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Principal Investigator: Ke Zhang
Organization: NORTHEASTERN UNIVERSITY
Fiscal Year: 2024
Award: $473,599
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
Oligonucleotides face several biopharmaceutical difficulties, including stability and delivery issues as well
as non-hybridization activities such as coagulopathy and unwanted activation of the immune system. We
have developed a unique oligonucleotide delivery system, termed pacDNA, which uses a high-density
bottlebrush polymer to provide oligonucleotides with binding selectivity. The polymer amounts to an
entropic barrier, reducing access to the oligonucleotide by various proteins (and thus side effects) but still
allows for unhindered hybridization. This novel strategy not only improves nuclease stability, preserves
target-binding capability, and minimizes off-target side effects, but also massively enhances plasma
pharmacokinetics, tissue retention, and antisense potency in vivo. Our current studies also reveal that the
pacDNA’s pharmacological properties are intimately related to the bottlebrush backbone. In addition, the
pacDNA appears to be uniquely capable of evading anti-carrier adaptive immunity, which is useful for
therapies that requires long-term/frequent dosing. Finally, the pacDNA deposits into tissues and organs
that lack mature delivery technologies for, such as the skin, the skeletal muscle, and the heart. These
surprising and enabling discoveries will be the basis for investigations in the next funding period, in which
we will 1) explore the property space of the pacDNA structure using a combinatorial polymer library with
specific backbone compositions and monomer sequences; 2) probe in vivo properties of the pacDNA in
mouse and non-human primate models and how it is able to evade adaptive immunity; and 3) explore the
potential of pacDNA to create first/best-in-class therapies that take advantage of its unique strengths using
a relevant preclinical disease model (progeria). We anticipate that accomplishment of these objectives will
yield significant fundamental understanding of this class of materials and bring us much closer to clinical
evaluation of pacDNA.
Terms: <Adopted><Affect><Antisense Agent><Antisense Oligonucleotides><Area><Benign><Binding><Binding Proteins><Bioavailability><Biodistribution><Biological Agent><Biological Availability><Biological Products><Blood><Blood Coagulation Disorders><Blood Plasma><Blood Reticuloendothelial System><Body Tissues><Brain><Brain Nervous System><C-K-RAS><Calf Thymus Ribonuclease H><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Characteristics><Chemicals><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Coagulation Disorder><Coagulopathy><Cytoplasm><DNA><DNA Structure><Deoxyribonucleic Acid><Deposit><Deposition><Development><Disease><Disorder><Dose><Drug Kinetics><Encephalon><Endoribonuclease H><Endosomes><Endowment><Enzyme Stability><Exhibits><Face><Food and Drug Administration><Frequencies><Functional RNA><Funding><Genes><Genetic Diseases><Goals><Heart><Hutchinson-Gilford Disease><Hutchinson-Gilford Syndrome><Hydrophobicity><Immune Cell Activation><Immune system><Immunologic Stimulation><Immunological Stimulation><Immunostimulation><Injections><Investigation><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kinetics><Libraries><Ligand Binding Protein><Ligand Binding Protein Gene><Lipids><Liver><Machine Learning><Messenger RNA><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modality><Modeling><Modification><Molecular><Molecular Interaction><Molecular Tumor Suppression><Murine><Mus><Muscle><Muscle Tissue><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nuclear><Nucleic Acids><Oligo><Oligonucleotides><Oncogene K-Ras><Organ><Peptides><Pharmacokinetics><Philosophy><Physiologic Availability><Plasma><Plasma Enhancement><Plasma Serum><Polymers><Pre-Clinical Model><Pre-mRNA><Preclinical Models><Premature Senility Syndrome><Progeria><Property><Protein Binding><Proteins><RASK2><RNA><RNA Gene Products><RNA Splicing><RNA, Messenger, Precursors><RNase H><Receptosomes><Renal clearance function><Reticuloendothelial System, Serum, Plasma><Ribonuclease H><Ribonucleic Acid><Safety><Side><Site><Skeletal Muscle><Skin><Spinal Column><Spine><Splicing><Structure><Syndrome><System><Technology><Therapeutic><Therapeutic Agents><Thermodynamic><Thermodynamics><Thesaurismosis><Tissues><Toxic effect><Toxicities><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transfection><Translational Inhibition><Translational Repression><Treatment Efficacy><Tumor Suppression><USFDA><United States Food and Drug Administration><Untranslated RNA><Vertebral column><Viral Diseases><Virus Diseases><Voluntary Muscle><Xenograft Model><adaptive immunity><antisense oligo><backbone><biologics><biopharmaceutical><biotherapeutic agent><bleeding disorder><bound protein><class material><clinical test><clotting disorder><combinatorial><cost><course material><curricular material><delivery vector><delivery vehicle><density><design><designing><determine efficacy><developmental><disease model><disorder model><dosage><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetic regulation><evaluate efficacy><examine efficacy><faces><facial><fomivirsen><genetic condition><genetic disorder><hepatic body system><hepatic organ system><immune activation><improved><in vivo><insight><instructional materials><intervention efficacy><learning materials><mRNA><mRNA Precursor><machine based learning><metabolism disorder><monomer><muscular><nano particle><nano-sized particle><nanoparticle><nanosized particle><neglect><new approaches><non-human primate><noncoding><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><nuclease><nucleic acid delivery><nucleobase><oligonucleotide delivery><oligonucleotide drug><oligonucleotide therapeutics><oligonucleotide therapies><oligonucleotide treatment><oligos><pharmacologic><polymer><polymeric><pre-clinical><preclinical><preservation><renal clearance><research clinical testing><side effect><simulation><stem><therapeutic efficacy><therapy efficacy><tool><uptake><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><vector><viral infection><virus infection><virus-induced disease><xenograft transplant model><xenotransplant model>