Mitochondrial dysfunction, including reduced mitochondrial length and density in primary motor neuron neurites, is known to be one of the earliest pathophysiological events in ALS, including familial ALS associated with mutations in TAR DNA-binding protein 43 (TDP-43). TDP-43 pathology has also been observed in multiple other neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD), Lewy body dementia (LBD), progressive supranuclear palsy (PSP), and Alzheimer's disease. SBT-272 is a novel, clinical-stage mitochondria-targeted product candidate which is known to cross the blood-brain barrier, with the potential to treat neuronal mitochondrial dysfunction.
This preclinical study evaluated the effects of SBT-272 on mitochondrial function, morphology, and motility in mouse corticospinal motor neurons with mutant TDP-43 pathology. Systemic administration of SBT-272 in rodents resulted in sustained SBT-272 levels across different regions of the brain and protected mitochondria against ischemic stress, confirming that the compound crosses the blood brain barrier and has mitoprotective effects. Mitochondrial motility, which was significantly impaired in TDP-43 upper motor neuron cultures, was improved in a dose-dependent manner with SBT-272 treatment. Mitochondrial ultrastructural defects associated with TDP-43 pathology were also reduced with SBT-272 treatment. The improved mitochondrial motility and ultrastructure were associated with improved axon outgrowth in cultured mutant TDP-43 neurons treated with SBT-272. These data highlight the potential of SBT-272 as a systemically administered therapy for treating neurodegenerative diseases.
"We are excited about the promise of SBT-272 as a potential therapeutic for neurodegenerative diseases including ALS," said Chief Executive Officer Reenie McCarthy. "These encouraging data add to our growing body of evidence in other preclinical models of ALS, Parkinson's disease, and other neurodegenerative disorders, providing early therapeutic direction as we plan to advance SBT-272 in dose-ranging Phase 1 clinical studies early next year."
We are a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction. Mitochondria, found in nearly every cell in the body, are the body's main source of energy production and are critical for normal organ function. Dysfunctional mitochondria characterize a number of rare genetic diseases and are involved in many common age-related diseases, typically involving organ systems with high energy demands such as the heart, the eye, and the brain. We believe our lead product candidate, elamipretide, has the potential to treat both rare metabolic cardiomyopathies, such as Barth syndrome, Duchenne muscular dystrophy and Friedreich's ataxia, rare mitochondrial diseases entailing nuclear DNA mutations, as well as ophthalmic diseases entailing mitochondrial dysfunction, such as dry age-related macular degeneration and Leber's hereditary optic neuropathy. We are evaluating our second-generation clinical-stage candidate, SBT-272, and our new series of small molecules, SBT-550, for rare neurological disease indications following promising preclinical data. We have optimized our discovery platform to identify novel mitochondria-targeted compounds which may be nominated as therapeutic product candidates or utilized as mitochondria-targeted vectors to deliver other compounds to mitochondria.
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SOURCE Stealth BioTherapeutics Inc.