Introduction of small interfering RNAs (siRNAs) into cells results in potent and specific gene silencing by RNA interference (RNAi). Unfortunately, while siRNA-based drugs represent a potentially significant therapeutic paradigm, the ability to apply this technology to human afflictions, in particular, diseases associated with chronic inflammation, has been impeded by the absence of efficient, non-toxic and tissue-specific delivery systems. We have recently shown that P1, 3-D-Glucan particles can be efficiently employed to deliver siRNAs to macrophages via oral administration (Aouadi, Tesz et al. 2009). As low dose, oral administration of chemically synthesized oligonucleotides was previously thought to be impossible, this discovery is viewed as a significant scientific breakthrough. The objective of this proposal is to employ this technology to develop a Glucan particle formulated with TNFalpha targeting siRNAs and validate this platform's efficacy in accepted models of inflammation. Completion of this project is expected to enable rapid progression into the preclinical /clinical development of an orally administered anti-inflammatory drug, for autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis and psoriasis.
Public Health Relevance: RNAi (RNA interference) has large potential for the treatment of human disease. Efficient delivery is a major road block for therapeutic development. We have recently shown that 1, 3-D-Glucan particles can be efficiently employed to deliver siRNAs to macrophages via oral administration (Aouadi, Tesz et al. 2009). Completion of this project is expected to enable rapid progression into the preclinical /clinical development of an orally administered anti-inflammatory drug, first for autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis and psoriasis.
Thesaurus Terms: "aids Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Administration, Oral; Air; Animal Model; Animal Models And Related Studies; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Inflammatory; Antiinflammatories; Antiinflammatory Agents; Area; Assay; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Atrophic Arthritis; Autoimmune Diseases; Bioassay; Biologic Assays; Biological Assay; Body Tissues; Cells; Characteristics; Chemistry; Chronic; Chronic Cancer Pain; Clinical; Collaborations; D-Glucan; Development; Diabetes Mellitus; Disease; Disease Model; Disorder; Dose; Drug Administration, Oral; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Targeting; Drug Targetings; Drugs; Encapsulated; Formulation; Formulations, Drug; Foundations; Future; Gene Expression; Gene Inactivation; Gene Products, Rna; Gene Silencing; Gene Targeting; Glucans; Glucose Polymer; Hiv; Htlv-Iii; Housekeeping Gene; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type Iii; Human T-Cell Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iii; Human, General; Inflm; Immune; Immune System; In Vitro; Inflammation; Inflammatory Arthritis; Inflammatory Bowel Diseases; Inflammatory Bowel Disorder; Inflammatory Intestinal Disease; Inflammatory Intestinal Disorder; Inflammatory Response; Intestinal; Intestines; Intravenous; Kidney; Lav-Htlv-Iii; Lead; Lymphadenopathy-Associated Virus; Lytotoxicity; Man (Taxonomy); Man, Modern; Measures; Medication; Messenger Rna; Modeling; Nature; Oligo; Oligonucleotides; Oral; Oral Administration; Pathway Interactions; Pb Element; Penetration; Performance; Peritoneal Macrophages; Phagocytes; Phagocytic Cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Polyglucoses; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Procedures; Protocol; Protocols Documentation; Psoriasis; Publications; Publishing; Quality Control; Quelling; Rna; Rna Interference; Rna Silencing; Rna Silencings; Rna, Messenger; Rna, Non-Polyadenylated; Rna, Small Interfering; Rnai; Reagent; Research; Rheumatoid Arthritis; Ribonucleic Acid; Science Of Chemistry; Scientific Publication; Sequence-Specific Posttranscriptional Gene Silencing; Small Interfering Rna; Stomach; System; System, Loinc Axis 4; Targetings, Gene; Technology; Testing; Therapeutic; Tissues; Toxic Effect; Toxicities; Urinary System, Kidney; Validation; Virus-Hiv; Amebocyte; Atheromatosis; Atherosclerotic Vascular Disease; Autoimmune Disorder; Base; Body System, Allergic/Immunologic; Bowel; Cytotoxicity; Diabetes; Disease/Disorder; Disorder Model; Drug/Agent; Gastric; Heavy Metal Pb; Heavy Metal Lead; Human Disease; In Vivo; Intraoral Drug Delivery; Mrna; Macrophage; Model Organism; New Technology; Organ System, Allergic/Immunologic; Particle; Pathway; Polyglucosan; Pre-Clinical; Preclinical; Psoriasiform; Psoriatic; Psoriatiform; Public Health Relevance; Renal; Sirna; Small Molecule; Therapeutic Development; Tool"
