Protein-like polymers (PLPs) are next generation biotherapeutics with the potential to improve treatment outcomes for patients suffering from devastating neurodegenerative diseases. We have developed a lead PLP that disrupts the Keap1-Nrf2 intracellular protein-protein interaction (PPI) that restricts the therapeutic activity of Nrf2 (nuclear factor-erythroid factor 2-related factor 2), a validated transcription factor target that regulates a system of hundreds of genes involved in protective responses against oxidative stress and proteostasis that has eluded selective intervention. This application is directly relevant to Alzheimer's Disease/Alzheimer's Disease Related Dementias (AD/ADRD) since enhanced Nrf2 activation in the brains of multiple mouse models of AD demonstrate significantly reduced AD associated pathology in the mice. The reduction in beta-amyloid levels, plaque numbers, and tau pathology in these models attest to the importance of Nrf2 in mitigating AD/ADRD. Thus, the studies outline in this proposal will lead to the development of completely novel Nrf2 activating biologics that could be used in the treatment of AD/ADRD. Preliminary data demonstrates that PLPs activate Nrf2 in primary cortical neurons in vitro and exhibit a 4d half-life in vivo. Our central objective is to optimize our PLP lead to improve its ability to activate Nrf2 in cells by tuning its architecture to balance its biochemical potency and cellular entry. Information from these studies will be used to nominate an advanced lead for follow-on Phase II pharmacodynamic studies in ARE-hPAP transgenic reporter and AD (APPK595N,M596L/PS1âE9) models to nominate a development candidate, which will be the focus of our Phase II plan.
Public Health Relevance Statement: PUBLIC HEALTH RELEVANCE STATEMENT Dysfunction in regulatory protein complexes underlie many devastating diseases, from cancer to neurological disorders, yet these targets are challenging and often considered "undruggable" due to various shortcomings of current drug modalities (small molecules, peptides, antibodies, etc.). Grove Biopharma is leveraging a platform technology to develop a new class of synthetically enhanced biotherapeutic for safely and selectively engaging regulatory complexes inside cells. In this program, we aim to nominate a lead candidate that activates a potent regulatory response against oxidative stress elevations that underpin many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Success will further validate our platform for addressing high value drug targets and position this lead program for late-stage optimization toward IND-enabling studies. 1
Project Terms: Affect; AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; Amyotrophic Lateral Sclerosis Motor Neuron Disease; Gehrig's Disease; Lou Gehrig Disease; Amyotrophic Lateral Sclerosis; inhibitor; Antibodies; Antioxidants; anti-oxidant; Architecture; Engineering / Architecture; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Biotechnology; Biotech; Brain; Brain Nervous System; Encephalon; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cells; Cell Body; Charge; Cytoplasm; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Equilibrium; balance; balance function; Exhibits; Gene Expression; Genes; Goals; Half-Life; Healthcare Systems; Health Care Systems; In Vitro; Inflammation; Kinetics; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Ligase; Ligase Gene; Synthetases; Mus; Mice; Mice Mammals; Murine; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Oxidation-Reduction; Redox; oxidation reduction reaction; Parkinson Disease; Paralysis Agitans; Parkinson; Primary Parkinsonism; Pathology; Peptides; Polymers; polymer; polymeric; Proteins; Endosomes; Receptosomes; Role; social role; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; Vertebral column; Spinal Column; Spine; backbone; transcription factor; Basal Transcription Factor; Basal transcription factor genes; General Transcription Factor Gene; General Transcription Factors; Transcription Factor Proto-Oncogene; Transcription factor genes; Universities; ubiquitin-protein ligase; E3 Ligase; E3 Ubiquitin Ligase; Ubiquitin Protein Ligase; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligase E3; 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; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; tau Proteins; Treatment outcome; Peptide Domain; Protein Domains; Tertiary Protein Structure; density; sensor; improved; Clinical; Penetration; Phase; Variation; Variant; Biochemical; Medical; Series; Reporter Genes; Individual; Oxidative Stress; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; polymerization; tool; scaffold; scaffolding; programs; Complex; Clinic; System; Nuclear; Neurodegenerative Disorders; 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; monomer; success; Response Elements; Transgenic Organisms; transgenic; novel; Disease model; disorder model; Modality; Positioning Attribute; Position; genetic regulatory protein; Regulatory Protein; regulatory gene product; Pharmacodynamics; Modeling; Property; response; protein protein interaction; Intervention; Intervention Strategies; interventional strategy; Molecular Interaction; Binding; protein complex; small molecule; GATA1 gene; ERYF1; GATA Binding Protein 1; GATA-1; GATA1; GATA1 protein; GATA1 transcription factor; GF-1 protein; NF-E1 erythroid-specific transcription factor; NFE1 protein; Transcription Factor GATA1; globin transcription factor 1; nuclear factor-erythroid 1; transcription factor NFE-1; Address; Length; Affinity; Avidity; Data; in vivo; Cellular Assay; cell assay; Erythroid; Nuclear Translocation; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Ubiquitination; Ubiquitilation; Ubiquitinoylation; ubiquination; ubiquitin conjugation; Therapeutic Effect; Development; developmental; nuclear factor-erythroid 2; NF-E2 protein; NF-E2 transcription factor; NFE2 protein; Pathway interactions; pathway; next generation; murine model; mouse model; AD model; alzheimer model; Alzheimer's disease model; public health relevance; Drug Targeting; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; ineffective treatment; ineffective therapies; protein homeostasis; proteostasis; lead candidate; AD related dementia; ADRD; Alzheimer's and related dementias; Alzheimer's disease and related dementia; Alzheimer's disease and related disorders; Alzheimer's disease or a related dementia; Alzheimer's disease or a related disorder; Alzheimer's disease or related dementia; Alzheimer's disease related dementia; technology platform; technology system
