USP30 Other Indications

Pipeline

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

Renal Disease

One of Mission’s lead assets, MTX652, which is now in the clinic, is intended to address the important unmet need of treatment of acute kidney injury (AKI). AKI is important in itself, but also leads to chronic kidney disease (CKD) and end stage renal disease.

AKI occurs in about 13.3 million people globally per year and it is thought to contribute to about 1.7 million deaths every year (Mehta, Cerda et al. 2015). As a result of increased diagnostics and awareness, the severity of the burden of AKI has become undeniable. The attributable healthcare costs for AKI were estimated in 2017 to be around 1% of the total NHS budget in England and between US$5.4 – 24 billion in the US (Silver S.A., Chertow G.M. Nephron 2017;137:297–301).

AKI can result from a wide spectrum of physiological causes, with significant morbidity/mortality outcomes, substantial effect on quality of life and healthcare cost. AKI frequently results in permanent kidney damage (i.e., CKD) and may also cause damage to non-renal organs. AKI is therefore a significant public health concern, particularly when taking into account the absolute number of patients developing incident CKD, progressive CKD, and end-stage renal disease. There is therefore a clear unmet medical need, making the development of medicinal products for the prevention and/or treatment of AKI an urgent matter.

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.

Disease Indication

Duchenne Muscular Dystrophy Disease

Duchenne Muscular Dystrophy (DMD) is a rare inherited disorder occurring mainly in young boys caused by lack of Dystrophin. The disease manifests in early childhood as a progressive neuromuscular disease resulting in loss of myofiber integrity in skeletal and cardiac muscle. Patients become wheelchair-bound in their teenage years and die in their 3rd/4th decade, usually from cardio/respiratory complications. Mitochondrial dysfunction is an early pathogenic event downstream of dystrophin loss. This leads to poor bioenergetic function and muscle weakness. Additional disease mechanisms driven by mitochondrial dysfunction include calcium dysregulation, inflammation, and ER stress.

Importantly, muscle stem cell regeneration is impeded by poor mitochondrial function. Mitophagy, the process of dysfunctional mitochondria elimination, is defective in DMD patient tissue and animal models of disease. Mitophagy activators have shown benefit in the mdx mouse DMD model and mitophagy reduction causes cardiomyopathy. MTX652 is a USP30 inhibitor which promotes mitochondrial quality through mitophagy, leading to improved mitochondrial bioenergetics and functional outcomes, myoprotection through reduced oxidative stress/inflammation, and improved muscle regenerative capacity by enhancing stem cell function. In addition, MTX652 may also reduce cardiomyopathy, leading to improvement of long-term heart outcomes.