SBIR-STTR Award

Alzheimer’s disease (AD) is the most common cause of dementia and is a growing problem as populations age. More than 25 million people are affected by dementia worldwide with most suffering from AD. AD is characterized by the presence of plaques of insoluble amyloid-beta (A?) and tangles of hyperphosphorylated aggregates of the cytoskeletal protein, tau. Thus far, most AD treatments have targeted A? aggregation and plaque formation, but these therapies have largely failed to translate from preclinical rodent models to humans. Interestingly, tau pathology has been shown to correlate better with cognitive decline than A?, and thus restricting the spread of neurofibrillary tau has become a growing focus for development of treatments for various tauopathies, including AD. It was recently discovered that LRP1 is a master regulator of tau uptake and spread in the brain, indicating that LRP1 may be an important therapeutic target for slowing the progression of various tauopathies. Novoron Bioscience is developing novel large-molecule therapies targeting LDL receptor-related protein 1 (LRP1), a master regulator of tau uptake and spread in the brain, to slow the progression of tauopathies such as (AD) and improve functional outcomes in patients. Novoron’s lead compound, NOVO-118, is a high-affinity LRP1 antagonist that is actively taken up into the brain via both subcutaneous and intravenous administration. The purpose of this proposal is to evaluate the therapeutic potential of NOVO-118 by assessing its ability to restrict the spread of tau in the rodent brain. We will accomplish this by uncoupling proof of concept studies for effective tau restriction from assessment of translatability in terms of clinically relevant utilization. To accomplish this, we have designed this project with two primary goals: 1) generate necessary proof of concept demonstrating the ability of NOVO-118 to abrogate tau spread; and 2) de-risk the technology by demonstrating that we can deliver the drug and elicit benefit in a clinically translatable fashion.

Public Health Relevance Statement:
Project Narrative Tauopathies, of which Alzheimer’s disease is the most prominent example, are a group of neurodegenerative conditions characterized by the spread of neurofibrillary tau, which is a process shown to be regulated by the LRP1 receptor. As tau spread has been shown to correlate strongly with cognitive decline, therapies to restrict such spread may provide a first-in-class approach to slowing the devastating effects of these diseases. The purpose of this proposal is to test the ability of NOVO-118, a novel antagonist of LRP1 that readily enters the brain, to reduce the spread of tau in the brain and consequently slow the cognitive decline associated with various tauopathies.

Project Terms:
Affect ; 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 ; Astrocytes ; Astrocytus ; Astroglia ; astrocytic glia ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Active Biological Transport ; Active Biologic Transport ; Active Transport ; Uphill Transport ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; Cells ; Cell Body ; Central Nervous System Agents ; CNS agent ; Central Nervous System Drugs ; centrally acting drug ; Cytoskeletal Proteins ; Cytoskeletal Gene ; Disease ; Disorder ; intravenous administration ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Future ; Goals ; Human ; Modern Man ; In Vitro ; intravenous injection ; Subcutaneous Injections ; subdermal injection ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Pathology ; Patients ; Risk ; Rodent ; Rodentia ; Rodents Mammals ; Technology ; Testing ; Translating ; Work ; LDL-Receptor Related Protein 1 ; Apo E Receptor ; ApoE Receptor ; Apolipoprotein E Receptor ; Low Density Lipoprotein Receptor-Related Protein ; Low-Density-Lipoprotein Receptor-Related Protein-1 ; alpha-2-Macroglobulin Receptor ; alpha2-Macroglobulin Signaling Receptor ; 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 β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Measures ; Drug Delivery Systems ; Drug Delivery ; Neurofibrillary Tangles ; neurofibrillary degeneration ; neurofibrillary lesion ; neurofibrillary pathology ; tangle ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; τ Proteins ; Outcome Measure ; TimeLine ; improved ; Physiological ; Physiologic ; Failure ; uptake ; Therapeutic ; Amyloid Plaques ; Neuritic Plaques ; amyloid beta plaque ; amyloid-b plaque ; aβ plaques ; cored plaque ; diffuse plaque ; Senile Plaques ; cleaved ; Cleaved cell ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Nature ; Investigation ; Hour ; Event ; Ipsilateral ; subdermal ; subcutaneous ; Route ; cell type ; Amentia ; Dementia ; Receptor Protein ; receptor ; success ; novel ; disorder model ; Disease model ; Reporting ; Bypass ; Modeling ; response ; drug development ; CNS Nervous System ; Central Nervous System ; Neuraxis ; tau associated neurodegeneration ; tau associated neurodegenerative process ; tau induced neurodegeneration ; tau mediated neurodegeneration ; tau neurodegenerative disease ; tau neuropathology ; tauopathic neurodegenerative disorder ; tauopathy ; Tauopathies ; preventing ; prevent ; Dose ; Affinity ; in vivo ; Rodent Model ; Transgenic Model ; transgenic trait ; Pathologic ; Process ; Modification ; pre-clinical ; preclinical ; vector ; tau expression ; τ expression ; design ; designing ; novel strategies ; new approaches ; novel approaches ; novel strategy ; functional outcomes ; Outcome ; Population ; clinically relevant ; clinical relevance ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; abeta accumulation ; abeta aggregation ; amyloid beta accumulation ; amyloid beta aggregation ; amyloid β accumulation ; amyloid β aggregation ; aβ accumulation ; aβ aggregation ; therapeutic target ; therapy development ; develop therapy ; intervention development ; treatment development ; overexpression ; overexpress ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; clinically translatable ; preclinical development ; pre-clinical development ; human model ; model of human ;

7. Alzheimer's disease (AD) is the most common cause of dementia and is a growing problem as populations age.More than 25 million people are affected by dementia worldwide with most suffering from AD. AD is characterizedby the presence of plaques of insoluble amyloid-beta (Aβ) and tangles of hyperphosphorylated aggregates ofthe cytoskeletal protein, tau. Thus far, most AD treatments have targeted Aβ aggregation and plaque formation,but these therapies have largely failed to translate from preclinical rodent models to humans. Interestingly, taupathology has been shown to correlate better with cognitive decline than Aβ, and thus restricting the spread ofneurofibrillary tau has become a growing focus for development of treatments for various tauopathies, includingAD.It was recently discovered that LRP1 is a master regulator of tau uptake and spread in the brain, indicating thatLRP1 may be an important therapeutic target for slowing the progression of various tauopathies. NovoronBioscience is developing novel large-molecule therapies targeting LDL receptor-related protein 1 (LRP1),a master regulator of tau uptake and spread in the brain, to slow the progression of tauopathies such as(AD) and improve functional outcomes in patients.Novoron's lead compound, NOVO-118, is a high-affinity LRP1 antagonist that is actively taken up into the brainvia both subcutaneous and intravenous administration. The purpose of this proposal is to evaluate thetherapeutic potential of NOVO-118 by assessing its ability to restrict the spread of tau in the rodent brain. Wewill accomplish this by uncoupling proof of concept studies for effective tau restriction from assessment oftranslatability in terms of clinically relevant utilization. To accomplish this, we have designed this project with twoprimary goals: 1) generate necessary proof of concept demonstrating the ability of NOVO-118 to abrogate tauspread; and 2) de-risk the technology by demonstrating that we can deliver the drug and elicit benefit in aclinically translatable fashion.

Public Health Relevance Statement:
8. Project Narrative Tauopathies, of which Alzheimer's disease is the most prominent example, are a group of neurodegenerative conditions characterized by the spread of neurofibrillary tau, which is a process shown to be regulated by the LRP1 receptor. As tau spread has been shown to correlate strongly with cognitive decline, therapies to restrict such spread may provide a first-in-class approach to slowing the devastating effects of these diseases. The purpose of this proposal is to test the ability of NOVO-118, a novel antagonist of LRP1 that readily enters the brain, to reduce the spread of tau in the brain and consequently slow the cognitive decline associated with various tauopathies.

Project Terms:
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