Despite decades of research, effective treatments for Parkinson’s disease are proving elusive. Could immunotherapy finally provide a solution?
More than seven million people worldwide are currently living with Parkinson’s disease, an incurable neurodegenerative disorder. Current treatment options are limited as they only attempt to mask the symptoms rather than address the cause.
But there is hope on the horizon. Multiple biotech companies are developing a range of immunotherapies to slow down or even completely halt the progression of Parkinson’s.
Researchers believe the main culprit is a toxic form of a protein called alpha-synuclein, which accumulates in the brain over time due to mutations in the gene that encodes the protein. As clusters of alpha-synuclein form inside neurons, they cause the characteristic Parkinson’s symptoms, ranging from tremors to muscle stiffness. Eventually, the neurons die.
Scientists have been designing antibodies that specifically target and bind to the toxic form of alpha-synuclein and remove it from the body.
“The belief is that if you can reduce the levels of this toxic species, you can slow down the progression of the disease,” Gunilla Osswald, CEO of Stockholm-based BioArctic, told me. “This is what we’ve seen in preclinical models using mice. Our antibody makes the motor symptoms come much later, and they survive far longer.”
At the moment, there are two main approaches to immunotherapy for Parkinson’s: passive and active. Most of these immunotherapies are currently in early-stage clinical trials, which are expected to indicate which approach may prove most effective.
The most common approach to Parkinson’s immunotherapy is known as passive immunotherapy. This involves regular intravenous injections of artificially generated antibodies that bind to the toxic form of the alpha-synuclein protein.
“The advantage of using artificially generated antibodies is that it gives us full control of the dosage and exactly where the antibody binds,” said Wagner Zago, CSO of Prothena, which has its headquarters in Dublin. “We’ve learnt that to drive efficacy, it’s really important for the antibody to have a very high binding affinity with alpha-synuclein. It also makes clinical trial design more straightforward as you can ensure that every patient has the same exposure.”
Prothena is one of the most advanced companies developing passive immunotherapies for Parkinson’s. The firm is about to start a phase IIb clinical trial of its immunotherapy in partnership with Roche. In a previous phase II trial with over 500 Parkinson’s patients, the treatment was able to reduce the decline in motor function within a year by 35% compared to a placebo.
“One of the key aspects of our approach is that our antibody does not just neutralize these forms of alpha-synuclein after it binds to them, but it also helps the brain clear them very quickly,” noted Zago.
Vienna-based company AFFiRiS is attempting to reduce the levels of toxic alpha-synuclein using active immunotherapy. This method involves injecting a synthetically engineered protein fragment that mimics the toxic form of alpha-synuclein. In response, the immune system produces antibodies that will bind to and remove toxic alpha-synuclein from the brain.
While passive immunotherapy would need to be applied in regular weekly or monthly infusions, active immunotherapy has the potential to have long-lasting effects, possibly only requiring yearly injections.
“We don’t get the same concentrations of antibodies with our approach compared to passive immunotherapy,” explained Gunther Staffler, CTO of AFFiRiS. He pointed out that passive approaches can result in the body creating antibodies against the drug, making it ineffective. That would not be an issue with active immunotherapy.
So far, AFFiRiS has completed a phase I trial that recruited 32 Parkinson’s patients where the therapy reduced levels of toxic alpha-synuclein and showed signs of stabilizing some of the symptoms of the disease, such as tremors and problems with physical movement. The company is in the process of preparing a phase II trial to confirm these findings.
Key questions remain
There are a number of key questions that will only begin to be answered over the next few years as the results return from clinical trials. For example, we still don’t know whether reducing levels of toxic alpha-synuclein will be an effective method to stabilize or improve symptoms in Parkinson’s patients over a prolonged period of time.
Staffler cautions that it may still turn out that scientists have been chasing the wrong drug target all along, as seems to be the case with Alzheimer’s disease. “The alpha-synuclein theory of Parkinson’s is still just a hypothesis,” Staffler says. “But we are now on the cusp of either falsifying or validating that hypothesis.”
Even if the new immunotherapies make it all the way to market, it will be far from a complete cure for Parkinson’s. But they may still offer the potential to halt the disease in its tracks, which would be life-changing for the millions of patients affected.
“Finding a complete cure will take a long time,” says Osswald. “But these disease-modifying treatments in development right now could be a huge step forward, adding to the symptomatic treatments on the market, which are good to some extent, but have some other difficulties. I think Parkinson’s is really an area where we will see things evolving in the future, more and more.”
Images via Shutterstock. This article was originally published in November 2018 and has been updated to reflect recent advancements in the field of Parkinson’s research.