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Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease

Award Number: R01AG066080
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease - Abstract Brain-derived neurotrophic factor (BDNF) is a nervous system growth factor that enhances synaptic plasticity and regulates neuronal function. BDNF gene therapy for Alzheimer’s disease (AD) is a promising alternative to amyloid- and tau-targeted therapies: BDNF reduces neuronal degeneration and stimulates neuronal activity in rodent and non-human primate models of AD. Direct injection of an Adeno- Associated Virus (AAV) vector into entorhinal cortex mediates safe and long-lasting BDNF expression, and will soon begin human clinical trials. Although promising, intraparenchymal AAV-BDNF injection is invasive and treats only a small percentage of the cerebral cortex. Intrathecal administration of AAV9-BDNF to the cerebrospinal fluid could solve these problems by broadly treating the entire cortex from a single minimally invasive infusion. We recently reported that two hours of Trendelenburg positioning, in which the body lies supine on a reclining table with the head 30° below the feet, dramatically increases the strength and consistency of gene transfer to cerebral cortex after intrathecal AAV9 infusion in rats. More than 95% of transduced cells in cortex are neurons, and gene expression in off-target brain regions and spinal cord is minimal. This novel delivery method has strong potential for clinical treatment of AD. We propose systematic preclinical testing of intrathecal AAV9-BDNF gene therapy for AD. Aim 1 will test therapeutic efficacy by directly comparing intrathecal and intraparenchymal AAV9-BDNF infusion in a transgenic mouse model of AD and analyzing behavioral and anatomical outcomes. Aim 2 will test the safety of intrathecal AAV9-BDNF infusion at escalating doses and over prolonged treatment periods in the non-human primate. Aim 3 will enhance the specificity of intrathecal AAV9-BDNF therapy by testing cell-specific promoters to reduce or eliminate off- target gene expression. These studies aim to simplify delivery, enhance efficacy, and increase clinical feasibility of BDNF gene therapy for AD, and will support both upcoming clinical trials and preclinical development of new gene therapies for AD.


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	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	5/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $394,965 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	5	2/15/2024	NON-COMPETING CONTINUATION	$355,468
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	5	7/3/2024	NON-COMPETING CONTINUATION	$39,497
														Subtotal = $394,965

Issue Date FY: 2023 ( Subtotal = $394,401 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	4	2/24/2023	NON-COMPETING CONTINUATION	$394,401
														Subtotal = $394,401

Issue Date FY: 2022 ( Subtotal = $394,412 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	3	3/1/2022	NON-COMPETING CONTINUATION	$354,970
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	001	3	6/13/2022	NON-COMPETING CONTINUATION	$39,442
														Subtotal = $394,412

Issue Date FY: 2021 ( Subtotal = $394,032 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	2	2/19/2021	NON-COMPETING CONTINUATION	$394,032
														Subtotal = $394,032

Issue Date FY: 2020 ( Subtotal = $393,261 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	4/1/2020	NEW	$393,261
														Subtotal = $393,261

Grand Total All Awards = $1,971,071

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Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease

Award Number: R01AG066080

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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