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 1 a 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 2 a 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.
In addition to its well-known role as an inhibitory neurotransmitter, supraphysiological levels of GABA can disrupt autophagy resulting in increased mitochondrial number and oxidative stress, an effect mitigated by rapalogue drugs (rapamycin, Torin 1) via interaction with the autophagy regulator, mTOR (mechanistic target of rapamycin). GABA-related pathology is manifest in both heritable and drug-induced instances of disordered GABA metabolism, including succinate semialdehyde dehydrogenase deficiency (SSADHD), as well as application of the broadly used antiepileptic drug (AED) vigabatrin (VGB). VGB irreversibly inactivates GABA-transaminase, a mechanism of action unique among AEDs, but its long-term use is curtailed with the development of ocular retinal toxicity. Our proposal develops a framework leading to the clinical development of novel rapalogue therapeutics to treat heritable GABA metabolic disorders, while simultaneously providing an adjuvant therapy that will significantly extend the clinical utility of VGB.
| Vogel, Kara R; Ainslie, Garrett R; Walters, Dana C et al. (2018) Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies. J Inherit Metab Dis 41:699-708 |
| Vogel, K R; Ainslie, G R; Jansen, E E W et al. (2017) Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. Biochim Biophys Acta Mol Basis Dis 1863:33-42 |
| Vogel, Kara R; Ainslie, Garrett R; Schmidt, Michelle A et al. (2017) mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice. Pediatr Neurol 66:44-52.e1 |
| Vogel, K R; Ainslie, G R; Pearl, P L et al. (2017) Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity? Clin Pharmacol Ther 101:458-461 |
