# Modeling gene-specific therapy of intractable childhood epileptic encephalopathy

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $29,889

## Abstract

Project Summary
 Early onset pharmacoresistant epileptic encephalopathies (EE) are often caused by de novo variants in
neuronal protein genes. Dynamin 1 (encoded by DNM1), a key neuron-specific GTPase involved in
endocytosis, is a prototypical example of both the disease and its intractable nature, whereby pathogenic
dominant-negative missense mutations cause intractable seizures, developmental delays and cognitive
impairment. We study the Dnm1Ftfl (“fitful”) model of DNM1 EE, which mimics key disease features and
provides a compelling platform to develop and test gene therapies.
 For DNM1 and other genetic EE where the mutation exerts a genetically dominant effect, supplying the
wildtype copy of the mutated product is expected to be of limited, if any, benefit. Thus, elimination or alteration
of the mutated product is a more logical recourse. We have begun to model dominant negative gene silencing
therapy via microRNAs shuttled through neurotrophic self-complementary adeno-associated viral (AAV)
vectors for the treatment of genetically dominant EE, utilizing the Dnm1Ftfl mouse model. We hypothesize that
this approach will rescue the core disease phenotypes, including lethal seizures and major comorbidities and
provide a more permanent therapy option.
 Preliminary treatment of homozygous fitful mice via intracerebroventricular neonatal injection, remedied
developmental deficits, decreased severe seizure-associated lethality, and extended lifespan. To propel this
project forward, our aims are to: 1) optimize our rescue of the disease-defining core phenotypes of fitful mice
towards full rescue; 2) identify neuronal structural and functional defects that culminates in the core
phenotypes; and 3) assess rescue of neuronal structural and functional defects with scAAV9-miDnm1a
treatment. Successful completion of these aims will inform on a possible treatment for both the seizure
phenotype, and associated developmental delays while providing a generalizable approach for other similar EE
models, informing future clinical applications.

## Key facts

- **NIH application ID:** 10220162
- **Project number:** 5F31NS111808-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Osasumwen Virginia Aimiuwu
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $29,889
- **Award type:** 5
- **Project period:** 2019-09-03 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220162

## Citation

> US National Institutes of Health, RePORTER application 10220162, Modeling gene-specific therapy of intractable childhood epileptic encephalopathy (5F31NS111808-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10220162. Licensed CC0.

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