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Investigating Divergent Disease Severity in Human Neuronal Models of KCNQ2-Related Developmental and Epilepsy Disorders

Award Number: R21NS125503
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Mutations in KCNQ2 encoding voltage-gated K+ (KV7.2) channel are associated with monogenic early-onset childhood epilepsies with overlapping characteristics but divergent clinical severity. The clinical spectrum of KCNQ2-related epilepsy disorders ranges from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe Developmental and Epileptic Encephalopathy (DEE). Mutations in KCNQ2 account for approximately 5% of all mutations identified in genetic epilepsy and 10% of those associated with early-onset epilepsy. The mechanisms that drive the differential severity between BFNS and DEE cases are poorly understood. Currently 30% of all epilepsy patients are completely refractory to any existing anti-epileptic treatments and there are no treatments for the lifelong developmental and physical disabilities associated with DEE. Thus, addressing this overarching question can facilitate development of novel and targeted therapeutic strategies. Studies using heterologous expression systems and mouse models have provided many advances in our understanding of KCNQ2-related epilepsies, but fail to account for some of the sources of phenotypic variation associated with cellular and network-level development of the human brain. As a result of these limitations there is a fundamental need to develop more human-relevant model systems for epilepsy. Recent advances in the generation of human patient-specific induced pluripotent stem cells (hiPSCs) have allowed patient somatic cells to be reprogrammed to pluripotency and differentiated into neurons. Thus, the present proposal seeks to take advantage of these technologies to address how stable mutations in KCNQ2 affect: 1) intrinsic and network excitability in specific human neuronal subtypes and 2) electrophysiological maturation and plasticity of complex neuronal networks to determine whether these properties are altered in a disease-severity specific manner. Here, we will use an established patient-specific iPSC-based platform to determine how BFNS and DEE variants differentially impact human neurons using patch-clamp electrophysiology and multi-electrode array (MEA) techniques.


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: 2023 ( Subtotal = $200,000 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/31/2023	NON-COMPETING CONTINUATION	$20,000
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/25/2022	NON-COMPETING CONTINUATION	$180,000
														Subtotal = $200,000

Issue Date FY: 2022 ( Subtotal = $240,000 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/15/2021	NEW	$240,000
														Subtotal = $240,000

Grand Total All Awards = $440,000

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Investigating Divergent Disease Severity in Human Neuronal Models of KCNQ2-Related Developmental and Epilepsy Disorders

Award Number: R21NS125503

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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