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Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD

Award Number: R01NS110398
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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Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD - Project Summary The often debilitating side-effect of standard pharmacotherapy for Parkinson disease (PD), levodopa-induced dyskinesia (LID) continues to be a serious complication of medical treatment for individuals with PD. Despite eventually occurring in greater than 90% of individuals, there is the only one FDA-approved drug for LID. However, it is only partially effective, works best in cases of mild LID, and can itself produce significant adverse events. Maintaining the motor benefits of PD therapies while avoiding LID remains a significant unmet clinical need. Our research program has been validating striatal voltage gated CaV1.3 calcium channels as a therapeutic target for LID amelioration. Our initial proof-of-principle data demonstrated that reducing striatal CaV1.3 expression with adeno-associated virus (rAAV) CaV1.3 short-hairpin (sh)RNA expression in YOUNG (2mo) MALE parkinsonian rats provided near complete, uniform protection against LID induction, and provided significant (60%) reversal of already established severe LID. Importantly this approach did NOT interfere with, and in fact appeared to enhance, motor activation of levodopa. As age is the greatest risk factor for PD and that there are sex-related differences in both PD and LID, in the first iteration of this R01 we expanded our target validation studies into older male and female parkinsonian rats and nonhuman primates (NHPs). For these studies, we principally employed the proactive approach of preventing LID induction, reasoning that if aging precluded, or significantly diminished the ability of this molecular therapy to ameliorate LID severity, a proactive paradigm was the most reasonable initial approach. Using a mix of proactive (rat & NHP) and reversibility paradigms (rat only), our studies performed during the first iteration of this award continue to robustly support the concept that striatal CaV1.3 silencing is a potent therapeutic for preventing LID induction (rats & NHPs) and escalation of pre-existing mild LID (rats) in aging parkinsonian subjects of both sexes. However, these studies provide crucial scientific insight that advancing age, female sex, and introducing CaV1.3 silencing after LID induction in older parkinsonian rats (15-18 mos) increased variability and decreased overall benefit of therapeutic response. In contrast, in aged parkinsonian NHPs (24-29 yo) proactive intervention with AAV-CaV1.3-shRNA provided profound antidyskinetic benefit and significant diminution of long-standing severe parkinsonian disability, ‘ON’ and ‘OFF’ levodopa, in both male and female aged macaques. We posit the next logical steps for this research program, aimed at understanding the potential clinical application of this gene therapy in PD, is to define the therapeutic benefit (i.e., reversal of LID and parkinsonian disability) once LID have been induced using the gold standard preclinical parkinsonian NHP model. We propose here a series of studies directed at determining the capacity and/or limitations of reversing established LID and long-standing parkinsonian disability, modeling therapeutic efficacy of CaV1.3 silencing in two demographics of PD, specifically in those with idiopathic PD and those with young onset PD (YOPD).


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 = $0 )
2025	2024	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/27/2025	COMPETING CONTINUATION	$152,637
2025	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/27/2025	NON-COMPETING CONTINUATION	-$152,637
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $952,368 )
2024	2024	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/24/2024	COMPETING CONTINUATION	$952,368
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $952,368

Issue Date FY: 2022 ( Subtotal = $468,320 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/21/2022	NON-COMPETING CONTINUATION	$468,320
														Subtotal = $468,320

Issue Date FY: 2021 ( Subtotal = $568,415 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/11/2021	NON-COMPETING CONTINUATION	$568,415
														Subtotal = $568,415

Issue Date FY: 2020 ( Subtotal = $590,058 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/3/2020	NON-COMPETING CONTINUATION	$590,058
														Subtotal = $590,058

Issue Date FY: 2019 ( Subtotal = $561,645 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/9/2019	NON-COMPETING CONTINUATION	$561,645
														Subtotal = $561,645

Issue Date FY: 2018 ( Subtotal = $598,419 )
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/21/2018	NEW	$598,419
														Subtotal = $598,419

Grand Total All Awards = $3,739,225

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Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD

Award Number: R01NS110398

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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