Potential disease-modifying therapy for Parkinson’s disease


An experimental drug has shown potential as a disease-modifying therapy for Parkinson’s disease, according to a new study published in Nature Communications.

The peer-reviewed article titled ‘Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease (PD) mouse model’ was the result of collaborative work between Cambridge University, Harvard Medical School, and Mission Therapeutics.

Mission Therapeutics develops therapeutics that promote mitophagy, which enables the removal of dysfunctional mitochondria, thereby improving cell health and function.

Parkinson’s disease is highly associated with mitochondrial dysfunction. Mission believes that by improving mitophagy, it can reduce the burden of dysfunctional mitochondria and thus slow or prevent the progression of PD.

Dr Paul Thompson, Chief Scientific Officer at Mission Therapeutics, said: “It is well recognised that mitochondrial dysfunction is a key driver of PD 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 PD.”

Importance of healthy mitochondrial function

Dysfunctional mitochondria are usually tagged for removal via mitophagy with a protein ‘flag’ called ubiquitin. However, the enzyme USP30 removes these flags, inhibiting normal mitophagy, leading to a build-up of dysfunctional mitochondria in cells. By inhibiting USP30, MTX325 helps restore normal mitophagy and thus cellular health.

Using both a USP30 knockout mouse model and USP30 inhibitor drug MTX325, the researchers found that USP30 inhibition led to protection against loss of dopamine and dopaminergic neurons induced by alpha-synuclein in vivo. It also reduced potential biomarkers of disease including phosphorylated alpha-synuclein and glial cell activation.

These new findings suggest that maintaining healthy mitochondrial function by blocking USP30 may slow or even stop the progression of pathology which drives PD.

Professor Gabriel Balmus, Cambridge University, 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 PD, which would typically result in the neurons’ death. This research provides compelling evidence that USP30 is a promising therapeutic target for PD, where there is a pressing need for disease-modifying treatments.”

Mission is planning to initiate a MTX325 Phase I trial in humans in early 2024.

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