Science - Our approach for Parkinson’s

Pursuing a misfolded protein

April 25, 2017

Bad proteins
Proteins are the miniature action figures of cells, carrying out everything from metabolism to movement. In order to work properly, they need to be folded into the correct 3-dimensional structure. If misfolded or mutated, a protein may go rogue and join up with other such proteins, forming clumps, which then interfere with normal cell function.

Misfolded proteins are often the underlying cause of neurological diseases. For the last seven years, I’ve been carefully studying one particular villain, the protein alpha-synuclein, and its role in Parkinson’s disease.

Clumps of misfolded alpha-synuclein protein (Lewy bodies) are often observed in patients with Parkinson’s disease. Alpha-synuclein is abundant in our brain, especially at the synapses, where nerve cells communicate with each other via the release of neurotransmitters. When alpha-synuclein is misfolded, it forms clumps that these cells can’t get rid of, which eventually block the action of dopamine, an important neurotransmitter that controls muscle movement.

It is believed that aggregates of alpha-synuclein can spread from diseased cells to healthy cells, turning good cells bad and further contributing to the progressive nature of Parkinson’s disease. This prompted an idea to design a trap to capture and neutralize these protein aggregates.

Setting the trap
After my post-doctoral training at Harvard Medical School, I started up the alpha-synuclein program at Neurimmune, a Swiss company that specializes in immunotherapeutics, and through their unique platform, helped develop a human-derived antibody (BIIB054) that recognizes the disease-causing, aggregated form of alpha-synuclein.

I then moved to Biogen, and together with Paul Weinreb, Director of the Biologics Drug Discovery group, led the team that moved the program through research into clinical development.

In pre-clinical studies in cultured neurons done in collaboration with Anthone Dunah’s group (Principal Scientist, Neurology Research) we showed that BIIB054, an investigational compound, may also prevent alpha-synuclein aggregates from spreading to neighboring cells. And we saw similar effects in disease models that involve the spread of alpha-synuclein throughout the brain.  We think that BII054, an investigational compound, works by recognizing aggregates outside of the cell, in the space between nerve cells where the protein aggregates are most harmful. Accordingly, we didn’t see any binding to the type of synuclein found in healthy subjects. After “trapping” an aggregate, in these pre-clinical studies the whole BIIB054 – alpha-synuclein complex was then flushed out with normal cerebral spinal fluid renewal, which occurred about 4 times every 24 hours.

Our investigational program is studying the potential to produce a disease-modifying treatment, with a hope that in addition to addressing symptoms, we may potentially see an impact of delaying the progression of Parkinson’s disease. BII054 is an investigational drug and is now in early clinical trials and we look forward to the results.

Other scientists have made antibodies that bind to the physiological form of alpha-synuclein. Our antibody focuses on aggregated forms of alpha-synuclein, thereby potentially increasing our chance of eliminating these potentially toxic protein molecules.

We continue to work on understanding the biology of alpha-synuclein. Although its presence in Parkinson’s disease is well-documented, it is still unknown how the alpha-synuclein protein kills cells; whether the protein acts inside or outside of the cell; and why some cells, like dopamine-producing cells, are especially vulnerable. Insights into how alpha-synuclein functions normally, and how it malfunctions in disease, can potentially help further improve therapies for Parkinson’s disease.

Andreas Weihofen, Senior Scientist, Neurology Research

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