropman (A)

Children's National Medical Center, Washington, DC, USA.

Lenora Lehwald (L)

Nationwide Children's Hospital, Columbus, OH, USA.

Angela Maxwell-Horn (A)

Vanderbilt University Medical Center, Nashville, TN, USA.

Stephanie Morris (S)

Washington University Medical Center, Saint Louis Children's Hospital, St. Louis, MO, USA.

Amanda Palladino Bennett (AP)

Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Lisa Prock (L)

Boston Children's Hospital, Boston, MA, USA.

Amy Talboy (A)

Emory University Medical Center, Atlanta, GA, USA.

Nicole Tartaglia (N)

Children's Hospital of Colorado, Denver, CO, USA.

Jeremy Veenstra-VanderWeele (J)

Center for Autism and the Developing Brain, New York-Presbyterian, New York, NY, USA.
Department of Psychiatry, Columbia University, New York, NY, USA.
New York State Psychiatric Institute, New York, NY, USA.

Flora Tassone (F)

MIND Institute, University of California Davis, Sacramento, CA, USA.
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, USA.

Classifications MeSH