The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Philadelphia, US · Author affiliation
Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.Location evidence
Tucson, US · Author affiliation
Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, AZ, USA.Location evidence
Barcelona, ES · Author affiliation
Mitochondrial Neuropathology Laboratory, Institut de Neurociències and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.Location evidence
Lund, SE · Author affiliation
Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, BMC A13, Lund 221 84, Sweden.Location evidence
Copenhagen, DK · Author affiliation
Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark.Location evidence
Cambridge, GB · Author affiliation
Isomerase Therapeutics Ltd, Chesterford Research Park, Cambridge CB10 1 XL, UK.Location evidence
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Original abstract
Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.