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Brain myeloid cell-targeted multiplexed gene editing for SIV/HIV eradication

Award Number: R01MH130193
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/05/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Brain myeloid cell-targeted multiplexed gene editing for SIV/HIV eradication - Project Summary The long-lived myeloid cells such as perivascular macrophages and microglia in the central nervous system (CNS) persistently harbor HIV. These infected cells could contribute to the source of residual viremia during long-term antiretroviral therapy (ART) or to rebounding virus upon ART cessation. It is undoubtfully and urgently needed to develop novel strategies to specifically target CNS myeloid cells for HIV eradication and a cure. Be- cause the effects of the widely-studied “Shock and Kill” approach could exacerbate neuroinflammation, gene therapy emerges as the optimal strategy, particularly the advanced CRISPR genome editing technology. Simian immunodeficiency virus (SIV) infection of macaques is the best available model for testing novel strategies prior to clinical studies. We have shown that SIV infection has a broad spread in the CNS even in animals on ART. Because the virus enters the brain within a few days after infection and the establishment of the latent reservoir occurs very early, the initiation of ART should be as early as possible. In addition, numerous studies suggest that CCR5/CCR2 play a major role in HIV entry and neuroinflammation. Most importantly, we have used AAV delivery of a CRISPR/Cas genome editor to eradicate HIV/SIV provirus in models of humanized mice and non- human primates. However, the lack of AAV serotypes that are highly effective and reliable to transduce myeloid cells in the CNS remains a key challenge. Therefore, we hypothesize that the multiple-targeting gene editing system across the blood brain barrier (BBB) can remove SIV provirus in infected myeloid cells, protect cells against new infection, and inhibit neuroinflammation. To test this hypothesis, we will optimize a novel AAV sero- type with BBB penetration and myeloid-specific transduction (namely AAV-BM) to effectively deliver the smaller cjCas9 with multiplex sgRNAs (BMCj4) specific for 4 target sites (SIV LTR, gag, and host CCR5, CCR2) into the entire CNS for in vivo HIV/SIV eradication (Aim 1). We will evaluate the efficacy of BMCj4 early treatment in preventing brain SIV infection or/and excising SIV proviral DNA from brain myeloid cells in acute SIV infection with early ART (Aim 2a). We will also determine the therapeutic effect of BMCj4 with ART and then boost it with an alternative AAV-BM for eradication of persistent brain SIV latent infection (Aim 2b). We expect that early or long-term repeated BMCj4 AAV gene therapy will effectively eradicate acute and latently-infected HIV provirus and extensively minimize the size of the brain viral reservoir to achieve a sterilizing or functional cure of HIV/AIDS, particularly NeuroAIDS.


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 = $655,499 )
2025	2025	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Mental Health Research Grants	000	4	3/5/2025	NON-COMPETING CONTINUATION	$655,499
														Subtotal = $655,499

Issue Date FY: 2024 ( Subtotal = $786,365 )
2024	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Mental Health Research Grants	001	3	5/3/2024	NON-COMPETING CONTINUATION	$78,637
2024	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Mental Health Research Grants	000	3	2/5/2024	NON-COMPETING CONTINUATION	$707,728
														Subtotal = $786,365

Issue Date FY: 2023 ( Subtotal = $795,229 )
2023	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Mental Health Research Grants	000	2	2/8/2023	NON-COMPETING CONTINUATION	$795,229
														Subtotal = $795,229

Issue Date FY: 2022 ( Subtotal = $915,398 )
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Mental Health Research Grants	001	1	9/16/2022	NEW	$89,315
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Mental Health Research Grants	000	1	4/5/2022	NEW	$826,083
														Subtotal = $915,398

Grand Total All Awards = $3,152,491

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Brain myeloid cell-targeted multiplexed gene editing for SIV/HIV eradication

Award Number: R01MH130193

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/05/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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