# Defining the therapeutic window for the treatment of Lafora Epilepsy

> **NIH NIH P01** · UNIVERSITY OF KENTUCKY · 2020 · $138,858

## Abstract

Lafora disease (LD) is an intractable fatal epilepsy with onset in teenage years. Our groups across this 
project discovered the genetic causes and disease mechanisms of LD. The LD genes, EPM2A and EPM2B, 
encode respectively the laforin glycogen phosphatase and the malin ubiquitin E3 ligase, which regulate glycogen 
synthesis, in particular its structure. The pathogenic pathology is the neuronal accumulation of poorly branched 
and insoluble glycogen, termed polyglucosan, into massive inclusions, Lafora bodies (LB), which drive the 
epilepsy. Polyglucosans, though malformed glycogen, are glycogen nonetheless, and only one enzyme 
generates glycogen strands, namely glycogen synthase (GS). 
 We showed in LD mouse models that 50-100% elimination of GS activity through GS knockout 
experiments rescues LD.  Several projects in this proposal leverage this discovery to devise a comprehensive 
approach towards therapy, ranging from genome editing of the GS gene to small molecule inhibition of the 
enzyme. It is anticipated that inhibiting glycogen synthesis will prevent further LB formation and stop disease 
progression. Since these patients are no sicker than regular epilepsy cases early in their course, stopping the 
disease will be tantamount to cure. But what about cases already in the throes of intractable seizures? It is not 
known whether LB are straight accumulations versus a net accumulation where clearance mechanisms are 
overwhelmed by the constant formation of new polyglucosans. If the latter is the case, inhibiting further 
polyglucosan generation may lead to disease reversal, i.e. would be effective even in advanced cases. 
 In Aim 1, we generate a mouse model in which the glycogen synthase 1 gene (Gys1), the muscle and 
brain isoform of GS, is deleted at various time points of the disease course in which LBs have already formed, 
and we analyze the progression or reversal of the phenotype histologically and by electrophysiological and 
behavioral experiments. In Aim 2, we  generate a mouse model in which only one allele of the Gys1 gene is 
deleted at various time points in which LBs have already formed to check whether a 50% inhibition would be 
sufficient to prevent/revert the progression of this condition. These two aims will specify the window of opportunity 
for therapeutic intervention in LD for therapies aimed at glycogen synthesis inhibition. In Aim 3 we answer 
another unknown, namely whether reintroducing the actual missing genes (EPM2A or EPM2B) in LD can arrest 
the disease, or reverse it. We generate an Epm2b-/- LD mouse in which we activate Epm2b expression in 
different phases of the disease to determine whether this can stop disease, and whether it can reverse it. The 
results of this project will be crucial knowledge towards future human therapy.

## Key facts

- **NIH application ID:** 9989209
- **Project number:** 5P01NS097197-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Joan J Guinovart
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $138,858
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989209

## Citation

> US National Institutes of Health, RePORTER application 9989209, Defining the therapeutic window for the treatment of Lafora Epilepsy (5P01NS097197-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989209. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*