# Rapalog Therapy in Heritable and Vigabatrin-Induced GABA Metabolic Disorders

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $395,549

## Abstract

Supraphysiological GABA, the primary inhibitory neurotransmitter, can disrupt autophagy resulting in increased
mitochondrial number and oxidative stress, an effect mitigated by rapalog drugs (rapamycin, Torin 1) via
interaction with the autophagy regulator, mTOR (mechanistic target of rapamycin). GABA-related pathology is
manifest in genetic and drug-induced states, including heritable succinate semialdehyde dehydrogenase
deficiency (SSADHD), and intervention with the antiepileptic drug (AED) vigabatrin (VGB), whose irreversible
inactivation of GABA-transaminase (GABA-T) is mechanistically unique among AEDs. Long-term VGB
intervention (the sole FDA-approved treatment for infantile spasms), however, is curtailed due to the
development of retinal toxicity. Hypothesis 1 posits that autophagic pathways involving GABA, mTOR and
mitochondrial function can be mitigated with rapalogs that will provide clinical benefit in patients with heritable,
or medication-induced (VGB), dysfunction of GABA-T and SSADH. Hypothesis 2 posits that rapalogs applied
locally (eye), in combination with VGB, will ameliorate retinal toxicity and extend the utility of this AED. Aim 1
chronically administers VGB to wild type mice in clinically relevant dosages, followed by characterization of
systemic/ocular effects and the potential of rapalogs to mitigate pathology. Aim 1a will employ visual evoked
potentials (VEPs) in the visual cerebral cortex to assess VGB ocular (retinal) toxicity, while aim 1b systematically
examines the retina of VGB-treated mice using light/electron microscopy and immunohistochemistry to pinpoint
cell layers associated with VGB-induced toxicity. Aim 2 evaluates the efficacy of preclinical rapalog
administration in a murine model of SSADHD. Aim 2a interrogates the neurobehavioral and neurophysiological
effects of rapalog intervention in aldh5a1-/- mice, while aim 2b examines the efficacy of rapalogs in reversing cell
signaling-autophagy-mTOR abnormalities, coupled to a preliminary in vitro assessment of drug safety and
toxicity. We will employ ANOVA to understand the impact of rapalog intervention on phenotype, and their
interactions, followed by adjusted post hoc t-tests. Ongoing clinical evaluation of rapalogs in patients with
heritable tuberous sclerosis provides the precedent for translating our preclinical outcomes to the bedside.
Pharmaceutical agents that eliminate the retinal toxicity of VGB will have enormous clinical value in epilepsy
therapeutics. Such agents will also have therapeutic relevance to SSADHD, while potentially leading to novel
treatment paradigms for other disorders (autism, addiction, Down syndrome) in which elevated GABA may well
have pathophysiological roles, further highlighting the broad clinical impact of our proposal.

## Key facts

- **NIH application ID:** 9918905
- **Project number:** 5R01EY027476-04
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** K Michael GIBSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,549
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918905

## Citation

> US National Institutes of Health, RePORTER application 9918905, Rapalog Therapy in Heritable and Vigabatrin-Induced GABA Metabolic Disorders (5R01EY027476-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9918905. Licensed CC0.

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