Clinical Trials in Mitochondrial Disease

Abstract

Mitochondrial dysfunction results in the production of an abnormally high amount of reactive oxygen and nitrogen species, which results in redox imbalance and glutathione deficiency. Therapeutics such as EPI-743 (a-tocotrienol quinone) and RP103 (cysteamine bitartrate) have the theoretical potential to improve redox imbalance by increasing intracellular glutathione and are currently under investigation in multiple clinical trials. This review provides an update on the use of these compounds in clinical trials related to primary and secondary mitochondrial disorders. These clinical trials have not only provided hope to affected patients and their families and caregivers, but also will serve as important stepping stones for further studies as our understanding of mitochondrial disease pathogenesis continues to improve.

Pathway Maps of Orphan and Complex Diseases Using an Integrative Computational Approach

“…Tocotrienols are known to target and inhibit the cyclooxygenase-2 (COX-2), a proinflammatory enzyme which is activated in gastric, hepatocellular, esophageal, pancreatic, colorectal, breast, bladder, cervical, endometrial, skin, and lung cancers and is involved in promoting cell survival, angiogenesis, and metastasis [ 37 – 39 ]. An open-label study of the alpha-tocotrienol quinone therapy in 10 children with genetically confirmed Leigh syndrome caused by pathogenic variants in a number of different genes showed stabilization and even reversal of disease progression [ 40 ]. Similar integrative approaches may help to provide more complete pictures on the disease relationships and drugs that can be used to target common pathways and treat different diseases.…”

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

“…For example, Idebenone, a CoQ10 derivative, is the first line of treatment in LHON patients [ 69 ]. EPI-743 (α-tocotrienol quinone) and RP103 (cysteamine bitartrate) are two other small molecules in clinical trials [ 70 ] for their potential therapeutic application in several other mtDNA genetic disorders. The status of these and other pharmacological interventions have been recently reviewed [ 71 ].…”

Clinical trials in mitochondrial disorders, an update

“…During the extension phase, there was a decline in hospital admissions and serious adverse events. The number of hospital admissions per patient declined by 40% [ 25 ]. In another open-label study, five children with a mitochondrial syndrome named RARS2 deficiency received EPI-743 during a year with an extension phase that is still ongoing.…”

“…In another open-label study, five children with a mitochondrial syndrome named RARS2 deficiency received EPI-743 during a year with an extension phase that is still ongoing. Two children showed resolution of status epilepticus whereas the other three had a decrease in the frequency and duration of seizures [ 25 ]. EPI-743 prevented ferroptosis in cells derived from patients with mitochondrial disease-associated epilepsy [ 26 ].…”