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Long-term microglia-targeted endogenous retrovirus-like particle (ERVLP) delivery of Cas12f editor to cure HIV

Award Number: R01DA056876
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Long-term microglia-targeted endogenous retrovirus-like particle (ERVLP) delivery of Cas12f editor to cure HIV - Summary Latently infected brain myeloid cells including microglia (MG) and perivascular macrophages can serve as HIV reservoirs, contributing to NeuroHIV persistence, chronic neuroinflammation and HIV-associated neurocognitive disorders (HAND). Strategies aimed at eliminating HIV reservoirs are highly promising to cure HIV, even in the presence of effective anti-retroviral therapy. Extensive studies including FDA-approved phase I clinical trial have demonstrated the therapeutic potential of CRISPR/Cas genome editing to cure HIV. However, a major barrier to the clinical application is the lack of effective and specific delivery to the targeted disease-relevant tissues and/or cells in vivo, particularly in NeuroHIV. The overall objective of this proposal is to develop AAV-mediated stealth cargo delivery of miniature Cas12f genome editor to the HIV cellular reservoir in the brain. We will utilize novel PEG10-mediated endogenous retrovirus-like particle (ERVLP) technology that relies on endogenous PEG10 and syncytin-A for Cargo(Cas12f) mRNA transfer into MG. This approach will harness the benefits of the most promising AAV gene therapy. Several AAV serotypes such as AAV1, 2, 5, 6 can transduce MG (AAV-M) with >80% efficiency in vitro and in vivo, but cannot cross the blood-brain barrier (BBB). In contrast, the currently available BBB-penetrating AAV serotypes (AAV-B) such as AAV9, PhP.B, PhP.eB, F, B10 or B22 have low efficiency in transducing MG both in vitro and in vivo. Therefore, novel AAV serotypes that effectively cross the BBB and transduce MG (AAV-BM) are urgently needed. We hypothesize that AAV-B can offer a one-time injectable systemic delivery of stealth cargo (cDNA) into astrocytes and/or neurons thatin turn serve as relay stationsfor sustained mRNA/sgRNA transfer to MG. This stealth AAV cargo will also include a designer exosome transfer into cells (EXOtic) device via CD63 linked with MG-specific peptide (CD63M). We expect that PEG10-mediated ERVLP and CD63M-mediated EXOtic will synergistically boost the endogenous spreading of HIV eradicator to MG. To accomplish this, we will first use the Cre-LoxP system for proof of concept that MG-targeted exosome-enveloped ERVLP system (Exo-ERVLP) via AAV-B can efficiently deliver Cargo(Cre)-mRNA in vivo from transduced astrocytes/neurons to non-transduced MG in LoxP-STOP- LoxP (LSL)-tdTomato reporter mice (Aim 1). Then, we will assess MG-targeting and genome editing efficiency of multiplexed Cas12f mRNA/sgRNA sustained delivery in LSL-tdTomato mice and HIV Tg26 transgenic mice (Aim 2). Finally, we will explore the therapeutic potential of Exo-ERVLP AAV-B-Cas12f systemic injection in HIV Tg26 transgenic mice (Aim 3). This high-risk high-reward proposal brings together several advancing technologies and established teams with complementary expertise. The all-in-one multiplexed Cas12f/sgRNA transgene is delivered via AAV-B, PEG10 cargo and CD63M EXOtic for sustained targeting and HIV eradication. The expected positive outcomes will offer a novel tool to systemically deliver CRISPR/Cas editor to MG, and provide new avenues for therapeutics development for multiple MG-related diseases.


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 = $862,593 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	003	5	7/25/2025	NON-COMPETING CONTINUATION	$576,854
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	002	4	7/24/2025	NON-COMPETING CONTINUATION	$0
2025	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	3	5/7/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$293,056
2025	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	5/7/2025	NEW	-$7,317
														Subtotal = $862,593

Issue Date FY: 2024 ( Subtotal = $550,569 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	002	4	7/3/2024	NON-COMPETING CONTINUATION	$576,854
2024	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	2	1/31/2024	NON-COMPETING CONTINUATION	-$578,971
2024	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	3	1/31/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$552,686
														Subtotal = $550,569

Issue Date FY: 2023 ( Subtotal = $618,757 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	2	7/17/2023	NON-COMPETING CONTINUATION	$618,757
														Subtotal = $618,757

Issue Date FY: 2022 ( Subtotal = $627,757 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	8/18/2022	NEW	$627,757
														Subtotal = $627,757

Grand Total All Awards = $2,659,676

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Long-term microglia-targeted endogenous retrovirus-like particle (ERVLP) delivery of Cas12f editor to cure HIV

Award Number: R01DA056876

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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