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Exploiting KCNQ2 upstream open reading frames for therapeutic opportunity

Award Number: F31NS135753
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Exploiting KCNQ2 upstream open reading frames for therapeutic opportunity - PROJECT SUMMARY Heterozygous loss-of-function (LOF) is a common genetic mechanism among many monogenic epilepsy genes including KCNQ2, which encodes a brain voltage-gated potassium channel (Kv7.2). Pathogenic KCNQ2 variants are associated with severe developmental and epileptic encephalopathies that lack targeted treatments. We identified an upstream open reading frame (uORF) within the 5’-untranslated region (5’-UTR) of the KCNQ2 mRNA transcript that competes with the canonical reading frame for translation and attenuates Kv7.2 functional expression in non-neuronal cells. Because suppressing uORF translation could be an effective strategy for boosting KCNQ2 expression in the setting of heterozygous LOF, we seek to determine the physiological relevance of the KCNQ2 uORF (Aim 1), and to target the uORF with antisense oligonucleotides (ASO) using a structure-driven approach (Aim 2). Our approach to Aim 1 will involve genome editing of human induced pluripotent stem cells (iPSC) to inactivate the uORF start codon and to compare uORF usage, Kv7.2 translation, and electrophysiological properties of the channel in neurons differentiated from edited and non-edited iPSC lines. For Aim 2, we will experimentally deduce the secondary structure of the KCNQ2 5’-UTR, then design a series of ASOs targeting the least structured regions proximal to the uORF. We will then confirm binding of candidate ASOs to the KCNQ2 mRNA transcript and determine if an ASO strategy will boost Kv7.2 translation and function. These studies will clarify the physiological relevance of the uORF and identify a potential therapeutic strategy to correct heterozygous LOF in this epilepsy gene.


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 = $45,312 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/4/2025	NON-COMPETING CONTINUATION	$44,748
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/17/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $45,312

Issue Date FY: 2024 ( Subtotal = $44,187 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	9/26/2024	NEW	$1,280
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	11/27/2023	NEW	$0
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/27/2023	NEW	$42,907
														Subtotal = $44,187

Grand Total All Awards = $89,499

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Exploiting KCNQ2 upstream open reading frames for therapeutic opportunity

Award Number: F31NS135753

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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