Farnesol as Novel Treatment in Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD)

Speragen, Inc., Austin TX

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Abstract

SUMMARY Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disease caused by mutations in the ALDH5A1 gene. The disorder is associated with significant developmental delay and extensive neurological morbidity including seizures. Seizures increase with age, in patients as well as in experimental aldh5a1-deficiency (aldh5a1-/- mice) where seizures increase in frequency and severity starting at 10-12 days of life to culminate with death at the time of weaning. There is no cure and available treatments are primarily symptomatic. In this proposal, we focus on evaluating the antiseizure properties of farnesol and structurally related analogues in experimental SSADHD. Farnesol is a bioactive primary alcohol with neuronal voltage-gated Ca2+ channel blocker properties, active in alcohol withdrawal seizures. Preliminary work by the research team recently showed that farnesol is a positive allosteric modulator of human GABAA receptors which suppresses seizures in experimental SSADHD. Three aims are proposed to further characterize the anti- seizure properties of farnesol with an evaluation of dose dependency and long-term efficacy (Aims #1 & #3), and to begin to identify the structural determinants of farnesol that are critical to its antiseizure activity (Aim #2), this in a phenocopy of the human disease, the SSADHD knock-out (aldh5a1-/-) mouse. The proposed studies will bridge gaps in the development of targeted therapies for SSADHD, while providing insight on the use of farnesol and analogues in the treatment of other forms of epilepsies.