Following a previous grant awarded in 2017, this research grant will support testing of Mission’s lead CNS-penetrant USP30 DUB inhibitors in an in vivo model of Familial Parkinson’s Disease (PD), as well as ongoing preclinical development towards candidate selection.
Parkinson’s disease is a chronic, degenerative neurological disorder that affects one in 100 people over age 60. Estimates of the number of people living with the disease vary due to high rates of misdiagnosis, but research indicates that it is at least one million people in the United States and more than five million worldwide.
USP30 is a mitochondrial-associated DUB that negatively regulates mitophagy – a process in which dysfunctional mitochondria are tagged with ubiquitin and selectively degraded and cleared from the cell. In some forms of familial PD, the protein that adds the ubiquitin, Parkin, is impaired, leading to reduced mitochondrial quality control. This can lead to degeneration of highly active substantia nigra neurons in the brain, which results in Early Onset Parkinson’s Disease (EOPD). It is believed that inhibition of USP30 will improve mitochondrial quality control, resulting in neuroprotection.
The MJFF grant will fund a set of studies to measure the effect of Mission’s lead CNS USP30 inhibitor on dopaminergic neuron protection. They will also assess indicators of mitochondrial quality control loss that are commonly observed in EOPD patients, such as elevated mitochondrial DNA mutations and inflammation.
Shalini Padmanabhan, PhD, Director of Research Programmes at MJFF, said: “The number of people living with Parkinson’s continues to grow, but there are currently no treatments capable of stopping or reversing progression of this debilitating disease. Mission’s CNS-penetrant USP30 DUB inhibitors may offer an opportunity to make a meaningful impact on the lives of PD patients by improving the health of cells in the brain. We are proud to support a project aiming to meet this critical unmet need.”
Dr Paul Thompson, Mission’s Chief Scientific Officer, added: “Receiving funding from the Michael J Fox Foundation is a great accolade, recognising the importance of USP30 as a potential therapeutic target for PD, and the quality of Mission’s chemistry. We are also pleased to contribute to further validation of non-clinical in vivo models of PD, an area which requires ongoing collaboration and support. We hope this will be the first of many Mission DUB inhibitor programmes that can address specific disease-driving pathologies in both Parkinson’s Disease and other neurodegenerative disorders.”
It is anticipated that USP30 inhibitor mechanisms will apply to idiopathic PD, neurodegenerative disorders, and other diseases more broadly. Mission’s first USP30 inhibitor, a non-CNS penetrant molecule, is scheduled to enter the clinic in early 2022 for kidney and liver disease.