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Novel Reengineered Microbiome-based Biologic Therapy to Treat Cognitive and Behavioral Symptoms of Alzheimer's Disease and Related Dementias

Award Number: U01AG074960
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Novel Reengineered Microbiome-based Biologic Therapy to Treat Cognitive and Behavioral Symptoms of Alzheimer's Disease and Related Dementias - Abstract Our early-stage ADDP proposal aims to develop a novel genetically engineered bacterial biologic to treat the most common early symptoms of Alzheimer's disease (AD), including cognitive impairment and other neuropsychological symptoms, such as anxiety and depression. This debilitating disease imposes a huge emotional, social and financial burden on society. No effective disease-modifying AD drug exists to dampen the Aβ and tau proteinopathies associated with disease progression. Current FDA-approved cholinergic and glutamatergic neurotherapeutics are very modest at best in rescuing memory in mild cognitive impairment (MCI) and prodromal or early stages of AD cases, and often worsen anxiety, apathy, depression, agitation, and other neurobehavioral symptoms, GI irritations, and even mortality. Recent biological evidence indicates that AD is a neural circuit disorder. The onset and progression of cognitive and behavioral symptoms involve a deficiency in monoamine neurotransmitter signaling networks, including norepinephrine (NE) and dopamine (DA). Thus, we propose that restoring brain DA/NE inputs holds the excellent potential to be an effective approach to alleviating cognitive and behavioral deficits in AD and could even delay disease onset. Currently, oral tablet dosing of L- DOPA/carbidopa 3-4 times/day remains the most effective therapy at restoring brain DA/NE levels in humans. However, this repeated chronic pulsatile delivery causes severe side effects. Thus, our therapeutic hypothesis to address this unmet clinical problem is that systemic delivery of genetically engineered L-DOPA bacterial live- therapeutics (LDBL) will avoid large fluctuations in plasma L-DOPA and provide more consistent delivery of L- DOPA to the brain for restoring DA/NE to stable levels that better relieve AD symptoms without additional side effects. Our proof-of-concept data support that 1) the genetically engineered probiotic E. coli Nissle 1917 strains (EcNL-DOPA) efficiently produce L-DOPA both in vitro and in vivo, 2) oral dosing of EcNL-DOPA readily colonizes the mouse gut, achieves a steady-state plasma L-DOPA level that corresponds to the clinically effective plasma level in humans, and increases L-DOPA and DA/NE levels in the brain of rodents and canines, and 3) EcNL-DOPA treatment leads to improved neurobehavioral outcomes and reduces Aβ levels in AD animal models including canines. The overarching goal of our patent-pending ADDP strategy is to optimize the lead LDBL and test its preclinical efficacy in alleviating the cognitive and behavioral deficits, such as apathy, of early AD. To achieve this goal, we will pursue the following specific aims: (i) Optimize the lead LDBL for animal testing, (ii) Evaluate the chronic pharmacokinetic (PK), and safety profile of the lead LDBLs for preclinical efficacy studies, (iii) Determine in vivo pharmacodynamic (PD) efficacy of two lead LDBLs in transgenic (Tg) AD rodent models, and (iv) Assess the efficacy of the most effective lead LDBL in canine models of dementia. Together, our unique therapeutic pipeline strategy involving chronic delivery of probiotic L-DOPA is expected to establish a new line of engineered microbiome-based monoamine neurotherapeutic modalities for AD-related dementias (ADRD).


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 = $1,441,664 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	000	4	6/18/2025	NON-COMPETING CONTINUATION	$1,441,664
														Subtotal = $1,441,664

Issue Date FY: 2024 ( Subtotal = $1,492,444 )
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	002	3	8/22/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	001	3	5/29/2024	NON-COMPETING CONTINUATION	$1,492,444
2024	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	000	2	11/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,492,444

Issue Date FY: 2023 ( Subtotal = $1,503,532 )
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	001	2	6/1/2023	NON-COMPETING CONTINUATION	$1,503,532
2023	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	000	1	4/11/2023	NEW	$0
														Subtotal = $1,503,532

Issue Date FY: 2022 ( Subtotal = $1,459,176 )
2022	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Aging Research	000	1	8/5/2022	NEW	$1,459,176
														Subtotal = $1,459,176

Grand Total All Awards = $5,896,816

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Novel Reengineered Microbiome-based Biologic Therapy to Treat Cognitive and Behavioral Symptoms of Alzheimer's Disease and Related Dementias

Award Number: U01AG074960

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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