# Infantile Spasms:  Molecular Underpinnings of a Novel Combination Therapy

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $346,719

## Abstract

Infantile spasms is a severe childhood seizure disorder. The incidence is 1 in every 2000 -3000 live births.
The spasms are only a few seconds in duration but occur in clusters of up to 100 in a few minutes. The EEG
correlates of the disorder are unique. Coincident with each behavioral spasm is a brief ictal event and the
interictal EEG is dominated by a chaotic pattern called hypsarrhythmia. The majority of children are
intellectually disabled later in life and most of them develop other forms of drug resistant epilepsy. ACTH and
vigabatrin can abolish spasms and hypsarrhythmia in 30-80% of patients - depending on the study. However,
both drugs can have significant side effects and usually do not prevent the development of the intellectual
disabilities and severe epilepsy seen later. Thus better treatments are needed and the hope is that with the
advent of relevant animal models, the discovery of underlying mechanisms will lead to new therapies. Our
laboratory has developed a model of infantile spasms that recreates the critical features of the disorder. Like
infants, the majority of these animals respond to both ACTH and vigabatrin. However, our work has also
pointed to a potential new therapy for this disorder. We have found that the expression of Insulin-like Growth
Factor -1 (IGF-1) is suppressed in the neocortex of animals with spasms as is signaling through the PI3K-AKT-
mTOR growth pathway. At the same time, the expression of parvalbumin and synaptotagmin 2, biomarkers for
an important class of inhibitory interneurons and their presynaptic nerve terminals, are also reduced. This has
led us to hypothesize that reduced signaling through the PI3K-AKT-mTOR pathway impairs inhibitory
interneuron growth which results in an imbalance in synaptic excitation and inhibition and epileptic spasms.
Remarkably, treatment with (1-3)IGF-1, a tripeptide derivative of IGF-1, rescues the inhibitory interneurons and
abolishes spasms and hypsarrhythmia in over 60% of animals. Moreover, (1-3)IGF-1 dramatically augments
the anticonvulsant effects of vigabatrin, reducing the dosage needed to abolish spasms and potentially
eliminates its retinotoxicity. This synergy is likely produced by (1-3)IGF-1’s increase in the number of
GABAergic nerve terminals and vigabatrin-induced increase in GABA levels in the same synapses. However,
very little is known about (1-3)IGF-1 and experiments proposed here focus on understanding its mechanism of
action. We plan to test 2 hypotheses. The first is that (1-3)IGF-1 acts through the IGF-1 receptor to activate
the PI3K-AKT-mTOR growth pathway. The second is that (1-3)IGF-1 stimulates the growth of parvalbumin
interneurons and thereby adds new GABAergic nerve terminals to the neocortex. Lastly, we will attempt to
show that (1-3)IGF-1 acts via the IGF-1 receptor when it augments the anticonvulsant effects of vigabatrin.
Our results will advance an understanding of the actions of a novel, naturally occurring neuropeptide that likely
...

## Key facts

- **NIH application ID:** 10109159
- **Project number:** 5R01NS105913-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** John William Swann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109159

## Citation

> US National Institutes of Health, RePORTER application 10109159, Infantile Spasms:  Molecular Underpinnings of a Novel Combination Therapy (5R01NS105913-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10109159. Licensed CC0.

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