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Rescuing KCC2 Dysfunction in CDKL5 Deficiency Disorder to Restore GABA(A) Receptor-Mediated Hyperpolarization and Seizure Protection.

Award Number: R21NS126914
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Rescuing KCC2 Dysfunction in CDKL5 Deficiency Disorder to Restore GABA(A) Receptor-Mediated Hyperpolarization and Seizure Protection. - Abstract. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a neurodevelopmental epileptic encephalopathy that is characterized by early-onset epilepsy, sleep disturbances, and developmental challenges. Pharmaco-resistant epilepsy with generalized, multifocal, and myoclonic seizures are a major issue for CDD patients. Currently, no targeted treatment or gene therapy exists for CDKL5 disorder. CDKL5 is a serine/threonine protein kinase and although it is known to be essential for normal brain development and function it is unknown which proteins are targeted by CDKL5. KCC2 is the principal Cl--extrusion mechanism employed by developing and mature neurons in the CNS. Its activity is a prerequisite for the efficacy of fast synaptic inhibition mediated by γ-aminobutyric acid type A receptors (GABAAR), which are Cl- permeable ligand- gated ion channels. The postnatal development of canonical hyperpolarizing GABAAR currents reflects the progressive decrease of intraneuronal Cl- levels that is caused by the upregulation of KCC2 expression and subsequent activity. The developmental appearance of hyperpolarizing GABAAR currents is determined by the phosphorylation status of KCC2, a process that facilitates its membrane trafficking and activity. Deficits in KCC2 expression levels and activity have been detailed in patient and animal models of epilepsy. Furthermore, we have demonstrated that KCC2 loss of function is strongly correlated with cognitive impairment, and the development of pharmaco-resistant seizures that are insensitive to GABAAR positive allosteric modulators such as benzodiazepines. To address this issue, we have developed novel small molecule activators that potentiate KCC2 activity which, in preliminary studies, have been shown to effectively terminate pharmaco-resistant seizures. CDKL5 null mice have seizure-like EEG events at postnatal day 12 and had a significant decrease in the amount of phosphorylated KCC2. We will further examine this relationship between KCC2-S1022 phosphorylation and CDKL5. Our working hypothesis is:Loss of CDKL5 results in a reduced phosphorylation of S1022 KCC2, decreased KCC2 activity, and an increased susceptibility to pharmacoresistant seizures. Small molecule activators of KCC2 will increase KCC2 activity and prevent pharmacoresistance seizures. To test this hypothesis, we propose the following aims: Aim1. To determine the effects of ablating CDKL5 expression on KCC2 phosphorylation. Aim 2. To determine the effects of ablating CDKL5 expression on KCC2 activity. Specific Aim 3. Determine the consequences of ablating KCC2 S1022 phosphorylation on KCC2 function and expression. The result of this study will provide new insights into the targets of CDKL5 and the mechanisms that result in the debilitating pharmaco-resistant epilepsy occurring in CDD. Such insights may promote the development of new therapeutics to alleviate the burdens of pharmaco- resistant epilepsies that affect many epileptic patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $204,300 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/11/2023	NON-COMPETING CONTINUATION	$204,300
														Subtotal = $204,300

Issue Date FY: 2022 ( Subtotal = $245,550 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/1/2022	NEW	$245,550
														Subtotal = $245,550

Grand Total All Awards = $449,850

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Rescuing KCC2 Dysfunction in CDKL5 Deficiency Disorder to Restore GABA(A) Receptor-Mediated Hyperpolarization and Seizure Protection.

Award Number: R21NS126914

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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