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Next-generation calcium channel modulators

Award Number: R01HL149926
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Next-generation calcium channel modulators - CaV1.2 Ca2+ channels are critical conduits for Ca2+ entry into a diverse array of excitable cells. As such, these channels must be precisely tuned to function appropriately for each cell type, and in response to varying physiological cues. To this end, the channels employ multiple mechanisms of regulation, including alternative splicing, voltage dependent inactivation and calcium dependent inactivation. However, a growing number of mutations have been identified in CaV1.2, leading to severe phenotypes including neurological deficits, long-QT syndrome (LQTS), and death. Timothy Syndrome (TS) represents one such class of mutations, in which a single point mutation within CaV1.2 leads to a severe multisystem disorder characterized by developmental delays, autism and profound LQTS. Many of the known TS mutations have been shown to decrease channel inactivation, implicating Ca2+ channel blockers (CCBs) as a promising treatment option. However, despite some modest success with verapamil, CCBs have had limited efficacy in treating TS. Here, we postulate that this lack of efficacy may be due to a differential effect of CCBs on mutant versus wild type CaV1.2, necessitating the exploration of alternative therapeutic options for these patients. We propose that manipulating CaV1.2 splicing represents just such an alternative strategy, with significant promise for the treatment of these patients. Specifically, as the majority of TS patients harbor a mutation within a mutually exclusive exon, we will design antisense oligonucleotides (AONs) targeted to the exon containing the mutation. As such, we expect to force the exclusion of the deleterious exon, induce inclusion of the unaffected alternate exon, and produce a fully functional alternate channel splice variant. Importantly, this strategy will bypass the current limitations of conventional therapies, providing significant clinical benefit for TS patients. Moreover, application of this technique to WT CaV1.2 channels may lead to promising new therapeutic insights within a broader population of patients. In particular, we will apply our splice modulating AONs to test the hypothesis that atypical splice patterns in some patients may render them more susceptible to detrimental cardiac effects of DHP treatment. Finally, as numerous genetic mutations occur within mutually exclusive exons, our application of AONs to TS will serve as a generalizable strategy applicable to numerous genetic mutations in a multitude of proteins. Overall, targeted manipulation of protein splicing represents a large and untapped opportunity, providing a path forward for treatment of a diverse array of diseases.


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 = $764,179 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	6	1/22/2025	COMPETING CONTINUATION	$764,179
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	5	3/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $764,179

Issue Date FY: 2024 ( Subtotal = $386,250 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	5	11/15/2023	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2023 ( Subtotal = $386,250 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	4	11/11/2022	NON-COMPETING CONTINUATION	$347,625
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	4	2/11/2023	NON-COMPETING CONTINUATION	$38,625
														Subtotal = $386,250

Issue Date FY: 2022 ( Subtotal = $386,250 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	3	6/15/2022	NON-COMPETING CONTINUATION	$38,625
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	3	11/15/2021	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $386,250

Issue Date FY: 2021 ( Subtotal = $386,250 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$38,625
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	2	1/4/2021	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $386,250

Issue Date FY: 2020 ( Subtotal = $386,250 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	12/20/2019	NEW	$386,250
														Subtotal = $386,250

Grand Total All Awards = $2,695,429

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Next-generation calcium channel modulators

Award Number: R01HL149926

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/20/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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