Promising results with anle138b, a new drug that prevents protein clumping

Original article: Depopulation of dense alpha-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. Acta Neuropathol: June 5, 2019.

The takeaway

anle138b prevents the clumping of alpha synuclein, and leads to improvements in both dopamine release, neuron survival and movement symptoms in a transgenic mouse model of Parkinson’s.

Why is it important?

anle138b had neuroprotective, anti-clumping effects even when it was introduced after the onset of dopaminergic dysfunction. If found to be safe and well tolerated in humans, these results are promising for future translation to people with Parkinson’s who might be commencing such a therapy at a similar time, when the pathological process is causing early symptoms.

Background

Alpha synuclein is the main protein which misfolds and forms larger, harmful clumps in Parkinson’s, causing damage to neurons. A new drug, anle138b, previously shown to prevent the clumping together of other types of proteins seen in conditions like Alzheimer’s, has been tested in a new transgenic mouse model of Parkinson’s.

In these transgenic mice, alpha synuclein clumps together in parts of the brain including the movement centres and olfactory region which are affected in people with Parkinson’s, and also leads to movement problems. This new model is therefore an excellent means of assessing the potential of anle138b to interfere with alpha synuclein and thereby reduce dopamine neuron loss and the symptoms associated with it.

The details

The researchers first generated the transgenic mouse line, which would be compared against a control group. They showed that indeed these mice were impaired in terms of movement (walking and balance). After checking for markers of neuronal dysfunction at different times beginning at 3 months of age, they found dopaminergic decline was present at 12 months in these animals, while gait problems were apparent already at 9 months.

The transgenic mice were treated with anle138b, starting at 9 months of age when dopaminergic problems had already begun but before significant neuronal death had occurred, and ending at 12 months when no more than 30% of neurons in the movement centre of the brain are lost.

This 3 month treatment with the drug which was added to the animals daily feed produced several beneficial effects, when compared to animals that had received an inactive placebo: the treated animals showed improved dopamine release in vivo, that is, when it was measured while the animals were freely walking around, less clumped alpha synuclein, and better walking and movement. Transgenic mice treated with anle138b had a greater number of surviving dopamine neurons compared with placebo-treated transgenic animals, and a similar number of neurons seen in other groups of mice that had no alpha synuclein pathology.

Next steps

It is important to acknowledge that these promising results were obtained in transgenic mice. Before any trial of efficacy for Parkinson’s, a Phase I safety and tolerability study is an essential rate limiting step. Future preclinical studies may also address the effects of anle138b on non-motor symptoms as well.

Original article: Wegrzynowicz M, Bar-On D, Calo L, Anichtchik O, Iovino M, Xia J, Spillantini MG. June 5, 2019. Depopulation of dense alpha-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. 

 

 

print

Pin It on Pinterest

Share This