# Genome editing, mRNA suppression and chain termintion as therapy for Lafora Epilepsy

> **NIH NIH P01** · UNIVERSITY OF KENTUCKY · 2020 · $462,095

## Abstract

Lafora disease (LD) is a catastrophic epilepsy with onset in teenage years in otherwise normal adolescents. Its 
causes are known, its pathogenesis in advanced understanding, in major part through the research of members 
of this proposed program project. The disease genes, EPM2A and EPM2B, encode the laforin glycogen 
phosphatase and the malin ubiquitin E3 ligase, which regulate glycogen synthesis, in particular glycogen 
structure. Mutations of either gene lead to formation of malstructured glycogen (polyglucosan), which 
precipitates, aggregates, and accumulates into Lafora bodies (LB). These overtake neuronal somatodendritic 
cytoplasm and initiate a progressive soon-intractable epilepsy that aggressively escalates, and leads to death 
after 10 years of essentially constant seizing. Our groups have shown in the LD mouse models that reducing 
glycogen synthesis by 50-100% through knockouts of the glycogen synthase (GS) gene or the GS activator PTG 
gene are safe, and fully rescue murine LD. Here, we propose to translate these findings from gene knockout 
experiments to therapeutic interventions, in mouse, as a step towards human therapy. In Aim 1, we target the GS 
and Ptg genes at the DNA level through CRISPR/Cas9 genome editing, in collaboration with F Zhang, co- 
discoverer of the CRISPR system. We deliver CRISPR/Cas9 using the AAV9 virus, in collaboration with B 
Kaspar, an AAV9 field leader. We utilize a new Cas9 enzyme recently developed in the Zhang lab with a size that 
for the first time allows packaging in AAV9. In Aim 2, we target the GS and Ptg genes at the mRNA level using 
antisense oligonucleotides with unique brain-specific chemistries. Here, we already preliminarily show rescue. In 
Aim 3 we target glycogen itself. We utilize an innovative chain-termination approach, which introduces glucose 
derivatives into the growing chains of polyglucosans to block extension, and thus prevent their formation, and 
prevent LB and LD. Finally in Aim 4 we utilize the ketogenic diet, under which the brain utilizes ketones for 
energy in lieu of glucose and determine whether this can prevent LB formation. The aims of this and our other 
projects of this CWOW are a comprehensive intervention on the pathogenic pathway in LD. We expect that one, 
though more likely a combination, of these aims will succeed in our murine models and later translate to 
eliminating LD from the roster of intractable epilepsies.

## Key facts

- **NIH application ID:** 9989207
- **Project number:** 5P01NS097197-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Berge A Minassian
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,095
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989207

## Citation

> US National Institutes of Health, RePORTER application 9989207, Genome editing, mRNA suppression and chain termintion as therapy for Lafora Epilepsy (5P01NS097197-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989207. Licensed CC0.

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