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Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid

Award Number: R01DA052271
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid - Targeting Inflammasome with stable endocannabinoid ligand AMG315: CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid. PROJECT SUMMARY (ABSTRACT): Although the use of cannabis for medical purposes has shown great promise for the treatment of certain medical conditions, cannabinoid abuse exerts significant impairments in neurocognitive and behavioral functions and these effects are exacerbated in patients with HIV infection. Studies suggest that even after HIV-1 suppressing combined antiretroviral therapy (cART), HIV-1 Tat is being produced in the brain from proviral DNA and implicated as a causative agent for latent infection and development of inflammasome mediated neuroinflammation in HIV infected patients. CRISPR/Cas9 gene-editing technology has been shown by us and others to be effective for excising the HIV genome integrated into the host genome. Our preliminary studies using a recently discovered and potent metabolically stable endocannabinoid analog AMG315 demonstrate that this synthetic cannabinoid exerts anti-inflammatory properties by suppressing NLRP3 inflammasome and HIV infection. Accordingly, we hypothesize that elimination of the HIV-1 Tat gene in CNS cells using Tat specific CRISPR/Cas9 and suppression of inflammasome with CB1-specific stable endocannabinoid analog AMG315 can eliminate active HIV infection/induce permanent latency and prevent neurodegeneration, respectively. However, AMG-315 and CRISPR are impenetrable to the brain in sufficient quantities necessary to prevent HIV-infection, inflammasome activation, and subsequent neurodegeneration. To overcome this, we will use our patented magneto-electric nanoparticles (MENP) technology and liposomes to deliver CRISPR/Cas9 and AMG315, and for on-demand controlled-release. For the sustained release and to protect CRISPR from lysosomal degradation, MENP-bound CRISPR and AMG315 will be encapsulated in liposomes. Accordingly, in Specific Aim # 1, we will develop, characterize, and evaluate the delivery of Tat-specific CRISPR Cas9/gRNA and AMG315 across the in vitro BBB using MENP-based drug delivery approach to excise HIV-1 Tat gene, and attenuate cannabinoid and Tat-induced inflammasome, respectively. In Specific Aim # 2, we will study the in vivo therapeutic efficacy of MENP nanoformulation containing CRISPR, and AMG315 using doxycycline-inducible HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS and cannabinoid administration animal model. In Specific Aim-3, we will validate the effects of these nanoformulations on neuronal plasticity and neurocognitive functions in vivo. Successful completion of this grant will have a translational significance in preventing HIV-1 Tat and cannabinoid-mediated neurodegeneration in HIV infected cannabinoid-abusing patients. This multidisciplinary new break-through concept targeting inflammasome in the brain with stable endocannabinoid ligand AMG315 and Tat specific CRISPR/Cas9 using MENP-based technology is in response to RFA-DA-20-026 and will be useful for the suppression of HIV replication, NLRP3 inflammasome activity and to treat cannabinoid-induced neuronal impairments in HIV infected cannabinoid abusers.


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	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	5	12/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $370,347 )
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	5	5/22/2024	NON-COMPETING CONTINUATION	$370,347
														Subtotal = $370,347

Issue Date FY: 2023 ( Subtotal = $370,610 )
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	4	5/24/2023	NON-COMPETING CONTINUATION	$370,610
														Subtotal = $370,610

Issue Date FY: 2022 ( Subtotal = $370,861 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	3	5/11/2022	NON-COMPETING CONTINUATION	$370,861
														Subtotal = $370,861

Issue Date FY: 2021 ( Subtotal = $735,302 )
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	001	2	6/3/2021	SUPPLEMENT FOR EXPANSION	$364,202
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	2	5/13/2021	NON-COMPETING CONTINUATION	$371,100
														Subtotal = $735,302

Issue Date FY: 2020 ( Subtotal = $383,202 )
2020	2020	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	1	6/18/2020	NEW	$383,202
														Subtotal = $383,202

Grand Total All Awards = $2,230,322

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Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid

Award Number: R01DA052271

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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