Every year in the US ~1700 children are newly diagnosed with epileptic spasms during infancy (infantile
spasms; IS). IS develop between 3-12 months of age with a predominance (60%) in males. IS are associated
with significant mortality and morbidity. Medical treatment options for IS are different than for any other types of
epilepsy. There are two drugs with a reasonable evidence of efficacy, both approved by FDA: ACTH
(adrenocorticotropin) and vigabatrin, eliminating spasms in 50-55% of patients in long term. However, ACTH
carries enormous cost burden and, in up to 43% of cases has significant and serious adverse effects, which
include obesity, arterial hypertension, electrolyte imbalance, gastric ulcer, growth retardation, cardiomyopathy,
and immunosuppression as well as brain atrophy. Vigabatrin is almost as effective as ACTH short-term but it
lags in effects after one year. Vigabatrin has a significant risk for concentric visual field deficits due to
peripheral retinopathy, which develops in an unpredictable manner. Despite the treatments, up to 85% of
patients with IS have developmental regression and 67% suffer from intractable epilepsy later. We identified
the following gaps: There is no systematic rigorous approach in the preclinical search for novel IS treatments.
Current treatments of IS (even if in combination) are insufficient and may have serious adverse effects. Most of
the developed models of IS lack validation using the ACTH efficacy. Sigma-1 receptor ligands have not been
examined for efficacy against IS. Our proposal uses a validated rat model of IS consisting of prenatal priming
and postnatal trigger of spasms during developmentally appropriate period. The spasms in our model are
sensitive to treatment with ACTH as well as vigabatrin. There is good ictal and interictal EEG correlate of this
model with IS. There are also delayed spasms or seizures with delayed EEG epileptiform activity. The model,
including ACTH efficacy, has been used and reproduced in independent laboratories. In this proposal we will
initiate systematic search for compounds potentially effective against IS. Our preliminary studies show that
sigma receptor ligands (sigma-1 receptor allosteric modulators) have robust effects against the spasms in our
model. Therefore, this class of compounds may produce novel targets for IS treatment. Our proposal will test
the treatment candidates among sigma receptor ligands in the three-tier system. In Tier 1, all potential
treatment compounds will be tested against the expression of spasms in the randomized prospective trial. In
Tier 2, those drugs with >50% efficacy will be forwarded to the EEG study investigating their effects on both
acute and delayed EEG changes. Tier 3 will investigate cognitive improvements as well as rule out behavioral
adverse effects afforded by the candidate drugs successful in Tiers 1 and 2. Specific aim is to determine
efficacy of sigma receptor ligands against the spasms in prenatally primed rats in three tiers. The proposal will
take advantage of unique features of our rodent model of IS and deliver at least one prospective treatment
candidate with efficacy comparable to or better than ACTH and with fewer adverse effects for an IND study.
