Investigating Alzheimer’s from all sides

Research pursues many targets in neurodegenerative disease

By Paul Weinreb
Director, Biologics Drug Discovery

July 26, 2017

Scientists don’t fully understand what exactly drives Alzheimer’s disease (AD), but we have discovered a range of likely molecular targets for treating this widespread, highly complicated and heartbreaking illness.

Two kinds of proteins misfold and clump together in the brains of people with AD. Beta-amyloid proteins pile together in plaques between neurons, and tau proteins aggregate inside the cells themselves.

For years scientists have debated which protein is the main driver for the condition. Many now believe that these two mechanisms are interrelated, so we think it’s important to go after both protein targets as well as other biological pathways associated with AD.

Amyloid and tau – exploring multiple targets and technologies
Over the past two decades, many investigational medicines have been developed to break up beta-amyloid aggregates, typically with little success. At Biogen, we continue to believe in the importance of this target and are currently engaged in a range of research programs – featuring different kinds of antibody and small molecule approaches. Our goal is to either reduce plaques that have already formed or prevent these amyloid plaques from forming in the first place.

More recently, we have invested in multiple programs that target the tau protein deposits that do their damage inside neurons. Toxic tau proteins are believed to spread by being released into the extracellular space around these neurons, where they can enter and affect healthy cells.

In collaboration with leading academic researchers, we recently performed experiments in culture and in disease models that looked at toxic tau proteins in brain extracts. Studying a panel of tau antibodies with different properties, we confirmed that some, but not all, of these molecules could bind to and neutralize the forms of tau that spread among neurons. We look forward to further investigating this approach with the goal of advancing our tau programs in the clinic.

Finally, we also are exploring other ways to attack toxic amyloid and tau. For instance, we’re investigating “antisense” molecules designed to disrupt the production of tau proteins in the brain, as part of our collaboration with Ionis Pharmaceuticals.

Pursuing many paths
Additionally, we believe it’s crucial to explore alternate biological targets, beyond beta-amyloid and tau proteins, for AD therapies.

One prominent set of suspects are the immune cells found in the brain, called microglia, that are supposed to guard the health of neurons. Research has linked genetic mutations in microglia to Alzheimer’s progression, and we are actively investigating the biological pathways involved.

More generally, we’re looking at ways to get drugs past the blood-brain barrier, a membrane built on a unique layer of very tightly packed cells that line blood vessels in the brain. Today, only about 0.1% of the antibodies we inject into the bloodstream make it into the central nervous system. If we can make molecules that slip more easily into the brain, they might dramatically boost our ability to attack AD.

Several other neurodegenerative conditions, including Parkinson’s disease and amyotrophic lateral sclerosis, also appear to be caused by proteins that misfold and accumulate in destructive forms. It’s possible that similar mechanisms are working in all of these illnesses, and that research on one condition can help to inform our understanding of others.

Our hope is that eventually we can build a stable of different medicines to address different neurodegenerative diseases by precisely targeting the underlying biological causes, in order to help these conditions inflict patients, their families, and society.

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