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Mechanism of dual Nav1.7 and Nav1.8 block by a NaV inhibitory peptide

Award Number: R21NS137014
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: 04/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Mechanism of dual Nav1.7 and Nav1.8 block by a NaV inhibitory peptide - Mechanism of dual NaV1.7 and NaV1.8 block by a NaV inhibitory peptide aptamer Summary/Abstract: Multiple sensory neuronal sodium channels (NaVs) contribute to pain pathogenesis, indicating that development of a strategy for specific block of multiple NaVs in the pathological sensory neurons would be more effective for inhibiting pain signals than inhibiting only single NaV subtype. We discovered a polyacidic peptide from NaV1.7 intracellular segment and voltage-clamp recording shows that this peptide potently inhibits sodium currents conducted by both NaV1.7 and NaV1.8 (NaV1.7/1.8) channels. This dual NaV1.7/1.8 inhibitory peptide aptamer (named 1.7/1.8iPA, 38mer) contains a conserved Ankyrin (AnkG) binding domain and a multi-PDZ-domain protein class I binding domain (Pdzd2-I) between NaV1.7 and NaV1.8, suggesting that either AnkG or Pdzd2-I domain or both within 1.7/1.8iPA may contribute to its dual NaV1.7/1.8 inhibition. The overall goal of this proposal is to investigate 1) whether AnkG and/or Pdzd2-I domains in 1.7/1.8iPA is responsible for its dual NaV1.7/1.8 inhibition, and 2) whether expression of sequence defined 1.7/1.8iPA in the primary sensory neurons (PSN) will suppress PSN excitability, supporting 1.7/1.8iPA as a potential analgesic lead. Two specific aims will be investigated to test the hypothesis that 1.7/1.8iPA elicits dual block of NaV1.7/1.8 currents via a combined effects of AnkG and Pdzd2-I domains, leading to suppression of PSN action potential firing. Specific aim 1 will investigate and determine ion channel selectivity of 1.7/1.8iPA by in vitro of cell-based voltage-clamp recordings using HEK cells stably expressing various NaV subtypes and NG108-15 neuronal cells that naturally express potassium channels KV7.2/7.3 (both containing conserved AnkG binding domain). Specific aim 2 will determine electrogenesis and biological activity (neurotoxicity and animal behaviors) of 1.7/1.8iPA expression in the rat PSNs. Successful completion of this application will provide sufficient data to determine whether 1.7/1.8iPA is a potential analgesic lead to be further developed for AAV- mediated, PSN-specific dual NaV1.7/1.8 inhibition to treat chronic pain.


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 = $196,250 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/25/2025	NON-COMPETING CONTINUATION	$196,250
														Subtotal = $196,250

Issue Date FY: 2024 ( Subtotal = $249,250 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/12/2024	NEW	$249,250
														Subtotal = $249,250

Grand Total All Awards = $445,500

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Mechanism of dual Nav1.7 and Nav1.8 block by a NaV inhibitory peptide

Award Number: R21NS137014

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: 04/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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