Empagliflozin Repurposing for Lafora Disease: A Pilot Clinical Trial and Preclinical Investigation of Novel Therapeutic Targets
Abstract
1. Introduction
2. Experimental Design
2.1. Study Design and Setting
2.2. Eligibility Criteria
- Documented genetic diagnosis of LD (pathogenic mutations in the EPM2A or EPM2B genes);
- Age: 10–22 years;
- Patient able to understand and complete the protocol (even with the help of a caregiver over 18 years of age) and perform neuropsychological tests.
- Undocumented genetic diagnosis of LD;
- Advanced stage of disease (3–4 progression scale) [32];
- Participation in other ongoing therapeutic treatments for LD;
- Pregnancy;
- Allergy or known hypersensitivity to empagliflozin;
- Other conditions, at the discretion of the investigator, that could interfere with participation or completion of the study.
2.3. Discontinuation of Interventions
2.4. Sample Size
2.5. Data Collection and Management
2.6. Statistical Methods
2.7. In Silico Studies on Target Candidates
2.8. Validation in Cell Lines
3. Procedure
3.1. Recruitment
3.2. Intervention Description
3.3. Participant Timeline
3.4. Outcomes
- Safety: Type, severity, incidence, and timing of adverse events; incidence of treatment discontinuation due to adverse events; and changes in vital signs, ECG, and laboratory parameters.
- Efficacy: Change in the frequency of generalized tonic–clonic seizures compared to the 6 months prior to the study; EEG: changes in posterior background activity and frequency of epileptiform abnormalities; cognitive function: changes (no worsening or improvement) in neuropsychological assessments; motor function: changes (no worsening or improvement) in motor function assessments; global function and autonomy: changes (no worsening or improvement) in LDS, LESS, ADL, IADL, Barthel Index, Vineland-II, and CGI-I and PGI-CaGI-C scales.
- Biomarkers: Brain FDG-PET: changes (no worsening) in areas of cerebral hypometabolism. High-field brain MRI (3 Tesla): changes (no worsening) in measures of cerebral atrophy. Direct measurement of CSF polyglucosan levels, although potentially informative, is not feasible within the constraints of this pilot study. Thus, brain FDG-PET imaging is included as a surrogate biomarker to assess changes in cerebral metabolism. This choice was primarily due to the significant logistical challenges associated with sample collection and processing for this ultra-rare disease, as well as to the absence of widely available, fully validated assays for the quantitative analysis of CSF polyglucosan levels.
3.5. Ethics and Dissemination
3.5.1. Ethics Approval and Consent to Participate
3.5.2. Competing Interest
3.5.3. Protocol Amendments
3.5.4. Confidentiality
3.5.5. Access to Data
3.5.6. Dissemination Policy
3.6. In Silico Screening
3.7. In Vitro Cell Models Assays
4. Expected Results
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
LD | Lafora disease; |
LBs | Lafora bodies; |
AILA | Italian Lafora Association; |
AMPK | AMP-activated protein kinase; |
rhGAA | Recombinant human α-glucosidase; |
SGLT2 | Sodium-glucose cotransporter 2; |
EEG | Electroencephalogram; |
GLUT1 | Glucose transporter type 1; |
GLUT3 | Glucose transporter type 3; |
GSD | Glycogen storage disorder; |
LESS | Lafora Epilepsy Severity Scale; |
ADL | Activities of Daily Living; |
IADL | Instrumental Activities of Daily Living; |
LDS | Lafora Disease Performance Scale. |
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d’Orsi, G.; Liantonio, A.; Imbrici, P.; Gambacorta, N.; Dinoi, G.; Altomare, C.D.; DEFEAT-LD Study Group; Carella, M. Empagliflozin Repurposing for Lafora Disease: A Pilot Clinical Trial and Preclinical Investigation of Novel Therapeutic Targets. Methods Protoc. 2025, 8, 48. https://doi.org/10.3390/mps8030048
d’Orsi G, Liantonio A, Imbrici P, Gambacorta N, Dinoi G, Altomare CD, DEFEAT-LD Study Group, Carella M. Empagliflozin Repurposing for Lafora Disease: A Pilot Clinical Trial and Preclinical Investigation of Novel Therapeutic Targets. Methods and Protocols. 2025; 8(3):48. https://doi.org/10.3390/mps8030048
Chicago/Turabian Styled’Orsi, Giuseppe, Antonella Liantonio, Paola Imbrici, Nicola Gambacorta, Giorgia Dinoi, Cosimo Damiano Altomare, DEFEAT-LD Study Group, and Massimo Carella. 2025. "Empagliflozin Repurposing for Lafora Disease: A Pilot Clinical Trial and Preclinical Investigation of Novel Therapeutic Targets" Methods and Protocols 8, no. 3: 48. https://doi.org/10.3390/mps8030048
APA Styled’Orsi, G., Liantonio, A., Imbrici, P., Gambacorta, N., Dinoi, G., Altomare, C. D., DEFEAT-LD Study Group, & Carella, M. (2025). Empagliflozin Repurposing for Lafora Disease: A Pilot Clinical Trial and Preclinical Investigation of Novel Therapeutic Targets. Methods and Protocols, 8(3), 48. https://doi.org/10.3390/mps8030048