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A smart cell drug (SmaCD) delivery platform for mobile, targetable, and self-regulated combination therapy: a model project to rescue antibodies from Alzheimer's disease (AD) clinical trial failures

Award Number: R01AG081989
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT As with many other diseases, Alzheimer’s disease (AD) is a multifactorial disorder consisting of multiple pathologies that are each known to be deleterious in their own right. Clinical trials assessing disease-modifying drugs for Alzheimer’s disease (AD) have largely been focused on amyloid beta (Aβ) pathology rather than other pathological components including tau pathology and gliosis. This is in part due to Aβ pathology being viewed as the initiating event responsible for all other pathologies. The interim result is Aducanumab (AduhelmTM; Biogen) recently approved by the Federal Drug Administration (FDA)l, likely to be effective at early stages of AD where it would be most effective in halting downstream pathologies. Treatments for later stages of diseases will require therapeutics not only for Aβ, but also tau pathology and gliosis namely combination therapy (CT). CT has recently been strongly encouraged by the European Union-North American Clinical Trials in Alzheimer’s disease Task Force (EU/US CTAD Task Force) and the FDA5. Aducanumab on its own is already dose-limited due to its potential for off-target toxicity and development of a CT including its use would result in additive toxicity that the other drugs may introduce plus possible unknown drug interactions. This makes CT extremely complex to research and to date unattractive for big pharma. To overcome these challenges, we have designed a smart cell-based drug delivery (SmACD) system to enable in vitro research highly translatable to in vivo validation that has the capability of support a large number of drugs currently being used in clinical trials and to deliver them in combination to the brain without the toxicity associated with systemic or other forms of bulk drug administration. We propose to use SmaCD to target the most afflicted brain regions in AD equipped with a CT based on Aducanumab and Zagotenemab to elicit microglia-mediated clearance of neurotoxic oligomeric Aβ and disease- spreading tau, respectively, accompanied by an immunomodulator to enhance the phagocytic activity of microglia whilst suppressing inflammation. We plan to test the technology initially in human cells and mouse cells followed by in vivo validation in a transgenic mouse model of AD that presents Aβ and tau pathology accompanied by gliosis at mid and late stages of disease development. Our results, if successful, would directly provide ‘proof-of-concept’ for the translatability of SmaCD-delivered CT drug therapy for use in the intervention of human disease.


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: 2024 ( Subtotal = $476,782 )
2024	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	001	3	6/27/2024	NON-COMPETING CONTINUATION	$476,782
2024	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	1/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $476,782

Issue Date FY: 2023 ( Subtotal = $486,610 )
2023	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	6/22/2023	NON-COMPETING CONTINUATION	$486,610
														Subtotal = $486,610

Issue Date FY: 2022 ( Subtotal = $534,821 )
2022	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	8/29/2022	NEW	$534,821
														Subtotal = $534,821

Grand Total All Awards = $1,498,213

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A smart cell drug (SmaCD) delivery platform for mobile, targetable, and self-regulated combination therapy: a model project to rescue antibodies from Alzheimer's disease (AD) clinical trial failures

Award Number: R01AG081989

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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