Breaking down beliefs

Genentech shows the BBB remains intact in AD, limiting drug delivery

Researchers at the Genentech Inc. unit of Roche are challenging the widely held belief that the blood-brain barrier (BBB) breaks down in Alzheimer's disease to cause neurodegeneration and acts as a gateway for delivery of therapeutic antibodies. Instead, they claim the barrier remains intact and argue that designing drugs to enter by active transport will work better than the common approach, which assumes diffusion through the leaky membrane.

The team published its findings last month in Neuron, and the company is moving toward developing bispecific antibodies that use the endothelial transferrin receptors to get better brain penetration.

Nga Bien-Ly, first author on the study, told BioCentury the group decided to challenge the assumption because "so many people accept it," but human studies assessing BBB disruption have produced disparate results and data from clinical studies have shown little compound getting into the brain. "Review papers say that blood-brain barrier disruption is one of the main causes of neurodegeneration in Alzheimer's disease, but the evidence that it's happening has been very difficult to assess," she said.

The Genentech team performed a systematic analysis of BBB disruption by applying the same set of methods to five different mouse models of AD.

"We found no widespread disruptions of the blood-brain barrier that you would consider as contributing to the disease in any way," suggesting that BBB disruption is not driving disease pathology, said Marcel van der Brug, a scientist at Genentech and principal investigator on the

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