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Principal Investigator: Jennifer Eileen Adair
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2022
Award: $877,927
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT
The quest for an HIV cure remains incomplete, nearly half a century since the onset of the epidemic.
Antiretroviral drug cocktails can suppress HIV infection, but suffer in their success owing to side effects
and limitations in access and compliance. Injection of broadly neutralizing antibodies (bNAbs) to
prevent HIV rebound has had some success, but requires regular re-injection of multiple antibodies to
maintain suppression and viral escape. Thus, cost and continued access remain limitations. Genetic
engineering of patient cells has been proposed to overcome all of these shortfalls, and could constitute
a one-time treatment with lifelong therapeutic value if successful. In this proposal, we leverage a novel
approach developed by Dr. Justin Taylor’s laboratory to genetically engineer B cells to express bNAbs
for the treatment of human immunodeficiency virus (HIV). This strategy has already been used to
engineer B cells to produce antibodies protective against influenza virus, respiratory syncytial virus,
Epstein-barr virus and HIV [Moffett et al., Science Immunology, 2019]. While this approach can ensure
protective antibody production, the genetic engineering process required 10 days of complicated ex
vivo manufacturing and is not broadly distributable. To overcome these barriers, we will co-opt a novel,
synthetic nanoparticle that was developed in Dr. Jennifer Adair’s laboratory to deliver genetic
engineering in a single, passive step [Shahbazi et al., Nature Materials, 2019]. We show that this
nanoparticle can be assembled in less than a day to genetically engineer unstimulated, primary human
blood cells and can be modified to specifically interact with target blood cell types in vivo. Here we will
develop this scalable nanoformulation as a vaccine-like in vivo delivery system to direct humoral
immunity with multiple bNAbs in a clinically-relevant nonhuman primate model of HIV infection. We will
use these nanoparticles to directly genetically engineer native primary B cell subtypes, and
hematopoietic stem and progenitor cells, which can provide lifelong replenishment of antibody-
producing B cells. This research will not only develop a unique tool set against HIV but will provide
transformative advances in equitable distribution of gene editing therapies.
Terms: <7S Gamma Globulin><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Anti-Retroviral Agents><Antibodies><Antibody Formation><Antibody Production><Antibody Therapy><Antibody-Secreting Cells><Antigens><Antiretroviral Agents><Autograft><Autologous Transplantation><Autotransplant><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bar Codes><Blood Cells><Blood Plasma Cell><Blood Precursor Cell><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CRISPR><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 system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Survival><Cell Viability><Cell surface><Cells><Clustered Regularly Interspaced Short Palindromic Repeats><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><Collaborations><Coupling><DNA><DNA Therapy><Data><Deoxyribonucleic Acid><Drugs><E-B Virus><EB virus><EBV><Engineering><Ensure><Epidemic><Epstein Barr Virus><Frequencies><Gene Delivery><Gene Transfer Clinical><Genes><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Intervention><HHV-4><HHV4><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Half-Life><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><Human Herpesvirus 4><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Humoral Immunities><IgG><Immune><Immunes><Immunity><Immunoglobulin G><Immunoglobulin-Secreting Cells><Immunology><Infectious Mononucleosis Virus><Influenza Virus><Injections><Interruption><Intervention><Intervention Strategies><LAV-HTLV-III><Laboratories><Life><Liver><Lymphadenopathy-Associated Virus><Mediating><Medication><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><Modeling><Modern Man><Molecular Target><Murine><Mus><Nature><Patients><Peripheral Blood Cell><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma Cells><Plasmacytes><Process><Proliferating><Recombinant DNA Technology><Research><Research Resources><Resources><Respiratory syncytial virus><Risk><SHIV><Science><Single-Stranded DNA><Source><Surface><System><Technology><Testing><Therapeutic><Time><Tissues><Transplantation><Vaccines><Viral><Viral Diseases><Viral Vector><Virus Diseases><Virus-HIV><Work><anti-retroviral><antibody based therapies><antibody biosynthesis><antibody engineering><antibody treatment><antibody-based immunity><antibody-based therapeutics><antibody-based treatment><antiretroviral><autologous graft><autotransplantation><barcode><blood stem cell><cell type><clinical relevance><clinically relevant><cost><cost effective><design><designing><drug/agent><experience><fitness><gene repair therapy><gene therapy><gene-based therapy><gene-editing therapy><genetic therapy><genetically engineered><genetically engineered cells><genetically modified cells><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genomic therapy><gold nano particle><gold nanoparticle><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><hepatic body system><hepatic organ system><immunogen><immunogenic><immunoglobulin biosynthesis><improved><in vivo><in vivo evaluation><in vivo testing><influenzavirus><interventional strategy><lipid based nanoparticle><lipid nanoparticle><mouse model><murine model><nano formulation><nano gold><nano particle><nano-sized particle><nanoGold><nanoformulation><nanoparticle><nanosized particle><neutralizing antibody><new approaches><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><plasmocyte><preference><prevent><preventing><promoter><promotor><side effect><simian HIV><simian human immunodeficiency virus><success><synergism><therapeutic editing><therapeutic genome editing><tool><transplant><viral infection><viral rebound><virus infection><virus rebound><virus-induced disease>