MTX325 shows promise in mouse model as Parkinson’s therapy
First-in-human trial in healthy volunteers, patients expected in early 2024
Mission Therapeutics’ experimental oral therapy MTX325, for Parkinson’s disease, spurred brain cells in mice to clear damaged mitochondria — the powerhouses of the cells — ultimately protecting them from death caused by toxic alpha-synuclein protein clumping.
That’s according to the findings of a new study using a Parkinson’s mouse model and conducted by researchers from Harvard Medical School, in Boston, the University of Cambridge, in the U.K., and Mission.
“A large body of evidence implicates [a disbalance between mitochondrial production and clearance] as a key [disease-associated] mechanism in Parkinson’s,” the team wrote.
Building on these promising preclinical results, Mission is planning to launch a Phase 1 clinical trial in healthy volunteers and Parkinson’s patients in early 2024.
“We look forward to starting our first in-human trial of MTX325 early next year,” Anker Lundemose, MD, PhD, CEO of Mission, said in a company press release.
The study, “Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model,” was published in Nature Communications.
Therapy candidate MTX325 targets enzyme key in Parkinson’s
Mission’s candidate therapy for Parkinson’s, MTX325, works by suppressing a mitochondrial enzyme called USP30.
“Inhibiting the activity of USP30 in both mice and human cells … resulted in the increased removal of damaged mitochondria and the subsequent protection of dopaminergic [dopamine-producing] neurons against the harmful effects of Parkinson’s disease, which would typically result in the neurons’ death,” said Gabriel Balmus, PhD, one of the study’s senior authors at Cambridge’s U.K. Dementia Research Institute.
“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,” Balmus added.
Mitophagy is a process by which damaged mitochondria are tagged with ubiquitin, a molecular label that signals them for clearance from the cells. Problems with mitophagy result in a toxic pool of damaged mitochondria, which may contribute to Parkinson’s-hallmark death of neurons that produce dopamine, a major brain chemical messenger involved in motor control.
“It is well recognized that mitochondrial dysfunction is a key driver of Parkinson’s disease mechanisms … playing an important role in the degeneration of brain cells that produce dopamine,” said Paul Thompson, PhD, the chief scientific officer at Mission.
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.
The researchers hypothesized that mitophagy deficits may exacerbate the toxicity of the alpha-synuclein protein. Clumps of that protein accumulate to toxic levels inside neurons of Parkinson’s patients, and are thought to contribute to dopaminergic neuron death.
The team also thought that blocking the function of USP30 — an enzyme found in mitochondria that counteracts mitophagy by removing the ubiquitin tags — may promote mitochondria clearance, resulting in healthier neurons.
“Inhibition of USP30 is an attractive therapeutic strategy for restoring mitophagy to achieve neuroprotection in [Parkinson’s disease],” the researchers wrote.
Researchers ‘keen’ to see treatment’s effects in human trial
To test this hypothesis, Mission, in collaboration with the U.K. and U.S. researchers, turned to a mouse model of Parkinson’s in which the disease is induced through the production of an alpha-synuclein protein version that’s prone to clumping.
Healthy mice genetically modified to lack USP30 showed increased mitophagy in dopaminergic neurons, but not in other tissues like the muscle, compared with unmodified mice.
These mice also showed significantly lower dopaminergic neuron loss upon injection of the mutant alpha-synuclein protein into the brain. That indicated that “USP30 absence protects against [alpha-synuclein-induced dopaminergic] neuronal loss,” the team wrote.
Loss of USP30 also was found to reduce the levels of phosphorylated alpha-synuclein, a disease-causing form found in toxic clumps, and to ease motor symptoms, supporting “inhibition of USP30 as a promising strategy for further testing for potential disease-modifying effects in [Parkinson’s],” the researchers wrote.
The team next explored whether their findings could be reproduced with MTX325, a small molecule also known as MTX115325 that showed selectivity of more than 2,000 times for USP30 relative to other similar enzymes.
Mouse studies showed that the molecule had excellent oral bioavailability, low to moderate clearance from the body, and good penetration into the brain and spinal cord. MTX325 doses up to 300 mg/kg/day for two weeks were well tolerated by healthy mice, with no side effects reported.
In lab-grown neurons, the therapy spurred mitophagy in a dose-dependent manner. When given at 50 mg/kg twice daily for 10 weeks to the Parkinson’s mouse model, the therapy significantly increased the number of dopaminergic neurons compared with a harmless solution. That suggested it may protect them from death caused by alpha-synuclein clumping.
Treatment with MTX325 also resulted in a significant increase in dopamine levels and a reduction in phosphorylated alpha-synuclein levels. A lower dose of 15 mg/kg seemed somewhat less effective than the higher one, but more research is needed to confirm the optimal dose, the researchers noted.
These findings highlight “an advantage of removing USP30 for dopaminergic neuron protection and maintenance of normal motor function,” said David K. Simon, MD, PhD, one of the study’s senior authors at Harvard.
“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,” added Simon, who directs the Beth Israel Deaconess Medical Center, a Parkinson’s Foundation Center of Excellence.
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