Human trials to begin soon of Parkinson’s disease drug after promising research from Mission Therapeutics, Cambridge and Harvard

Human trials will begin early in 2024 of a potential new drug that it is hoped could slow the progression of Parkinson’s disease.

A collaboration involving Babraham Research Campus-based biotech company Mission Therapeutics, the University of Cambridge and Harvard Medical School has uncovered evidence that inhibiting an enzyme called USP30 can help remove dysfunctional mitochondria - the powerhouses of our cells, which are disrupted in Parkinson’s.

They believe that removing these will help dopaminergic neurons, which are the main source of dopamine in the mammalian central nervous system.

They play a key role in controlling many brain functions, including voluntary movement, cognition and behavioural processes including mood, reward and motivation.

Parkinson’s disease is associated with the loss of these dopaminergic neurons.

In a paper published in the journal Nature Communications, the researchers found the experimental drug to be effective in mice models and human cells.

Prof Gabriel Balmus, a group leader at the UK Dementia Research Institute at the University of Cambridge, said: “Our study has shown that it is possible to enhance the removal of damaged mitochondria through a process called mitophagy.

“We demonstrated this by inhibiting the activity of USP30 in both mice and human cells, which resulted in the increased removal of damaged mitochondria and the subsequent protection of dopaminergic neurons against the harmful effects of Parkinson's disease, which would typically result in the neurons’ death.

“This research provides compelling evidence that USP30 is a promising therapeutic target for Parkinson's disease, where there is a pressing need for disease-modifying treatments.”

Mission Therapeutics is focused on therapeutics that promote mitophagy - a quality control process that enables the removal of dysfunctional mitochondria to improve cell health and function.

Dr Paul Thompson, its chief scientific officer, said: "It is well recognised that mitochondrial dysfunction is a key driver of Parkinson’s disease mechanisms, in particular, playing an important role in the degeneration of brain cells that produce dopamine.

“By inhibiting the enzyme USP30, Mission’s experimental drug MTX325 helps promote mitochondrial quality control by increasing the removal of dysfunctional mitochondria. This is likely to have a positive impact on dopaminergic neurons undergoing chronic degenerative processes, which result in functional impairment. This paper strongly supports further study of USP30 inhibition as a potential disease-modifying therapy for Parkinson’s disease.”

CEO Dr Anker Lundemose added: “The exciting findings of this Nature Communications paper are a tremendous boost to Mission’s Parkinson’s disease programme. We look forward to starting our first in-human trial of MTX325 early next year.”

Dysfunctional mitochondria are usually tagged for removal via mitophagy in our bodies with a protein ‘flag’ called ubiquitin.

But the enzyme USP30 removes these flags, inhibiting normal mitophagy, which leads to a build-up of dysfunctional mitochondria in cells. By inhibiting USP30, it is believed the experimental drug could restore normal mitophagy and cellular health.

The research found USP30 inhibition protected against loss of dopamine and dopaminergic neurons induced by alpha-synuclein in vivo and reduced potential biomarkers of disease, including phosphorylated alpha-synuclein and glial cell activation.

Prof David K Simon, from Harvard Medical School, said: “Our study of USP30 KO mice in a synuclein-driven Parkinson’s disease model clearly shows an advantage of removing USP30 for dopaminergic neuron protection and maintenance of normal motor function. It has been our pleasure to collaborate with Cambridge and Mission Therapeutics on these studies, and we are keen to see the outcomes of early MTX325 clinical investigations.”