USP30 Other Indications

Mitochondrial dysfunction and disease

Mitochondrial dysfunction, which occurs when cells’ mitochondria do not work as well as they should, has emerged as a key factor in a multitude of diseases.

Dysfunctional mitochondria are the primary hallmark of many rare genetic mitochondrial disorders.

In addition, many age-related diseases including those that affect the nervous and metabolic system are associated with mitochondria dysfunction. These include Parkinson’s disease, Alzheimer’s disease and type 2 diabetes.

Disease Indication

Idiopathic Pulmonary Fibrosis

Scientific and clinical studies have demonstrated that insufficient or impaired mitophagy is involved in idiopathic pulmonary fibrosis (IPF) pathogenesis (Kurita et al. Respiratory Research, 2017 18:114). IPF is a specific type of lung fibrosis that is a chronic and ultimately fatal disease. Over time, tissue deep in the lungs becomes scarred, resulting in a progressive decline in lung function and shortness of breath.

There is a significant unmet medical need for the treatment of IPF, as there are currently no cures and the majority of people live for only 3 to 5 years after diagnosis. Current therapies are limited to reducing certain symptoms only.

Restoring mitophagy could help reduce both the aging and death of lung cells, as well as fibrosis. Enhancing mitophagy through USP30 inhibition therefore has the potential to be a promising therapeutic approach for treating IPF.

Disease Indication

Parkinson’s Disease

Parkinson’s disease is a chronic, degenerative neurological disorder that affects one in 100 people over the age of 60. There is no objective test or biomarker for Parkinson’s disease, so the rate of misdiagnosis can be relatively high. As a result, estimates of the number of people living with the disease vary, although recent research indicates that at least one million people in the United States, and more than five million worldwide, suffer from Parkinson’s disease.

Proposed Mechanism of Action and Therapeutic Rationale

USP30 has been highlighted as a promising new target in the Central Nervous System (CNS) arena (Bingol et al., 2014 Nature 510: p370) based on effects on the Parkin pathway, which is mutated in certain Parkinson’s patients. Given that adult neurons do not divide, removal of dysfunctional mitochondria is essential to prevent impaired neuronal function and aid survival. Failure of mitochondrial quality control may lead to degeneration of the highly active substantia nigra neurons in the brain, a pathological mechanism that results in Parkinson’s disease. Enhancing this quality control through inhibition of USP30 could therefore be beneficial in treating Parkinson’s.

Disease Indication

Rare Mitochondrial Diseases

Rare mitochondrial diseases are chronic, genetic disorders that are caused by various mutations, such as deletions, in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that codes for mitochondrial proteins. These mutations can be inherited or acquired. Around 200 mutations in mtDNA and 2,000 mutations in nDNA are linked to such diseases. Mitochondrial diseases that result from defects in the mtDNA are characterised by heteroplasmy and therefore contain a mixture of mitochondria with normal as well as mutated mtDNA.

Each year, about 1,000 to 4,000 children in the United States are born with a rare mitochondrial disease, and the incidence of mitochondrial disease is estimated at 1-5 per 10,000. However, due to the wide range of clinical symptoms attributed to mitochondrial disease as well as insufficient genetic screening and diagnostic tools, this number may be an underestimate of the exact number of people with this disease.

As a result of the pivotal roles that mitochondria play in the generation and regulation of energy metabolism, mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas. This can result in debilitating physical, developmental, and cognitive disabilities with symptoms including poor growth; loss of muscle coordination; muscle weakness and pain; seizures; vision and/or hearing loss; gastrointestinal issues; learning disabilities; and organ failure.

Rare mitochondrial diseases are progressive and there is no cure. As such, there is a significant unmet medical need for treatments.

Proposed Mechanism of Action and Therapeutic Rationale

Certain rare genetic mitochondrial diseases result from various mutations in mtDNA including deletions that lead to dysfunctional mitochondria.

Recent scientific data suggests that the removal of impaired mitochondria with mutant mtDNA can be achieved by activating the Parkin/mitophagy pathway. (Kandul et al., 2016). USP30 inhibition therefore has the potential to provide a novel approach for reducing mitochondrial dysfunction in these types of mitochondrial diseases.

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