CAPSID-ENGINEERED AAV VECTORS WITH BREC1-BASED GENE THERAPEUTICS FOR INACTIVATING THE HIV RESERVOIR - ABSTR…

Assistance award details

Assistance award identifier

ASST_NON_R01AI181053_075

FAIN

R01AI181053

Recipient

YALE UNIV

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$2,189,423

Period

Jul 16, 2024 – Jun 30, 2029

Fiscal year

2024

Place of performance state

CT

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

CAPSID-ENGINEERED AAV VECTORS WITH BREC1-BASED GENE THERAPEUTICS FOR INACTIVATING THE HIV RESERVOIR - ABSTRACT/SUMMARY PEOPLE LIVING WITH HIV (PLWH) CONTINUE TO HARBOR VIRUS-INFECTED CELLS DESPITE SUPPRESSION BY ANTIRETROVIRAL THERAPY. THESE RESERVOIR CELLS ARE THE SOURCE OF VIRUS REBOUND THAT TYPICALLY OCCURS IN 1-8 WEEKS IF TREATMENT IS DISCONTINUED. ELIMINATING THE PROVIRUS INTEGRATED IN THE GENOME OF INFECTED CELLS OR THE INFECTED CELLS THEMSELVES CAN CURE PLWH. THE RECENTLY DISCOVERED GENOME EDITING TECHNIQUE CALLED CRISPR IS BEING DEVELOPED AS AN APPROACH TO TARGET AND EXCISE HIV DNA SEQUENCES PRESENT IN INFECTED CELLS. LARGE CHALLENGES TO USING THE CRISPR APPROACH FOR HIV ELIMINATION ARE THE WIDE DIVERSITY OF VIRAL ISOLATES IN PLWH AND THE RISK OF GENOTOXICITY AS THE CAS9 ENZYME CAUSES DOUBLE-STRANDED BREAKS (DSBS) IN THE HOST CHROMOSOME. THE ABSENCE OF A TARGETED DELIVERY SYSTEM FOR CELLS THAT MAKE UP THE HIV RESERVOIR INCREASES THESE RISKS DUE TO OFF-TARGET EFFECTS. THIS R01 APPLICATION IN RESPONSE TO RFA-AI-20-076: “NEW TECHNOLOGIES FOR THE IN VIVO DELIVERY OF GENE THERAPEUTICS FOR AN HIV CURE” ADDRESSES THE CHALLENGES POSED BY CRISPR-BASED GENE THERAPY. WE WILL USE A DESIGNER RECOMBINASE, BREC1, THAT HAS BEEN DEVELOPED TO SOLELY TARGET HIV-1 PROVIRUS SEQUENCES AND REMOVE THESE FROM THE GENOME. 90% OF THE MAJOR HIV-1 SUBTYPE GROUPS A, B, AND C ARE EXPECTED TO HARBOR THE PRECISE BREC1 TARGET SEQUENCE. BREC1 SHOWS NO IMMUNOGENIC POTENTIAL, DOES NOT INDUCE CELLULAR TOXICITY OR DISPLAY OFF- TARGET ACTIVITY. WE WILL IN ADITION RE-ENGINEER BREC1 TO GENERATE A SUPER-REPRESSOR CALLED BREC1-OFF THAT CAN DURABLY SILENCE HIV TRANSCRIPTION BY EPIGENETICALLY MODIFYING HIV PROMOTER SEQUENCES. KEY TO THE SUCCESS OF THIS APPROACH IS OUR DEVELOPMENT OF CAPSID-ENGINEERED ADENO-ASSOCIATED VIRAL (AAV) VECTORS TO DELIVER BREC1 AND BREC1-OFF SPECIFICALLY TO HUMAN T CELLS AND MYELOID CELLS IN PERIPHERAL TISSUES AND THE CENTRAL NERVOUS SYSTEM. AAV VECTORS ARE ONE OF SAFEST