We propose to test a combination of two potentially potent therapies for Alzheimer’s disease (AD): Brain-Derived Neurotrophic Factor (BDNF) and an anti-amyloid treatment (gamma secretase modulator, GSM). In numerous animal models, modulation of amyloid beta levels (by immunotherapy or secretase blockade/modulation) has exhibited an ability to reduce AD-related neuropathology and improve functional outcomes. However, amyloid beta-modifying therapies have yielded disappointing results in clinical trials in which treatment is initiated after disease onset; for this reason, current clinical approaches are focusing on treating pre-symptomatic patients. Separately, we and others have shown that the nervous system growth factor BDNF can reduce neuronal loss, stimulate synaptic markers, improve transcriptional activity and ameliorate behavioral deficits in animal models of AD, ranging from APP transgenic (APP tg) mice to aged nonhuman primates. We propose to test whether a combination of these therapies will exhibit additive or multiplicative benefits in animal models of AD on molecular, cellular, biochemical and functional outcomes. The combination will be tested in APP tg mice (line 41) and on human iPSC-derived neurons from AD patients.
Thought leaders in the AD field, together with the National Institutes of Health and the Food and Drug Administration, are encouraging the exploration of combinatorial therapies for AD. We propose to pursue this promising approach, using two potent candidate therapies. We have performed first-in-human clinical trials of gene therapy in AD, and positive results of this work could similarly lead to human translation.