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Principal Investigator: Kuo-Ching Mei
Organization: STATE UNIVERSITY OF NY,BINGHAMTON
Fiscal Year: 2024
Award: $354,807
Funding agency: National Institute of General Medical Sciences
Complementary Biotherapeutic Delivery Platforms for Enabling Gene Re-delivery
Project Summary
Facing the universal challenge of re-delivering Adeno-associated viruses (AAVs), our project endeavors to
pioneer delivery-focused solutions in gene therapy. The core obstacle stems from the host immune system's
robust reactions to the vector and cytotoxic responses to its transduced cells & transgenes, highlighting a
pressing need for innovative delivery strategies that engage and modulate the corresponding immune
responses. Our approach is multifaceted, comprising three distinct delivery platforms, each addressing unique
aspects of the antigen-processing machinery and focusing on overcoming specific biological barriers for
delivering the “updated” instructions for modulated immune responses. (1) Targeted Cell Delivery of Regulatory
T Cell (Treg): While Tregs represent a novel avenue for cell-based therapies, their non-specific delivery can
lead to undesired immunosuppression. The first challenge involves directing Treg cells to immunogenic cell
death sites caused by transgene persistence. Our strategy to overcome this is to engineer Chimeric Antigen
Receptors (CAR) to enhance Treg navigation and delivery of Tregs to transgene persistence sites, enabling
rescued and sustained transgene gene expression. (2) Targeted Delivery System for IgG-Protease: The
second program targets the selective removal of antigen-specific IgG, specifically for neutralizing antibodies
that hinder AAV gene delivery vectors. IgG degrading protease is an effective way of eliminating pre-existing
naturalizing antibodies. However, non-specific delivery of IgG will lead to systematic disarming of our immune
defense. We are developing antigen/antibody-fused IgG protease to deliver a protease selectively, ensuring
that only unwanted, harmful immunogenic antibodies are present. (3) Targeted Lipid Nanoparticles for Cell-
Specific RNA-Delivery: The third program addresses the significant challenge of achieving cell-specific RNA
delivery for inducing tolerogenic antigen processing. mRNA delivery is a highly effective method for in vivo
antigen production, and siRNA delivery is a highly effective immune modulation method. However, non-specific
delivery of RNA at the wrong microenvironment might trigger immunogenic instead of tolerogenic responses.
By focusing on precision delivery to the antigen-presenting cells and their surroundings, we aim to synthesize
and formulate novel lipid nanoparticle formulations for achieving cell-type specific RNA delivery for better
controlling the intended tolerogenic response for AAV vectors. By addressing these challenges and pioneering
advanced delivery and targeting strategies, our research seeks to unravel the fundamental intricate between
the biological barriers in delivery to the immune system and re-enabling viral gene delivery vectors, paving the
way for transformative advancements in gene therapy and improved human health.
Terms: <7S Gamma Globulin><AAV vector><AAV-based vector><Abscission><Address><Adeno-Associated Viruses><Antibodies><Antigen-Presenting Cells><Antigens><Biological><Biological Response Modifier Therapy><Biological Therapy><Cell Body><Cell Therapy><Cells><DNA Therapy><Dependoparvovirus><Dependovirus><Engineering><Ensure><Enzyme Gene><Enzymes><Esteroproteases><Excision><Extirpation><Formulation><Gene Delivery><Gene Expression><Gene Transfer Clinical><Genes><Genetic Diseases><Genetic Intervention><Health><Human><IgG><Immune><Immune reaction><Immune response><Immune system><Immunes><Immunoglobulin G><Immunological response><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Instruction><Methods><Modern Man><Peptidases><Peptide Hydrolases><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Production><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Public Health><RNA delivery><Reaction><Regulatory T-Lymphocyte><Removal><Research><Safety><Site><Surgical Removal><System><Therapeutic><Transgenes><Treg><Update><Vaccines><Work><accessory cell><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><antigen processing><biologic><biological therapeutic><biological treatment><biologically based therapeutics><biotherapeutics><biotherapy><cell mediated therapies><cell transduction><cell type><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><cellular transduction><chimeric antigen receptor><cytotoxic><deliver mRNA><deliver messenger RNA><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for mRNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vector><delivery vectors for siRNA><delivery vehicle><disability><gene repair therapy><gene therapy><gene-based therapy><genetic condition><genetic disorder><genetic therapy><genomic therapy><host response><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogen><immunogenic><immunogenic apoptosis><immunogenic cell death><immunologic reactivity control><immunomodulatory><immunoreaction><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><innovate><innovation><innovative><lipid based nanoparticle><lipid nanoparticle><mRNA delivery><messenger RNA delivery><neutralizing antibody><novel><pharmaceutical><programs><regulatory T-cells><resection><response><short interfering RNA delivery><siRNA delivery><site targeted delivery><small interfering RNA delivery><stem><targeted delivery><transduced cells><transgene><vector><viral gene delivery>