Most drugs developed to treat Alzheimer’s disease have been ineffective in clinical trials for years. Indiana University School of Medicine researchers recently evaluated the effectiveness of a failed clinical trial drug using their rigorous pipeline.
Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) investigators, a consortium of experts from the IU School of Medicine, the Jackson Laboratory, Sage Bionetworks, the University of Pittsburgh School of Medicine and the University of California, Irvine, recently published their study in Alzheimer’s & Dementia: Translational Research & Clinical Intervention, a journal of the Alzheimer’s Association.
Adrian Oblak, PhD, assistant professor of radiology and imaging sciences at the UI School of Medicine and first author of the publication, said the study investigated the effectiveness of the drug verubecestat, a beta- secretase (BACE); administered in the early stages of Alzheimer’s disease, using the MODEL-AD core drug discovery pipeline of preclinical trials.
Although BACE inhibitors reduced amyloid-beta plaque in patients with late-stage Alzheimer’s disease during clinical trials, many of these studies were stopped due to adverse events or lack of clinical efficacy. The drug was also understudied for its effectiveness before the onset of Alzheimer’s disease, making it an ideal compound to study in MODEL-AD.”
Adrian Oblak, PhD, assistant professor of radiology and imaging sciences at the UI School of Medicine and first author
The researchers performed in vivo PET/MRI imaging to measure amyloid deposition and glucose uptake in the brains of the animal models, measured plasma and brain amyloid beta, and assessed clinical and behavioral characteristics.
Stacey Rizzo, PhD, associate professor of neurobiology and geriatric medicine at the University of Pittsburgh’s Institute on Aging and lead author of the paper, said this study validates the importance of the consortium in advancing Alzheimer’s disease research. Alzheimer’s
“The MODEL-AD consortium brings together experts from the fields of Alzheimer’s disease biology, mouse models, genetics, behavioral research, neuropharmacology and medical imaging to develop the research infrastructure that will benefit the entire Alzheimer’s research community. Alzheimer’s,” Rizzo said. “There is currently no cure for Alzheimer’s disease, and therefore there is an absolute need to find a treatment and develop prevention strategies.”
The National Institute on Aging, part of the National Institutes of Health, funded the MODEL-AD consortium to establish a robust infrastructure for the larger research community to improve preclinical to clinical translational studies and accelerate the pace of effective and safe treatments for patients at risk. for Alzheimer’s disease, Rizzo said.
“By virtue of our rigorous unbiased screening strategy, we were able to prevent significant amyloid-beta deposition, which was expected; however, the same dose range that was effective in preventing amyloid-beta plaque formation caused side effects similar reported in the clinic and in the absence of cognitive improvement,” Oblak said of the study. “Therefore, we would not have prioritized this compound for advancement to clinical trials if we had verified the compound using this rigorous and unbiased approach.”
The results of this research, Oblak said, like all animal models, protocols and validation data studied by MODEL-AD, are quickly made available to all researchers for preclinical drug development, thanks to NIA support . Researchers can visit stopadportal.synapse.org to submit compounds for consideration through this pipeline.
Source:
Indiana University School of Medicine
Journal reference:
Oblak, AL, et al. (2022) Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice. Alzheimer’s and dementia: translational research and clinical intervention. doi.org/10.1002/trc2.12317.