Therapy for Alzheimer's disease and related dementias (AD/ADRD), slow-progressing neurodegenerative diseases, remains elusive. Therapeutic approaches focusing on beta amyloid (Aß) removal from the brain or on targeting genes for which strong associations between their polymorphism and AD/ADRD are established, have had a mixed record of success. We propose a novel strategy to reverse AD/ADRD associated neuroinflammation and mitochondrial dysfunction via targeting pathological lipid rafts in inflammatory and activated cells. These cholesterol-rich plasma membrane structures become stable and enlarged to host the assembly of many inflammatory receptors and other molecules involved in pathological processes leading to neuronal cell death and neurodegeneration. We have identified apoA-I binding protein (AIBP, encoded by Apoa1bp gene) as a key regulator of cellular cholesterol metabolism, which can selectively target pathological lipid rafts via its binding to TLR4, without damaging physiological lipid rafts. In preliminary studies, the Apoa1bp-/- mice crossed with APP/PS1 transgenic mice presented more Aß plaques, an exacerbated dysfunctional microglia phenotype and increased neuronal cell death when compared to APP/PS1 mice. In addition, mitochondria in the brain of AIBP- deficient APP/PS1 mice were morphologically distorted, with a characteristic hyper-branched and cupped shape, typically associated with oxidative stress. The adeno-associated virus (AAV)-mediated overexpression of a secreted form of AIBP in the brain of Apoa1bp-/- APP/PS1 mice restored the microglial homeostatic phenotype. RAFT Pharmaceuticals proposes the development of an AAV-AIBP based therapy to provide effective neuroprotection in AD/ADRD. Specifically in this Phase 1 STTR project, we propose to construct and optimize an AAV-AIBP vector (RFT1041), which will be used in efficacy studies of Aim 2 and is expected to enter IND- enabling development for human clinical applications. We will explore intracranial and intrathecal routes of delivery and test if a single AAV-AIBP injection achieves sustained AIBP expression in the brain. The efficacy of RFT1041 (3 different doses) will be tested in APP/PS1 and 3xTg mouse models to evaluate survival, changes in memory and learning, the extent of Aß plaques and tau tangles, microglia activation, synaptotoxicity, neuronal cell death, autophagy, ER stress, and mitochondrial dysfunction. In addition, advanced EM will be used to assess mitochondrial morphology and function. Results of these studies will be used to prepare for and conduct an INTERACT meeting with the FDA to receive preliminary FDA feedback on the proposed development program and assists in minimizing the time spent in product development and reduce time to market.
Public Health Relevance Statement: NARRATIVE Many attempts to develop effective therapy for Alzheimer's disease and related dementias did not achieve their goal. We identified a novel target in treatment of Alzheimer's disease - pathologic lipid rafts in inflammatory and activated cells and the apoA-I binding protein (AIBP) targeting pathologic but not homeostatic lipid rafts. This project will test in mouse models a gene therapy approach to achieve sustained AIBP expression in the brain as a novel therapeutic strategy for Alzheimer's disease and related dementias.
Project Terms: Dependovirus; Adeno-Associated Viruses; Dependoparvovirus; adeno associated virus group; Age; ages; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Autophagocytosis; autophagy; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Brain; Brain Nervous System; Encephalon; Brain Pathology; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cells; Cell Body; Cholesterol; Elements; Evaluation Research; Feedback; Fibronectins; Cold-Insoluble Globulins; FN1; Fibronectin 1; LETS Proteins; Large External Transformation-Sensitive Protein; Opsonic Glycoprotein; Opsonic alpha(2)SB Glycoprotein; alpha 2-Surface Binding Glycoprotein; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene repair therapy; gene-based therapy; genetic therapy; genomic therapy; Genes; Goals; Human; Modern Man; Inflammation; Learning; Memory; Methods; Transgenic Mice; Mitochondria; mitochondrial; Mus; Mice; Mice Mammals; Murine; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Nerve Degeneration; Pathological Processes; Pathologic Processes; Patients; Phenotype; Play; polymorphism; Genetic Polymorphism; Program Development; Proteins; social role; Role; Signal Peptide; Signal Sequences; protein signal sequence; Peptide Signal Sequences; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Survival Rate; Testing; Time; Virus; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; Apolipoprotein A-I; Apo A-1; Apo A-I; Apo A1; Apo AI; ApoA-1; ApoA-I; Apolipoprotein A-1; Apolipoprotein A1; Apolipoprotein AI; Synaptophysin; Synaptic Vesicle P38 Membrane Protein; Synaptic Vesicle Protein P38; Neurofibrillary Tangles; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; tangle; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; Mediating; base; Phase; Physiological; Physiologic; Microglia; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; Ensure; Bilateral; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Oxidative Stress; Therapeutic; Morphology; Shapes; Inflammatory; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aß plaques; cored plaque; diffuse plaque; Senile Plaques; scaffolding; scaffold; Radius; Radial; Route; Pattern; brain tissue; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; meetings; membrane structure; Membrane; Receptor Protein; receptor; success; nerve cell death; nerve cell loss; neuron cell death; neuron cell loss; neuron death; neuronal cell death; neuronal cell loss; neuronal death; neuronal loss; neuron loss; neuroprotection; Animal Models and Related Studies; model of animal; model organism; Animal Model; TUNEL; terminal nick end labeling; In Situ Nick-End Labeling; novel; behavioral test; behavior test; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; protein distribution; Cell Membrane Lipid Rafts; Sphingolipid Microdomains; Sphingolipid-Cholesterol Rafts; lipid raft; Membrane Microdomains; Inflammatory Response; Molecular Interaction; Binding; protein expression; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; cholesterol metabolism; Cholesterol Homeostasis; Homolog of Drosophila TOLL; TLR4; Toll Homologue; toll-like receptor 4; TLR4 gene; Dose; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Small Business Technology Transfer Research; STTR; Pathologic; Characteristics; Development; developmental; Behavioral; vector; APP-PS1; APP/PS1; neuroinflammation; neuroinflammatory; novel strategies; new approaches; novel approaches; novel strategy; Neonatal; clinical application; clinical applicability; mitochondrial dysfunction; mouse model; murine model; 3xTg-AD mouse; 3xTg; 3xTg-AD mice; overexpression; overexpress; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; effective therapy; effective treatment; product development; efficacy testing; endoplasmic reticulum stress; ER stress; arm; OPA1 gene; KIAA0567; Mitochondrial Dynamin-Like 120-KD Protein; OPA1; ATF6 gene; ATF6; Activating Transcription Factor 6; efficacy study; clinical development; recruit; Injections; Alzheimer's disease related dementia; AD related dementia; ADRD; Alzheimer related dementia; water maze; Alzheimer's disease therapy; Alzheimer's therapy
