Document text
Principal Investigator: Christopher W Peterson
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $770,685
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
HIV-specific gene therapies are a powerful and promising means to achieve HIV cure/stable remission in the
absence of antiretroviral therapy (ART). Broadly neutralizing antibodies (bNAbs) and analogous molecules such
as eCD4-Ig offer one of the clearest paths to a cure, but are hindered by three key obstacles. First, passive
administration of bNAb/eCD4-Ig proteins is by definition a transient therapy; when circulating levels of these
potent anti-HIV factors decline, virus replication is able to resume. Second, gene therapy vector-based
approaches including adeno-associated virus (AAV) support prolonged expression of bNAbs and other antiviral
transgenes, but are frequently limited by host immune responses. Third, potent ART regimens suppress viral
replication to extremely low levels, rendering engineered HIV-specific lymphocytes unable to recognize and clear
persistently infected cells. We have generated an exciting set of tools and preliminary data that directly addresses
each of these barriers. To overcome the transient nature of bNAbs and associated immunogenicity of vectored
delivery approaches, we have performed an in vivo screen in nonhuman primates (NHP) and identified
engineered AAV variants that persist long term (consistent with a lack of recognition by the host immune system),
and specifically target B cells. B cell tropic vectors will be packaged with CRISPR-Cas9 gene editing machinery,
applying highly innovative covalent linkage methodology to double our vectors’ packaging capacity. We refer to
our novel in vivo delivery approach as Non-Immunogenic, Cargo-Enhanced (NICE) AAV: in a single dose, NICE-
AAV vectors will specifically reprogram B cells with bNAb or eCD4-Ig sequences targeted to the native IgG locus.
Finally, we will overcome the significant problem of insufficient viral antigen by supplying cell-associated HIV-1
Env in trans. Our recent publication in the NHP model demonstrates the immense success of this strategy to
stimulate HIV-1-specific chimeric antigen receptor (CAR) T cells and should similarly boost and trigger expansion
of our gene-edited B cells. The central goals of our proposal are to validate the efficiency and specificity of B
cell-targeted NICE-AAV (AIM 1), to demonstrate that this in vivo delivery approach enables persistent
bNAb/eCD4-Ig expression in HIV anatomical compartments and reservoir sites (AIM 2), and most importantly,
to achieve a therapeutic impact in humanized mouse and NHP models of HIV persistence (AIM 3). We will merge
one of the most promising therapeutic modalities for HIV cure (bNAbs/eCD4-Ig) with our extremely unique in
vivo delivery platform (NICE-AAV). Importantly, this approach will be applicable not only for HIV-1, but for the
broad range of pathologies where monoclonal antibody therapies offer clinical benefit.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><AAV vector><AAV-based vector><AIDS Virus><AIDS/HIV><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adeno-Associated Viruses><Anatomic Sites><Anatomic structures><Anatomy><Animals><Antibodies><Antibody Therapy><Antigens><Assay><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biological Assay><Blood Serum><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><COVID-19 virus><COVID19 virus><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><Cancers><Capsid><Cas nuclease technology><Cell Body><Cells><Clinical><Clinical Research><Clinical Study><Clinical Treatment Moab><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><CoV-2><CoV2><Communicable Diseases><DNA Therapy><Data><Dependoparvovirus><Dependovirus><Disease remission><Dose><Drugs><Engineering><Experimental Designs><Failure><Gene Therapy Vectors><Gene Transduction Agent><Gene Transduction Vectors><Gene Transfer Clinical><Genes><Genetic><Genetic Intervention><Goals><HIV><HIV Antibodies><HIV-1><HIV-Associated Antibodies><HIV-I><HIV/AIDS><HIV1><HTLV-III Antibodies><HTLV-III-LAV Antibodies><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Human immunodeficiency virus 1><IGH><IGH@ gene cluster><IgG><IgH locus><Immune response><Immune system><Immunocompetent><Immunodeficient Mouse><Immunoglobulin G><Immunoglobulin Heavy Chain Genes><Immunoglobulin Heavy Gene><Immunoglobulin Heavy Locus><Immunological response><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Injections><Knock-in><LAV Antibodies><LAV-HTLV-III><Libraries><Link><Low-resource area><Low-resource community><Low-resource environment><Low-resource region><Low-resource setting><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><Lymphatic cell><Lymphocyte><Lymphocytic><M mulatta><M. mulatta><Macaca mulatta><Malignant Neoplasms><Malignant Tumor><Measures><Medication><Methodology><Methods><Mice><Mice Mammals><Modality><Modeling><Modern Man><Monoclonal Antibodies><Monoclonal Antibody Therapy><Murine><Mus><Nature><PBMC><Pathology><Peripheral Blood Mononuclear Cell><Pharmaceutical Preparations><Phenotype><Proteins><Publications><Publishing><Regimen><Remission><Resource-constrained area><Resource-constrained community><Resource-constrained environment><Resource-constrained region><Resource-constrained setting><Resource-limited area><Resource-limited community><Resource-limited environment><Resource-limited region><Resource-limited setting><Resource-poor area><Resource-poor community><Resource-poor environment><Resource-poor region><Resource-poor setting><Rhesus Macaque><Rhesus Monkey><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SHIV><Scientific Publication><Secondary to><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Site><Specificity><T cells for CAR><Technology><Testing><Therapeutic><Therapeutic Effect><Therapeutic antibodies><Time><Tissues><Transgenes><Tropism><Variant><Variation><Viral><Viral Antigens><Viremia><Virus><Virus Replication><Virus-HIV><Withdrawal><Wuhan coronavirus><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><antiretroviral therapy><antiretroviral treatment><autoimmune condition><autoimmune disorder><autoimmunity disease><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><clinical applicability><clinical application><coronavirus disease 2019 virus><coronavirus disease-19 virus><delivery vector><delivery vehicle><drug/agent><experiment><experimental research><experimental study><experiments><fighting><gene editing method><gene editing methodology><gene editing platform><gene editing strategy><gene editing system><gene editing techniques><gene editing technology><gene editing tools><gene repair therapy><gene therapy><gene-based therapy><gene-editing approach><gene-editing toolkit><genetic information><genetic therapy><genomic therapy><global health><hCoV19><host response><humanized mice><humanized mouse><immune competent><immune system response><immunogen><immunogenic><immunogenicity><immunoglobulin heavy chain locus><immunoresponse><in vivo><innovate><innovation><innovative><knockin><lymph cell><mAB-based therapy><mAb therapy><mAb-based therapeutics><mAbs><malignancy><monoclonal Abs><nCoV2><neoplasm/cancer><neutralizing antibody><non-human primate><nonhuman primate><novel><pre-clinical study><preclinical study><programs><screening><screenings><simian HIV><simian human immunodeficiency virus><success><tool><trafficking><transduction efficiency><transgene><vector><vector biodistribution><viraemia><viral multiplication><viral rebound><viral replication><viral sepsis><virus antigen><virus multiplication><virus rebound><virusemia>