Project Grant R21EB033963
- This Project Grant award of $374,199 from the National Center for Advancing Translational Sciences (NCATS), CFDA 93.350, supports the development of an in situ capsid protein and DNA imaging platform to characterize therapeutic adeno-associated virus (AAV) titers. AAV is a leading gene delivery vector for treating human diseases, but safety challenges related to high AAV vector genome titers have resulted in adverse events, including patient deaths. This project aims to create analytical methods...
- This Project Grant award from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), under the Discovery and Applied Research for Technological Innovations to Improve Human Health program (CFDA 93.286), is focused on developing a stable production cell line for recombinant adeno-associated virus (rAAV) biomanufacturing. The $436,658 award aims to address key challenges with current transient transfection-based rAAV production methods, such as low productivity, scalability...
- This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) provides $284,331 to the University of Massachusetts Medical School (UMass Medical) to develop novel methods for characterizing the structure and stability of gene therapy vector genomes in human hepatocytes when challenged by natural viral infections. The key objectives are to: 1) Track changes in the abundance and episomal...
- This Project Grant award of $1,640,169 from the National Institute of General Medical Sciences (NIGMS) Biomedical Research and Research Training program (CFDA 93.859) supports Synvivia, Inc.'s development of a platform to identify cyclic peptides that can increase the yield and quality of adeno-associated virus (AAV) vectors for gene therapy manufacturing. The key products and services to be delivered include: Demonstrating that Synvivia's cyclic peptide discovery library contains compounds that...
- This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under CFDA 93.837 - Cardiovascular Diseases Research provides $704,635 to the University of Florida to develop optimized adeno-associated virus (AAV) vectors for gene therapy of hemophilia. Specifically, the award aims to engineer both capsid- and genome-modified AAV3 vectors that can transduce human hepatocytes more efficiently than current AAV5 vectors, potentially reducing the required vector dose and...
- This Project Grant award of $3,192,404 from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) supports research on immunomodulation in adeno-associated virus (AAV) gene therapy. The research aims to better understand, model, and manage immune responses that can arise from systemic dosing of recombinant AAV vectors, which pose a major challenge in the treatment of monogenic disorders using this gene...
- This federal Project Grant award from the National Institutes of Health (NIH) Office of Research Infrastructure Programs (CFDA 93.351) provides $887,626 to the University of Miami to conduct research focused on preventing immune responses towards adeno-associated virus (AAV)-delivered anti-HIV antibodies. The project aims to explore two strategies to induce tolerance and prevent anti-drug antibody (ADA) formation in response to AAV-mediated gene therapy delivering broadly neutralizing HIV...
- This federal Project Grant award from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), under the Discovery and Applied Research for Technological Innovations to Improve Human Health program (CFDA 93.286), is supporting research to develop an efficient synthetic RNA switch that can regulate the timing and dosing of gene therapies delivered via adeno-associated viral (AAV) vectors. The $1,158,262 award to the University of Massachusetts Medical School will fund the...
- This Project Grant award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), under the Child Health and Human Development Extramural Research program (CFDA 93.865), aims to extend the reach and efficacy of adeno-associated virus (AAV)-based gene therapy by utilizing endogenously produced extracellular vesicles (EVs) to transport engineered transgene mRNA or protein products among cells and across tissues. The $860,750 award to Emory University will...
- This federal Project Grant award from the National Eye Institute (NEI), part of the Department of Health and Human Services, provides $719,012 in funding to the University of California, Davis to conduct research on optimizing the delivery of adeno-associated virus (AAV) gene therapies via the suprachoroidal space in non-human primates for the treatment of retinal diseases. The goal is to enhance the biodistribution, cellular tropism, durability, and safety of suprachoroidal AAV administration...
MITIGATING THE IMMUNOGENICITY OF ENGINEERED AAV GENE DELIVERY VECTORS BY BIOMATERIAL-DRIVEN IMMUNOSUPPRESSION - MITIGATING THE IMMUNOGENICITY OF ENGINEERED AAV GENE DELIVERY VECTORS BY BIOMATERIAL-DRIVEN IMMUNOSUPPRESSION PROJECT SUMMARY RECOMBINANT ADENO-ASSOCIATED VIRUS (AAV) VECTOR-MEDIATED GENE DELIVERY IS PROMISING FOR A VARIETY OF CHRONIC AND GENETIC DISEASES. DESPITE HUGE CLINICAL OUTCOMES TO DATE, AAV VECTOR GENE DELIVERY HAS BEEN LIMITED DUE TO ITS DURABILITY. SINGLE AAV ADMINISTRATION CAN LAST FROM MONTHS TO SEVERAL YEARS OF GENE EXPRESSION ABOVE THERAPEUTIC LEVELS. HOWEVER, MANY INHERITED DISEASES REQUIRE LIFELONG TREATMENT TO AVOID IRREVERSIBLE TISSUE DAMAGE. THUS, THE ABILITY TO RE-ADMINISTER AAV IS CRUCIAL TO ACHIEVING SUSTAINED THERAPEUTIC EFFICACY OVER TIME. ALTHOUGH AAVS ARE CONSIDERED LOW IMMUNOGENIC AND SAFE AS COMPARED WITH OTHER VIRAL VECTORS, THE IMMUNOGENICITY OF CAPSIDS STILL REPRESENTS A MAJOR OBSTACLE TO THE RE-ADMINISTRATION OF AAV VECTORS. TO ADDRESS THESE CHALLENGES, WE ADOPT AN ENDOGENOUS IMMUNE TOLERANT STRUCTURE, PHOSPHOSERINE (PS) FROM NATURAL PHOSPHATIDYLSERINE LIPID, AS AN IMMUNOSUPPRESSIVE MOIETY TO ENABLE THE RE-ADMINISTRATION OF AAV VECTORS. TO AVOID EFFICACY LOSS OR SHORT CIRCULATION DUE TO THE INTRINSIC NEGATIVE CHARGE OF NATIVE PS STRUCTURE, WE PROPOSE TO ENGINEER THE PS STRUCTURE INTO A WELL-DEFINED IMMUNOSUPPRESSIVE DEGRADABLE PS PEPTIDE MATERIAL WITH OVERALL ZWITTERION/NEUTRAL CHARGE AND HIGH PS DENSITY AND CONJUGATE IT TO AAV CAPSIDS, THUS ENABLING THE MODIFIED GENE VECTORS WITH RE-ADMINISTRATION CAPABILITY. TWO SPECIFIC AIMS ARE (A) PREPARATION AND CHARACTERIZATION OF PS-CONTAINING ZWITTERIONIC PEPTIDE-MODIFIED AAVS; (B) IN VIVO IMMUNE TOLERANCE AND MULTI-DOSE STUDY OF GENE DELIVERY IN NORMAL AND FIX-DEFICIENT MICE. THE PROPOSED WORK WILL DEVELOP A BIOMATERIAL-DRIVEN, IMMUNOSUPPRESSION-ENABLING, ZWITTERIONIC PS PEPTIDE-BASED VIRAL VECTOR ENGINEERING PLATFORM, REALIZING THE RE-ADMINISTRATION OF AAV VECTORS WHILE MAINTAINING THEIR TRANSDUCTION EFFICIENCY. SUPPORT OF THIS PROJECT WILL INITIATE THE DEVELOPMENT OF A TRANSLATABLE BIOMATERIAL TECHNOLOGY FOR THE FIELD OF AAV-MEDIATED GENE DELIVERY. THE SUCCESS OF THIS PROJECT WILL ADVANCE THE CURRENT AAV-BASED GENE THERAPY AND PROVIDE CLINICAL BENEFITS TO PATIENTS.
Mod # | Description | ReasonForModification | Federal Obligation | Date |
|---|---|---|---|---|
| Not listed | $0 | 9/11/25 | ||
| Not listed | $435.4k | 7/20/23 |