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

SUMMARY
Succinic semialdehyde dehydrogenase deficiencySSADHDis a rare neurometabolic disease caused by
mutations in the ALDH AgeneThe disorder is associated with significant developmental delay and
extensive neurological morbidity including seizuresSeizures increase with agein patients as well as in
experimental aldh adeficiencyaldh amicewhere seizures increase in frequency and severity starting atdays of life to culminate with death at the time of weaningThere is no cure and available treatments are
primarily symptomaticIn this proposalwe focus on evaluating the antiseizure properties of farnesol and
structurally related analogues in experimental SSADHDFarnesol is a bioactive primary alcohol with neuronal
voltage gated Cachannel blocker propertiesactive in alcohol withdrawal seizuresPreliminary work by the
research team recently showed that farnesol is a positive allosteric modulator of human GABAA receptors
which suppresses seizures in experimental SSADHDThree aims are proposed to further characterize the antiseizure properties of farnesol with an evaluation of dose dependency and long term efficacyAimsandampand to begin to identify the structural determinants of farnesol that are critical to its antiseizure activityAimthis in a phenocopy of the human diseasethe SSADHD knock outaldh amouseThe proposed studies
will bridge gaps in the development of targeted therapies for SSADHDwhile providing insight on the use of
farnesol and analogues in the treatment of other forms of epilepsies NARRATIVE
Inherited succinic semialdehyde dehydrogenase deficiencySSADHDthe most common disorder of GABA
metabolismfeatures accumulation ofaminobutyric acidGABAconcomitant down regulation of inhibitory
neurotransmission pathwaysand a marked epileptic presentationClassical antiepileptic drugs are used but
their efficacy in SSADHD is variable and limited by potential significant side effectshencecalling for identifying
new drugs with improved therapeutic efficacyThe novel therapeutic blueprint generated in this proposal will
substantively contribute to finding a successful treatment for SSADHD and other disorders of GABA metabolism