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Principal Investigator: David Terry Curiel
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $1,289,517
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
A variety of gene therapy strategies have been developed to achieve HIV cure. These strategies include genetic
methods to render immune cells resistant to infection or to enhance immune effector cell anti-HIV activity. In this
latter instance, genetic engineering of B cells has provided a highly novel means to achieve vectored
immunotherapy for production of broadly neutralizing anti-HIV antibodies (bnAbs). Of note, the exceptional
utilities of gene editing have been successfully employed to achieve precision genome modification of B cells to
accomplish this technical end. In this approach, primary mature B cells from the periphery are modified to express
HIV bnAbs as functional antigen receptors spliced to cell endogenous heavy chain constant genes. These cells
are then expanded and affinity-matured, using vaccines or viral antigen in vivo, resulting in the elicitation of
durable, self-tolerant, and isotyped-switched broadly neutralizing antibodies and memory. Here-to-fore this
promising B cell approach has mandated ex vivo genetic modification to practically accomplish effective cell
engineering. This facet of the strategy thereby entrains technical and methodological complexities practically
limiting this approach. Clearly, the ability to accomplish genetic modification of B cells in vivo would render this
approach of greater applicability and accessibility. Further to this end, the ability to achieve such in vivo B cell
transduction, in an efficient and selective manner, would be key to realizing the benefits of this technology with
an acceptable margin of safety. To this end, we have explored the utilities of replication defective adenoviral
vectors (Ad) to address the mandates for in vivo transduction of B cells. In this regard, we have developed a
novel “triple targeting” approach that allows efficient and selective gene delivery to key target cells in vivo. In
addition, adenovirus provides a unique framework for effective and economical in vivo delivery of CRISPR/Cas9
and donor DNA for targeted integration of bnAb genes into the B cell genome by homology directed repair in
situ. Of additional note, the use of non-human primate Ads allows derivation of vectors that can traverse immune
barriers to human adenovirus-based vectors. In the aggregate, these combined facets of adenovirus provide the
critical functional capacities allowing us to address the mandates of an in vivo applied anti-HIV B cell vectored
immunotherapy strategy.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Activities of Daily Living><Activities of everyday life><Ad vector><Address><Adenoviral Vector><Adenoviridae><Adenovirus Vector><Adenoviruses><Adoptive Transfer><Affinity><Antibodies><Antibody Response><Antibody titer measurement><Antigen Receptors><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Biologic Models><Biological Models><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cells><Class Switching><Class Switchings><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><DNA><DNA Therapy><Deoxyribonucleic Acid><Derivation><Derivation procedure><Development><Effector Cell><Engineering><Evaluation><Funding><Gene Delivery><Gene Transfer Clinical><Genes><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Intervention><Genome><HIV><HIV Antibodies><HIV Antigens><HIV-Associated Antibodies><HIV-Associated Antigens><HTLV-III Antibodies><HTLV-III Antigens><HTLV-III-LAV Antibodies><HTLV-III-LAV Antigens><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Human T-Lymphotropic Virus Type III Antigens><Immune><Immune mediated therapy><Immune system><Immunes><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunologically Directed Therapy><Immunotherapy><In Situ><Infection><Investments><Isotype Switching><Isotype Switchings><Knock-in><LAV Antibodies><LAV Antigens><LAV-HTLV-III><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Antigens><Lymphadenopathy-Associated Virus><Mature B-Cell><Mature B-Lymphocyte><Mediating><Memory><Methodology><Methods><Mice><Mice Mammals><Model System><Modeling><Modern Man><Modification><Murine><Mus><NIH><National Institutes of Health><Production><RNA Splicing><Recombinant DNA Technology><Resistance><Running><Safety><Self Tolerance><Splicing><Technology><Therapeutic><United States National Institutes of Health><Vaccination><Vaccine Antigen><Viral Antigens><Viral reservoir><Virus reservoir><Virus-HIV><Work><adeno vector><adenovector><antibody titering><cell engineering><cell transduction><cellular engineering><cellular transduction><daily living function><daily living functionality><defective adenoviral vector><defective adenovirus vector><design><designing><developmental><functional ability><functional capacity><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genetically engineered><genomic therapy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><improved><in vivo><knockin><neutralizing antibody><new approaches><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><repair><repaired><resistant><response><transduced cells><vector><virus antigen>