Alzheimer's disease (AD) is a looming public health crisis that threatens millions of patients' ability to experience healthy aging. In addition to the challenges that AD poses to patients, healthcare providers and caregivers, there is also tremendous economic burden associated with AD and related dementias estimated to be well over $200B/year in the United States alone. Hundreds of attempts to develop therapies to halt the progression of or reverse AD have been tried, but unfortunately none have been successful to date. The results of these studies strongly support the pursuit of new therapeutic modalities and molecular targets. Adult hippocampal neurogenesis (AHN) has long been appreciated as critical for normal learning and memory in rodents, however its role in humans has historically been less clear. Several preclinical studies have underscored the role of AHN in improving cognition in an AD environment. Critically, several recent studies have supported that AHN is also robust in humans and persists throughout life in healthy adults, but declines dramatically in AD patients. Thus, restoring AHN has emerged as an attractive target for early intervention, ameliorating or delaying the onset of AD symptoms. In the proposed experiments, Bolden Therapeutics will develop therapeutic monoclonal antibodies (mAbs) that reduce bone morphogenetic protein (BMP) signaling in neural stem cells in vivo to increase AHN via targeting a novel BMP co-receptor. BMP signaling is an important negative regulator of adult neurogenesis, and increases both in normal aging and in AD. Inhibiting BMP signaling has been shown to increase neurogenesis, and that is the expected outcome of our project. The mAbs will be generated by immunizing proprietary, knock- in mice, which are expected to have a more robust immunological response and will overcome tolerance. The most promising mAb candidate will be administered using both direct hippocampal stereotactic injection and systemic delivery in AD mice to provide proof of concept data for augmenting AHN in the setting of disease pathology. These studies will support future Phase II studies for further characterization of the mAb, including evaluating its effect on not only neurogenesis, but also cognition and additional pathological hallmarks (e.g., amyloid, tau, inflammation). Ultimately, our goal is that these studies will enable Bolden to generate the requisite data package to begin clinical development of a pro-neurogenic therapeutic antibody for improving the clinical course in MCI/AD, as well as potentially in other neurological indications. Public Health Relevance Statement PROJECT NARRATIVE
Public Health Relevance: Augmenting neurogenesis in the setting of neurological disease pathology is a highly promising yet understudied approach. The experiments proposed herein will generate lead compounds and provide crucial in vivo data from an Alzheimer's disease mouse model that will guide future studies. If successful, the experiments performed in this Phase I effort will provide in vivo proof of concept data to support an entirely novel therapeutic modality to combat Alzheimer's disease via increasing adult hippocampal neurogenesis.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Aging ; 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 ; Amyloid ; Amyloid Substance ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Antibody Specificity ; Brain ; Brain Nervous System ; Encephalon ; Cognition ; Disease ; Disorder ; Animal Disease Models ; Engineering ; Environment ; Exhibits ; Future ; Goals ; Health Personnel ; Health Care Providers ; Healthcare Providers ; Healthcare worker ; health care personnel ; health care worker ; health provider ; health workforce ; healthcare personnel ; medical personnel ; treatment provider ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Human ; Modern Man ; In Vitro ; Inflammation ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Learning ; Memory ; Transgenic Mice ; Mus ; Mice ; Mice Mammals ; Murine ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Neuromuscular Junction ; Myoneural Junction ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Pathology ; Patients ; Public Health ; Rodent ; Rodentia ; Rodents Mammals ; Role ; social role ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Testing ; Time ; United States ; Work ; Agrin ; Bone Morphogenetic Proteins ; Bone Morphogenetic Protein Gene ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Caregivers ; Care Givers ; base ; improved ; Clinical ; Phase ; Neurologic ; Neurological ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Early Intervention ; Antibody Therapy ; antibody based therapies ; antibody treatment ; antibody-based therapeutics ; antibody-based treatment ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; Life ; experience ; Receptor Protein ; receptor ; novel ; Modality ; Reporting ; neurogenesis ; Neural Stem Cell ; neural precursor ; neural precursor cell ; neural progenitor ; neural progenitor cells ; neuron progenitors ; neuronal progenitor ; neuronal progenitor cells ; neuronal stem cells ; neuroprogenitor ; nerve stem cell ; Molecular Interaction ; Binding ; preventing ; prevent ; Signaling Factor Proto-Oncogene ; Signaling Pathway Gene ; Signaling Protein ; Mouse Homolog of Receptor Tyrosine Kinase NSK2 ; Muscle, Skeletal, Receptor Tyrosine Kinase ; Muscle-Specific Kinase ; NSK2 ; Receptor Tyrosine Kinase MuSK ; MUSK gene ; Dose ; Symptoms ; Data ; Economic Burden ; Molecular Target ; in vivo ; Knock-in Mouse ; KI mice ; knockin mice ; Pathologic ; sex ; Pathway interactions ; pathway ; preclinical study ; pre-clinical study ; novel strategies ; new approaches ; novel approaches ; novel strategy ; Outcome ; aged ; Therapeutic antibodies ; Therapeutic Monoclonal Antibodies ; MAb Therapeutics ; monoclonal antibody drugs ; therapeutic mAbs ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; Alzheimer's disease model ; AD model ; alzheimer model ; normal aging ; therapeutic target ; 3xTg-AD mouse ; 3xTg ; 3xTg-AD mice ; therapy development ; develop therapy ; intervention development ; treatment development ; healthy aging ; combat ; public health relevance ; effective therapy ; effective treatment ; adult neurogenesis ; efficacy testing ; phase 2 study ; phase II study ; Genetic study ; Alzheimer's disease pathology ; AD pathology ; Alzheimer's pathology ; experimental study ; experiment ; experimental research ; clinical development ; Immunize ; Injections ; in vivo evaluation ; in vivo testing ; Alzheimer's disease related dementia ; AD related dementia ; ADRD ; Alzheimer related dementia ; Alzheimer's disease therapy ; Alzheimer's therapy ; Alzheimer's disease patient ; Alzheimer's patient ;
