Last week our friends in the Alzheimer’s disease (AD) research field gathered in Washington, DC, for the Alzheimer’s Association International Conference, and many journalists in attendance took note that some AD disease-modifying drugs in development may have application for other brain diseases such as Parkinson’s and Lewy body dementia.
“All of these diseases are characterized by protein clumps,” says Mark Frasier, PhD, MJFF senior vice president of research programs. “We think the process of clumping happens in a similar way, so strategies against those processes may work across disease borders.”
Testing Antibodies against the Clumps, Not the Protein
Antibodies are not foreign to Parkinson’s disease (PD) research. Scientists are using these immune system soldiers against the primary component of the PD protein clumps: alpha-synuclein. The hypothesis is that if you can induce or introduce antibodies against alpha-synuclein, they’ll clear out the toxic clumps and protect cells.
The same thing is happening in Alzheimer’s research with antibodies against the proteins implicated in AD: amyloid-beta and tau.
At the conference, however, scientists at the New York University (NYU) School of Medicine presented an intriguing alternative: Why not go after the clumps, no matter what kind of protein they contain? That team’s so-called pan-therapy antibodies search for structure change rather than the specific protein and have shown affinity for amyloid-beta, tau and alpha-synuclein.
The potential benefits of this approach are more widespread application and perhaps treatment of multiple pathologies in one individual. Some people with PD also have shown clumps of amyloid-beta or tau and, conversely, people with AD have shown alpha-synuclein aggregates.
On the other hand, protein structure changes similar to those the NYU antibody targets may be part of natural processes, and disrupting those could have unintended consequences.
Studying Protein Misfolding to Find New Therapies
The way that proteins clump together in these brain diseases is through a process called misfolding.
“Sometimes [the protein] gets what I call a kink,” Marcia Taylor, director of biological research at biotech Treventis, told NPR. That misfolded protein binds to other proteins, forming a clump that is toxic to brain cells, scientists believe.
Treventis and another company, MJFF-funded Neurophage, are targeting that misfolding to prevent protein clumps and cell death. Both presented at the Alzheimer’s conference.
Treventis is using computer modeling to replicate the misfolding process and screen potential drug compounds that may prevent the toxic clumping. Their lead candidates have shown promising results in pre-clinical models against amyloid-beta and tau.
MJFF is supporting Neurophage in testing its lead drug candidate, NPT088, a biologic that includes what the company has named the general amyloid interaction motif (GAIM). This part of the therapeutic acts against misfolded proteins, and NPT088 has shown ability to prevent clumps of alpha-synuclein, amyloid-beta and tau.
Learning More about Protein Targets to Refine Therapies
These and other alpha-synuclein therapies in development would immensely benefit from greater understanding of their target. Many questions remain around this Parkinson’s protein: What type or form of alpha-synuclein misfolds? What tests are best to measure alpha-synuclein levels? Could we have different tests to measure the different kinds of alpha-synuclein?
Earlier this year MJFF launched two programs investigating these unknowns. In the latest iterations of our Linked Efforts to Accelerate Parkinson’s Solutions (LEAPS) program, teams are studying the species of alpha-synuclein and experiments to measure this protein. Read more about that work.
Watch a webinar on alpha-synuclein and the many ways researchers are going after this Parkinson’s disease player.
