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Develop GABAergic Neuron Protectors for Treating ApoE4-Related Alzheimer's Disease

Award Number: R44AG063691
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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Develop GABAergic Neuron Protectors for Treating ApoE4-Related Alzheimer's Disease - PROJECT SUMMARY (FAST-TRACK APPLICATION) Alzheimer’s disease (AD) is a neurodegenerative disorder affecting over 5.4 million individuals in the United States alone. The complexity and multifactorial nature of AD pose unique challenges for the development of effective therapies. Efforts to target specific AD-related pathways have shown promise in animal studies, only to fail during human trials. There is a pressing need to identify novel therapeutic targets and develop new drug candidates for AD. Carriers of apolipoprotein (apo) E4, one of the three apoE isoforms (apoE2, apoE3, apoE4), are associated with 60–80% of all AD cases, making apoE4 the major genetic risk factor for AD. This proposal builds on four novel findings from our studies of mouse models and human induced pluripotent stem cell (hiPSC)–derived neurons expressing different apoE isoforms. First, expression of apoE4 in knock-in (KI) mice causes age- dependent and cell-autonomous impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with hippocampal network activity deficits and learning and memory impairments. Second, optogenetic inhibition of hilar GABAergic interneuron activity impairs spatial learning and memory in wildtype mice, indicating that hilar GABAergic interneuron impairment can directly cause cognitive deficits. Third, treatment with the GABAA receptor potentiator pentobarbital or transplantation of mouse inhibitory neuron progenitors into the hippocampal hilus rescues the learning and memory deficits in apoE4-KI mice. Fourth, apoE4 expression results in GABAergic interneuron death in hiPSC-derived neuronal cultures and in the hippocampal hilus in AD patients. Together, these findings strongly suggest that apoE4 causes GABAergic interneuron impairment, leading to learning and memory deficits, and represents a novel therapeutic target for AD. We recently identified two classes of small molecules capable of protecting GABAergic neurons from apoE4’s detrimental effects. This proposal aims to further develop, optimize, and validate compounds targeting apoE4-induced GABAergic interneuron impairment as a novel therapeutic approach for AD. The goals of this proposal are 1) to perform ADME and physicochemical studies of the initial compounds and establish a pharmacodynamic (PD) marker by in vivo hippocampal electrophysiological recordings in apoE4-KI mice, 2) to identify and optimize the lead small-molecule GABAergic interneuron protectors through structure-activity relationship studies as well as pharmacokinetic and PD studies, and 3) to test the efficacy of the lead small- molecule GABAergic interneuron protectors in apoE4-KI mice and hiPSC-derived neurons carrying the apoE4 allele.


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: 2022 ( Subtotal = $0 )
2022	2021	GABAERON INC	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	3	2/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $1,086,082 )
2021	2021	GABAERON, INC.	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	3	12/4/2020	NON-COMPETING CONTINUATION	$1,086,082
														Subtotal = $1,086,082

Issue Date FY: 2020 ( Subtotal = $1,079,582 )
2020	2020	GABAERON, INC.	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	2	12/9/2019	EXTENSION WITH OR WITHOUT FUNDS	$1,079,582
2020	2020	GABAERON, INC.	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	002	2	3/7/2020	EXTENSION WITH OR WITHOUT FUNDS	$67,712
2020	2019	GABAERON, INC.	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	1	3/7/2020	NEW	-$67,712
														Subtotal = $1,079,582

Issue Date FY: 2019 ( Subtotal = $342,592 )
2019	2019	GABAERON, INC.	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	1	5/1/2019	NEW	$0
2019	2019	GABAERON, INC.	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	4/22/2019	NEW	$342,592
														Subtotal = $342,592

Grand Total All Awards = $2,508,256

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Develop GABAergic Neuron Protectors for Treating ApoE4-Related Alzheimer's Disease

Award Number: R44AG063691

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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