Document text
Principal Investigator: TREVOR P. CASTOR
Organization: APHIOS CORPORATION
Fiscal Year: 2024
Award: $504,732
Funding agency: National Institute on Aging
PROJECT SUMMARY
Alzheimer's disease is associated with multiple factors, including but not limited to amyloid plaque formation, tau
protein entanglement, enzyme degradation and inflammation. Inflammation is implicated in many aging diseases
and in the central nervous system (CNS) is associated with the CCR5 gene that increases with age. CCR5 has
been correlated with impairments in memory consolidation in aged mice, which was reversed with a CCR5
knockout and an FDA approved drug that inhibits this receptor.
We propose to develop targeted nanoparticles of an anti-CCR5 drug, and evaluate its impact on brain
inflammation and AD. In Phase I, we will: (i) Nanoencapsulate anti-CCR5 drug in targeted and non-targeted,
long circulating, pegylated nanoparticles utilizing a proprietary solvent-free technology, and characterize the size
and distribution of the nanoparticles, encapsulation or loading efficiency, and in vitro release characteristics; and
(ii) Evaluate the impact of the anti-CCR5 drug nanoparticles on in vitro models of brain inflammation and BBB
penetration to select best candidates for in vivo studies, perform pharmacokinetic, biodistribution and toxicity
studies in wild-type mice and efficacy studies in a transgenic mouse model of Alzheimer's disease. In Phase II,
we will more rigorously characterize the nanoparticles, conduct extensive in vitro and in vivo studies, and scale-
up manufacturing towards conducting IND-enabling studies and filing an IND for Phase I and/or Phase IIb studies.
We will then out-license the developed technologies and products to a multinational pharmaceutical or
biotechnology company.
Terms: <(TNF)-α><20-(S)-camptothecine><21+ years old><22-secocamptothecin-21-oic acid lactone 21><AD dementia><AD model><AIDS Virus><APP-PS1><APP/PS1><Absolute ethanol><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adult><Adult Human><Affect><Age><Allergic Reaction><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimer's disease therapeutic><Alzheimer's therapeutic><Alzheimers Dementia><Amentia><Amyloid (Aβ) plaques><Amyloid Plaques><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BBB crossing><BBB penetration><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Biodistribution><Biotech><Biotechnology><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Inflammation><Brain Nervous System><Bryostatin-1><Bypass><CCL5><CNS Nervous System><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Camptothecin><Cancer Drug><Central Nervous System><Characteristics><Chemokine (C-C Motif) Ligand 5><Chemokine Receptor Gene><Chemotactic Cytokines><Circulation><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><D-Glucose><D17S136E><Degenerative Neurologic Disorders><Dementia><Development><Dextrose><Disease><Disorder><Disturbance in cognition><Dose><Drug Kinetics><Drugs><ETOH><Encapsulated><Encephalitis><Encephalon><Enzyme Gene><Enzymes><Ethanol><Ethyl Alcohol><Europe><FDA approved><Future><Genes><Genetic><Glucose><Grain Alcohol><HIV><HIV Infections><HIV Receptors><HIV-1><HIV-I><HIV1><HPGF><HTLV-III Infections><HTLV-III Receptors><HTLV-III-LAV Infections><Hemato-Encephalic Barrier><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Hybridoma Growth Factor><Hydrophobicity><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-1β><IL-6><IL1-Beta><IL1-β><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL1B Protein><IL1F2><IL1β><IL6 Protein><Impaired cognition><Impairment><In Vitro><Inflammation><Inflammatory><Intercrines><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin 1beta><Interleukin-1 beta><Interleukin-17><Interleukin-1β><Interleukin-6><Interleukins><Investigators><Knock-out><Knockout><LAV-HTLV-III><Licensing><Life><Ligands><Link><Lipid Bilayers><Lipids><Liposomal><Liposomes><Liquid substance><Liver><Lymphadenopathy-Associated Virus><MGC17164><MGI-2><MT-bound tau><Macrophage><Macrophage-Derived TNF><Mediating><Medication><Methylcarbinol><Mice><Mice Mammals><Modern Man><Monocyte-Derived TNF><Murine><Mus><Myeloid Differentiation-Inducing Protein><Mφ><Neoplastic Disease Chemotherapeutic Agents><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neuritic Plaques><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neurons><Oral><Performance><Persons><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Plasmacytoma Growth Factor><Preinterleukin 1 Beta><Primary Senile Degenerative Dementia><Process><RANTES><Receptor Inhibition><Receptor Protein><Research Personnel><Researchers><Residual><Residual state><SCYA5><SIS cytokines><SIS delta><SIS-delta><SISd><Senile Plaques><Siderophilin><Skin><Small Inducible Cytokine A5><Solvents><Structure><System><T-Cell RANTES Protein><T-Cell Specific Protein p288><T-Cells><T-Lymphocyte><TCP228><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Therapeutic><Thermodynamic><Thermodynamics><Time><Toxic effect><Toxicities><Toxicology><Transferrin><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Specific Treatment Agents><United States><VIT D><Virus-HIV><Vitamin D><Wild Type Mouse><adulthood><age associated><age correlated><age dependent><age linked><age related><age specific><aged mice><aged mouse><ages><aging associated disease><aging related disease><alzheimer model><amyloid beta plaque><amyloid-b plaque><antagonism><antagonist><anti-cancer drug><aqueous><aβ plaques><blood-brain barrier crossing><blood-brain barrier penetration><bloodbrain barrier><bloodbrain barrier crossing><bloodbrain barrier penetration><bryostatin><chemoattractant cytokine><chemokine><chemokine receptor><cognitive dysfunction><cognitive loss><commercial scale manufacturing><cored plaque><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diffuse plaque><disease of aging><disorder of aging><drug/agent><efficacy study><elderly mice><experience><fluid><hepatic body system><hepatic organ system><hydrophilicity><in vitro Model><in vivo><interferon beta 2><lipid based nanoparticle><lipid bilayer membrane><lipid nanoparticle><liquid><manufacturing process><manufacturing ramp-up><manufacturing scale-up><memory consolidation><microtubule bound tau><microtubule-bound tau><nano particle><nano-sized particle><nanoparticle><nanoparticle drug><nanosized particle><neurodegenerative illness><neurological disease><neuronal><novel><old mice><particle><pharmaceutical><pharmacologic><primary degenerative dementia><receptor><scale up batch><scale up production><senile dementia of the Alzheimer type><side effect><tau><tau Proteins><tau factor><therapeutic target><therapeutically effective><thymus derived lymphocyte><transcytosis><transgenic AD model><transgenic Alzheimer's model><transgenic model of alzheimer disease><upscale manufacturing><vesicle transport><vesicular transport><wildtype mouse><τ Proteins>