Thursday, April 18, 2024
4/18/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
