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Disease Pathogenesis and Modification for CaV1.1-Associated Hypokalemic Periodic Paralysis

Award Number: R01AR063182
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Hypokalemic periodic paralysis (HypoPP) is a dominantly inherited disorder of skeletal muscle in which recurrent attacks of weakness are caused by intermittent failure of fiber excitability. Episodes occur in association with hypokalemia (K+ < 3 mM) and are often triggered by carbohydrate ingestion, exercise, or stress. The molecular defect in HypoPP is heterogeneous, with 60% of families having missense mutations in CACNA1S encoding the L-type Ca channel CaV1.1, and 20% have missense mutations in SCN4A encoding the voltage-gated Na+ channel NaV1.4. Management of symptoms is limited to avoiding trigger factors, optimizing serum K+ levels, or empirical use of carbonic anhydrase inhibitors that have modest response rates (~50%) and adverse side effects. An even greater concern, with no existing therapeutic intervention, is the slowly progressive permanent muscle weakness (PMW) that impairs mobility and may cause loss of ambulation. All 14 HypoPP mutations in NaV1.4 and 10 of 11 in CaV1.1 occur at arginine residues in S4 transmembrane segments of voltage-sensor domains (VSD). We have been the leading group to show this consistent motif gives rise to a shared functional defect in HypoPP mutant channels: the anomalous gating pore leakage current. Moreover, simulations with our computational model show that this small anomalous conductance in CaV1.1 or in NaV1.4 (about 1% of the total resting fiber conductance) is sufficient to cause paradoxical depolarization of and associated inactivation of sodium channels, with subsequent loss of fiber excitability and weakness. Based on these insights on the pathogenesis of episodic HypoPP, we now propose new pharmacological and gene editing approaches for improved clinical management of HypoPP that will be tested and optimized in our knockin mutant CaV1.1-R528H mouse model of HypoPP. In Aim 1, our pharmacological approaches are directed at two separate targets: (i) block the gating pore and (ii) stabilizing by activation of KV7 K+ channels. Preliminary data show that HIFs (developed by our collaborator, F. Tombola, to block Hv1 voltage-gated proton channels) attenuate the low-K+ induced loss of force for CaV1.1-R528H muscle and block an inward current, consistent with block of the HypoPP gating pore leak. Other data show that retigabine, a KV7 opener, can prevent the low-K+ induced loss of force and hasten the recovery from weakness in R528H muscle. In Aim 2, two gene editing technologies will be used to develop a more durable improvement in symptom management that also has the potential to attenuate or prevent the late-onset PMW. The first approach is disruption of the mutant allele with CRISPR/Cas9. The rationale is that HypoPP is a dominant trait caused by a gain-of-function defect (gating pore current) and that one normal CACNA1S allele appears to be sufficient for normal muscle function in mice and humans. Our preliminary data show allele-specific disruption of R528H in vivo, with complete suppression of the HypoPP phenotype. The second approach uses base editors to correct the mutation (without the risk of off-target double-strand breaks) and preserve both alleles.


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 = $560,181 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	11/20/2024	NON-COMPETING CONTINUATION	$560,181
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	11	1/24/2025	COMPETING CONTINUATION	$86
2025	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	1/24/2025	NON-COMPETING CONTINUATION	-$86
														Subtotal = $560,181

Issue Date FY: 2024 ( Subtotal = $645,859 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	12/21/2023	COMPETING CONTINUATION	$645,859
														Subtotal = $645,859

Issue Date FY: 2021 ( Subtotal = $437,725 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/24/2021	NON-COMPETING CONTINUATION	$437,725
														Subtotal = $437,725

Issue Date FY: 2020 ( Subtotal = $451,263 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/17/2020	NON-COMPETING CONTINUATION	$451,263
														Subtotal = $451,263

Issue Date FY: 2019 ( Subtotal = $451,263 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	7/1/2019	NON-COMPETING CONTINUATION	$451,263
														Subtotal = $451,263

Issue Date FY: 2018 ( Subtotal = $451,263 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	7/5/2018	NON-COMPETING CONTINUATION	$451,263
2018	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	10/24/2017	COMPETING CONTINUATION	$248,579
2018	2016	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	10/24/2017	NON-COMPETING CONTINUATION	-$248,579
														Subtotal = $451,263

Issue Date FY: 2017 ( Subtotal = $467,302 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	7/14/2017	COMPETING CONTINUATION	$467,302
2017	2016	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/12/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $467,302

Issue Date FY: 2016 ( Subtotal = $376,758 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/17/2016	NON-COMPETING CONTINUATION	$376,758
														Subtotal = $376,758

Issue Date FY: 2015 ( Subtotal = $376,758 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/9/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,758
														Subtotal = $376,758

Issue Date FY: 2014 ( Subtotal = $369,222 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/19/2014	NON-COMPETING CONTINUATION	$369,222
														Subtotal = $369,222

Issue Date FY: 2013 ( Subtotal = $357,921 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/25/2013	NON-COMPETING CONTINUATION	$357,921
														Subtotal = $357,921

Issue Date FY: 2012 ( Subtotal = $387,744 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/25/2012	NEW	$387,744
														Subtotal = $387,744

Grand Total All Awards = $5,333,259

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Disease Pathogenesis and Modification for CaV1.1-Associated Hypokalemic Periodic Paralysis

Award Number: R01AR063182

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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