Mission paper outlines potential of experimental drug MTX325 as a disease-modifying therapy for Parkinson’s

Published: 13-Nov-2023

The research was the result of collaborative work between Cambridge University, Harvard Medical School and Mission Therapeutics

Mission Therapeutics (Mission) announces the publication of a peer-reviewed article, titled "Knockout or Inhibition of USP30 Protects Dopaminergic Neurons in a Parkinson’s Disease (PD) Mouse Model," in the journal Nature Communications.

Mission Therapeutics is a global leader in discovering and developing innovative therapeutics that promote mitophagy. This quality control process enables the removal of dysfunctional mitochondria, thereby improving cell health and function.

Parkinson’s Disease is highly associated with mitochondrial dysfunction, making it a key pathophysiological driver.

Mission believes that by improving mitophagy, it can reduce the burden of dysfunctional mitochondria and thus slow or prevent the progression of Parkinson’s Disease, which is a major unmet need for patients with this condition.
Dr Paul Thompson, Chief Scientific Officer at Mission Therapeutics, 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.”
Dr Anker Lundemose, Chief Executive Officer at Mission Therapeutics, said: “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.”

The Nature Communications paper outlines how Mission’s drug MTX325 has potential as a novel, disease-modifying treatment for Parkinson’s, by enhancing mitophagy and clearing dysfunctional mitochondria.

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.
The paper provides key experimental evidence to support USP30 as a valid target in PD through both in vitro mechanisms as well as in vivo PD models.

Using both a USP30 knockout mouse model and a pharmacological strategy with Mission’s experimental USP30 inhibitor drug MTX325, it was found that USP30 inhibition led to protection 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. 
These new findings suggest that maintaining healthy mitochondrial function by blocking USP30 may slow or even stop the progression of pathology that drives PD.

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