TY - JOUR
T1 - Blood‐based biomarkers predictive of metformin target engagement in fragile X syndrome
AU - Jasoliya, Mittal
AU - Bowling, Heather
AU - Petrasic, Ignacio Cortina
AU - Durbin‐johnson, Blythe
AU - Klann, Eric
AU - Bhattacharya, Aditi
AU - Hagerman, Randi
AU - Tassone, Flora
PY - 2020/6
Y1 - 2020/6
N2 - Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self‐reported improvement in clinical phenotypes (CGI‐I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.
AB - Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self‐reported improvement in clinical phenotypes (CGI‐I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.
KW - Biomarker
KW - Fragile‐X syndrome
KW - Metformin
KW - MMP9
KW - RAS
UR - http://www.scopus.com/inward/record.url?scp=85088607209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088607209&partnerID=8YFLogxK
U2 - 10.3390/brainsci10060361
DO - 10.3390/brainsci10060361
M3 - Article
AN - SCOPUS:85088607209
VL - 10
SP - 1
EP - 12
JO - Brain Sciences
JF - Brain Sciences
SN - 2076-3425
IS - 6
M1 - 361
ER -