Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome
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 prepondera...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | Brain Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3425/10/6/361 |
| _version_ | 1797565648206823424 |
|---|---|
| author | Mittal Jasoliya Heather Bowling Ignacio Cortina Petrasic Blythe Durbin-Johnson Eric Klann Aditi Bhattacharya Randi Hagerman Flora Tassone |
| author_facet | Mittal Jasoliya Heather Bowling Ignacio Cortina Petrasic Blythe Durbin-Johnson Eric Klann Aditi Bhattacharya Randi Hagerman Flora Tassone |
| author_sort | Mittal Jasoliya |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:16:05Z |
| format | Article |
| id | doaj.art-7707f20da0274d9a9d7011c04f65cfcf |
| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-10T19:16:05Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Brain Sciences |
| spelling | doaj.art-7707f20da0274d9a9d7011c04f65cfcf2023-11-20T03:23:23ZengMDPI AGBrain Sciences2076-34252020-06-0110636110.3390/brainsci10060361Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X SyndromeMittal Jasoliya0Heather Bowling1Ignacio Cortina Petrasic2Blythe Durbin-Johnson3Eric Klann4Aditi Bhattacharya5Randi Hagerman6Flora Tassone7Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USACenter for Neural Science, New York University, New York, NY 10003, USAMIND Institute, University of California, Davis, Sacramento, CA 95817, USADepartment of Public Health Sciences, University of California, Davis, Davis, CA 95616, USACenter for Neural Science, New York University, New York, NY 10003, USACenter for Brain Development and Repair, Institute of Stem Cell Science and Regenerative Medicine, Bangalore 560065, IndiaMIND Institute, University of California, Davis, Sacramento, CA 95817, USADepartment of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA 95817, USARecent 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.https://www.mdpi.com/2076-3425/10/6/361biomarkerMMP9RASmetforminFragile-X syndrome |
| spellingShingle | Mittal Jasoliya Heather Bowling Ignacio Cortina Petrasic Blythe Durbin-Johnson Eric Klann Aditi Bhattacharya Randi Hagerman Flora Tassone Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome Brain Sciences biomarker MMP9 RAS metformin Fragile-X syndrome |
| title | Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome |
| title_full | Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome |
| title_fullStr | Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome |
| title_full_unstemmed | Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome |
| title_short | Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome |
| title_sort | blood based biomarkers predictive of metformin target engagement in fragile x syndrome |
| topic | biomarker MMP9 RAS metformin Fragile-X syndrome |
| url | https://www.mdpi.com/2076-3425/10/6/361 |
| work_keys_str_mv | AT mittaljasoliya bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT heatherbowling bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT ignaciocortinapetrasic bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT blythedurbinjohnson bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT ericklann bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT aditibhattacharya bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT randihagerman bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome AT floratassone bloodbasedbiomarkerspredictiveofmetformintargetengagementinfragilexsyndrome |