Dravet syndrome anti-epileptic control by targeting girk channels

Active Project Grant Awarded Last action

Award ID
R01NS131467
Recipient
Awarding agency
Obligated
$5,006,389

Award facts

Completion date 75% complete
Place of performance
Boston, MA 02115, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Dravet syndrome (DS) is a devastating form of epilepsy caused by loss of function of NAV1.1 (80-90% of cases), the predominant voltage-gated NA+ channel expressed in inhibitory (gabaergic) interneurons in the hippocampus and prefrontal cortex. This causes a decrease in the release of inhibitory neurotransmitter (gaba), resulting in hyperexcitability. The disease manifests itself within the first year of life and is usually triggered by hyperthermia causing frequent and prolonged seizures that result in a host of health problems including developmental delay, speech impairment, ataxia, hypotonia and sleep disturbances. Two small molecule monotherapies have been approved recently by the FDA: epidiolex (cannabidiol or CBD) in 2018 and fintepla (fenfluramine or FA) in 2020 for patients two years of age and older. Even though they reduce the frequency of seizures, these drugs at their effective dosages cause multiple side effects. Their mechanism(s) of action to reduce epileptiform activity remain(s) unknown. G protein-gated inwardly rectifying k+ (girk) channels have been strongly implicated in epilepsy. They are activated by the GSS dimer of g proteins and by [NA+]i in a synergistic manner. The basis of synergism lies in that they each work allosterically to control predominantly the two channel gates: GSS, the membrane gate and NA+, the cytosolic gate. In the case of the gabaergic interneurons, we hypothesize that NAV1.1 and GIRK1/2 are coupled, such that the NA+ entering through NAV1.1 promotes GIRK1/2 activity to hyperpolarize the cell and ensure removal of NAV1.1 inactivation for fast spiking. In DS this mechanism becomes compromised causing cell depolarization and inactivation of voltage-gated channels at large present in gabaergic neurons failing to compensate for the loss of NAV1.1. We use GAT1508, a specific activator of GIRK1/2 to compensate for the compromised NA+ entry. Since GAT1508 opens the cytosolic gate, we ask whether IT synergizes with CBD (via CB1R) and FA (via 5-HT1DR) to open more fully the membrane gates. In aim 1, experiments designed to test the hypothesis are aimed at the cellular level in both heterologous expression and in native gabaergic neurons. In aims 2 and 3, we utilize a DS mouse model, heterozygous for the SCN1A gene that encodes NAV1.1, and in aim 2, we test the hypothesis at the brain slice level, where synapses and transmitter release remain intact, and compare the DS model to a wild-type animal model. In aim 3, we pursue experiments at the whole animal level (DS model), using simultaneous EEG and 2-photon microscopy to monitor the neuronal circuits involved.

Transactions

Action Obligated Date
Amendment $0
Amendment $551,077
Amendment $551,077
Amendment $495,972
Amendment $39,937
Amendment $39,937
Amendment $513,496
Amendment $513,496
Amendment $513,496
Amendment $595,967
Amendment $595,967
Original award $595,967
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Subawards

Subrecipient Amount Awarded
Brigham & Womens Hospital Inc. We are committed to supporting Dr Diomedes Logothetis's effort to study the synergistic effects of cannabidiol and GIRK channel modulators in suppressing… $171,138
Foundation For Research And Technology Hellas (Forth The Subrecipient lab will investigate the effects of the novel compounds alone or in combination with known drugs. Specifically, the Subrecipient lab will use… $14,710
Foundation For Research And Technology Hellas (Forth The Subrecipient lab will investigate the effects of the novel compounds alone or in combination with known drugs. Specifically, the Subrecipient lab will use… $14,185
Foundation For Research And Technology Hellas (Forth $15,267
Brigham & Womens Hospital Inc. We are committed to supporting Dr Diomedes Logothetis's effort to study the synergistic effects of cannabidiol and GIRK channel modulators in suppressing… $203,400
Brigham & Womens Hospital Inc. $223,036

Quick answers

Who received award R01NS131467?

R01NS131467 was awarded to Northeastern University by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on March 1, 2023.

How much is award R01NS131467 worth?

$5,006,389 has been obligated on R01NS131467.

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