Mitochondrial diseases, estimated prevalence 1 in 4,300 adults, is caused by pathogenic
mutations in genes finally encoding for mitochondrial proteins of the various enzyme
complexes of the OXPHOS. Among these mutations, the 3243A>G nucleotide change in the
mitochondrially encoded transfer RNALeu(UUR) leucine 1 gene (MT TL 1) is the most prevalent
one. The OXPHOS dysfunction resulting from such mutations leads to increased production of
reactive oxygen species (ROS), ultimately leading to irreversible oxidative damage of
macromolecules, or to more selective and reversible redox modulation of cell signaling that
may impact (adult) neurogenesis.
Despite advances in the understanding of mitochondrial disorders, treatment options are
extremely limited and, to date, largely supportive. Therefore, there is an urgent need for
novel treatments. KH176, a new active pharmaceutical ingredient (API), is an orally
bio-available small molecule under development for the treatment of these disorders (see
Section 1.4). The current study will further evaluate the effect of KH176 in various
cognitive domains and evaluate the effect of different doses of KH176 (See Section 1.5).
In view of the growing recognition of the importance of mitochondrial function in maintaining
cognitive processes in the brain, as well as the understanding of the safety profile and
pharmacokinetics of KH176 following the two clinical studies described above, a more detailed
study is indicated of the effects of KH176 in various cognitive domains, using the confirmed
safe and well-tolerated KH176 dose of 100 mg bid, as well as a lower dose of 50 mg bid. The
primary objective is an evaluation of KH176 in the attention domain of cognitive functioning,
as assessed by the visual identification test score of the Cogstate computerised cognitive
testing battery.