Immunotolerance Molecules Show Promise in Mouse Model of PD

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Preclinical research supports the potential of small molecules that modulate the immune system to halt Parkinson’s disease (PD) progression and ease motor symptoms.

According to a new study, Aeterna Zentari’s autoimmunity-modifying biologicals (AIM Biologicals) were able to induce a state of immunotolerance in a mouse model of Parkinson’s disease and lessen motor progression.

“There is a growing interest in the induction of antigen-specific immunotolerance in neuroinflammatory diseases,” Joerg Wischhusen, PhD, at the School of Medicine, University of Wuerzburg, Germany, said in a press release. He was one of the leaders of the study.

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“Utilizing such therapeutic approaches is of particular interest in the potential treatment of PD, since currently available treatment options are symptomatic and immunomodulatory treatments have not yet been tested,” he added. “We were pleased with the results from this study and believe the translational potential of this approach deserves further exploration.”

Wischhusen presented the immunotolerance results, “αlpha-synuclein peptides presented on chimeric MHC class Ib molecules prevent loss of substantia nigra neurons in an animal model for Parkinson’s disease, at the Immunology 2022 meeting, which ran May 6–10 in Portland, Oregon.

One of the hallmark features of Parkinson’s is the formation of aggregates, or clumps, of the protein alpha-synuclein in the brain. These clumps have been shown to trigger an immune response, which contributes to chronic brain inflammation (neuroinflammation) and disease progression. Moreover, immune T-cells that react against alpha-synuclein are found in the blood of those with Parkinson’s, and their presence precedes the development of motor symptoms, “indicating an active and specific involvement of the immune system in disease progression,” the researchers wrote.

Aeterna’s AIM Biologicals are based on the concept of immune-tolerance that characterizes fetal development when a woman is pregnant. Despite the fact that the growing fetus is composed of 50% “foreign” proteins — those that come from the father — the mother’s immune system does not react against it.

In this case, the mother’s immune system becomes desensitized toward the fetus but fully active against real threats, such as infections.

Aeterna applied this principle to build molecules that can induce tolerance for several antigens (proteins capable of triggering an immune response) — in this case, alpha-synuclein.

They tested their molecule in lab (in vitro) studies as well as in a mouse model of Parkinson’s. The results showed that treatment with alpha-synuclein-specific AIM Biologicals lessened brain inflammation and induced the production of regulatory T-cells, a type of immune cell that works to shut down excessive inflammatory responses.

Moreover, treated animals showed a trend toward improved motor function and had less degeneration of nerve cells (neurons) in the substantia nigra, a brain region involved in the control of voluntary movements and one of the most affected in Parkinson’s.

“Under our collaboration with the University of Wuerzburg, Prof. Wischhusen, Prof. Chi Wang Ip, and their teams have provided data that we believe is important pre-clinical proof of concept for our AIM Biologicals platform,” said Klaus Paulini, CEO of Aeterna Zentaris.

“We are very pleased with the encouraging progress of our AIM Biologicals program and the potential utility for the treatment of PD,” he added.