Alzheimer's disease (AD) is a looming public health crisis that threatens millions of patients' ability toexperience healthy aging. In addition to the challenges that AD poses to patients, healthcare providers andcaregivers, there is also tremendous economic burden associated with AD and related dementias - estimatedto be well over $200B/year in the United States alone. Hundreds of attempts to develop therapies to halt theprogression of or reverse AD have been tried, but unfortunately none have been successful to date. Theresults of these studies strongly support the pursuit of new therapeutic modalities and molecular targets. Adulthippocampal neurogenesis (AHN) has long been appreciated as critical for normal learning and memory inrodents, however its role in humans has historically been less clear. Several preclinical studies haveunderscored the role of AHN in improving cognition in an AD environment. Critically, several recent studieshave supported that AHN is also robust in humans and persists throughout life in healthy adults, but declinesdramatically 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) thatreduce bone morphogenetic protein (BMP) signaling in neural stem cells in vivo to increase AHN via targetinga novel BMP co-receptor. BMP signaling is an important negative regulator of adult neurogenesis, andincreases 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. Themost promising mAb candidate will be administered using both direct hippocampal stereotactic injection andsystemic delivery in AD mice to provide proof of concept data for augmenting AHN in the setting of diseasepathology. These studies will support future Phase II studies for further characterization of the mAb, includingevaluating 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 therequisite data package to begin clinical development of a pro-neurogenic therapeutic antibody for improvingthe 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: <21+ years old> | | 