Background

This gene therapy uses an adeno-associated virus serotype 2 (AAV2) vector to carry a gene for human brain-derived neurotrophic factor into the brain. BDNF regulates neuron survival and function in key memory circuits in entorhinal cortex and hippocampus. In people with AD, BDNF is decreased. AAV2-BDNF attempts to restore normal levels of BDNF.

This program follows CERE-110, which attempted to deliver NGF via AAV (Mar 2018 news).

In early studies with mouse models of AD, BDNF gene therapy reversed synaptic loss, and restored learning and memory, without affecting amyloid plaque load (Nagahara et al., 2009; Nagahara et al., 2013). The same studies used rats and non-human primates to show that BDNF protein or lentivirus-BDNF delivered to the brain reduced age-related cognitive decline. Preclinical work with AAV2-BDNF injected into the entorhinal cortex in non-human primates demonstrated elevation of BDNF protein in neurons of that region, and in the hippocampus, with no apparent safety issues (Nagahara et al., 2018).

Findings

In February 2022, Phase 1 began with an open-label study of this gene therapy in six volunteers with early Alzheimer’s, and six with mild cognitive impairment. Participants are to undergo one MRI-guided surgery to infuse AAV2-BDNF into the entorhinal cortex, followed by two years observation. Primary outcomes are the number of treatment-related adverse events, and memory changes measured on the Ray Auditory Verbal Learning Task and Benson Complex Figure Draw and Memory test. Secondary outcomes are change in FDG-PET, CSF biomarkers of amyloid, tau and neurofilament, and MMSE ADAS-Cog. The study is underway at Ohio State University. Sponsored by the University of California, San Diego, it runs until October 2027.

For details on this trial, see clinicaltrials.gov.