USP30 Mitochondrial Disease Program

There is a significant unmet medical need for treatments of rare mitochondrial diseases.

Disease Indication

Treatment of rare mitochondrial diseases characterized by heteroplasmy – that is a mixture of mitochondria with normal and mutated mitochondrial DNA (mtDNA).

Proposed mechanism of action

Inhibition of USP30 activates mitophagy, which results in increased degradation of impaired mitochondria with mutant mtDNA, via the lysosome pathway.

Therapeutic Rationale

Certain rare genetic mitochondrial diseases, such as Kearns-Sayre syndrome, Pearson syndrome and MELAS syndrome, result from various mutations in mtDNA including deletions that lead to dysfunctional mitochondria. These diseases are characterized by heteroplasmy, a mixture of mitochondria with normal and mutated mitochondrial (mtDNA) that can result in the accumulation of dysfunctional mitochondria compared to normal 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). We are therefore testing the hypothesis that USP30 inhibition has the potential to provide a novel approach for reducing mitochondrial dysfunction in these types of mitochondrial diseases.

There is a significant unmet medical need for treatments of mitochondrial diseases, as current therapies are limited to treating certain symptoms only.

Rare primary genetic 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 in 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.

Mitochondria: the basics

Mitochondria are organelles that are present in almost every cell of the human body, where they perform many essential functions. They produce about 90% of the body’s energy and many biosynthetic intermediates, as well as influencing cellular stress responses such as autophagy and apoptosis (programmed cell death). There are several thousand mitochondria present in every cell, where they normally have a life span of approximately 40 days.