IMMUNOMODULATION IN AAV GENE THERAPY - ABSTRACT RECOMBINANT AAV VECTORS HAVE EMERGED AS PROMISING GENE DELI…

Assistance award details

Assistance award identifier

ASST_NON_R01AI194953_075

FAIN

R01AI194953

Recipient

DUKE UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$3,192,404

Period

Aug 21, 2025 – Jul 31, 2029

Fiscal year

2025

Place of performance state

NC

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

IMMUNOMODULATION IN AAV GENE THERAPY - ABSTRACT RECOMBINANT AAV VECTORS HAVE EMERGED AS PROMISING GENE DELIVERY VEHICLES IN THE TREATMENT OF MONOGENIC DISORDERS. WITH 6 DIFFERENT FDA APPROVED AAV-BASED THERAPIES, MANY ADDITIONAL DISEASE TARGETS REQUIRING SYSTEMIC DOSING CONTINUE ADVANCING TOWARDS THE CLINIC. HOWEVER, IMMUNE RESPONSES ARISING FROM PRIOR NATURAL AAV EXPOSURE OR NASCENT EXPOSURE TO RECOMBINANT AAV VECTORS DOSED IN HUMAN SUBJECTS POSES A MAJOR CHALLENGE. EVIDENCE FROM MULTIPLE GENE THERAPY CLINICAL TRIALS CONFIRMS THAT HIGH VECTOR DOSES CAN TRIGGER CYTOKINE RELEASE LEADING TO NAUSEA, FEVER, AND VOMITING, AND MANIFEST IN LIVER TOXICITY (ELEVATED ENZYMES). IN SOME PATIENTS, COMPLEMENT ACTIVATION FOLLOWING SYSTEMIC AAV DOSING HAS BEEN SHOWN TO RESULT IN THROMBOTIC MICROANGIOPATHY (TMA) AND ACUTE KIDNEY INJURY (ATYPICAL HEMOLYTIC UREMIC SYNDROME-LIKE), THROMBOCYTOPENIA, MYOCARDIAL INJURY, AND EVEN DEATH. MANY OF THESE ADVERSE REACTIONS CAN BE ATTRIBUTED TO AAV CAPSID-ANTIBODY INTERACTIONS HIGHLIGHTING A MAJOR (IF NOT PREDOMINANT) ROLE FOR HUMORAL IMMUNITY. PROPHYLACTIC MEASURES OR SYMPTOM MANAGEMENT HAVE GENERALLY INCLUDED PLASMAPHERESIS, ADMINISTRATION OF TAPERING, HIGH DOSES OF GLUCOCORTICOSTEROIDS, HEMODIALYSIS, PLATELET TRANSFUSION, DIFFERENT DRUGS OR MONOCLONAL ANTIBODIES TO BLOCK COMPLEMENT/B CELL ACTIVATION OR INDUCE B CELL DEPLETION AMONGST OTHERS. MORE RECENTLY, PRECLINICAL TESTING OF AGENTS SUCH AS IMLIFIDASE OR VYVGART FOR PROMOTING IGG CLEARANCE HAS BEEN INITIATED. HOWEVER, THESE CURRENT MANAGEMENT OR MITIGATION STRATEGIES FOR THESE CLINICAL SEQUALAE ARE APPLIED ON A CASE-BY-CASE BASIS WITH NO SPECIFIC CONSENSUS IMMUNOMODULATORY REGIMENS (IMRS) IN PLACE. THUS, THERE IS A CLEAR AND URGENT NEED TO BETTER UNDERSTAND, PRECLINICALLY MODEL AND MANAGE THESE COMPLEX SEQUALAE (FOCUS OF THE CURRENT PROPOSAL). TO THIS END, OUR LAB RECENTLY ENGINEERED A NOVEL IMMUNOMODULATORY AGENT, ICEMG – A RECOMBINANT, DUAL ACTIVITY PROTEASE THAT CAN SELECTIVELY AND EF