SBT-272 Supports Health of Mitochondria in ALS Mouse Model

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by Steve Bryson PhD |

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An investigational treatment for amyotrophic lateral sclerosis (ALS), SBT-272 was found to sustainably reach different brain regions, and to protect mitochondria — a cell’s energy source — from TDP-43 toxic aggregates in a mouse model of the disease.

“We are excited about the promise of SBT-272 as a potential therapeutic for neurodegenerative diseases including ALS,” Reenie McCarthy, CEO of Stealth BioTherapeutics, the therapy’s developer, said in a press release.

The company plans to launch dose-finding Phase 1 studies early next year, it added.

Results of this preclinical work were presented at the virtual 2021 Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) Meeting, held virtually Oct. 6–7.

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Damage to motor neurons, the nerve cells that control voluntary movements, is a hallmark of ALS. One of the earliest disease-related events is the impairment of mitochondria — the cellular components that generate most of a cell’s supply of chemical energy — within motor neurons.

Mitochondria length and density are lower in primary motor neurons of ALS patients, including those whose disease is associated with the abnormal accumulation and aggregation of the TDP-43 protein.

TDP-43 has also been implicated in other neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease, Lewy body dementia, frontotemporal lobar degeneration, and progressive supranuclear palsy.

SBT-272 is designed to aid mitochondria by targeting cardiolipin, a lipid (a type of fat) located in the inner membrane of mitochondria.

The investigative compound works to increase cellular energy production and lower mitochondrial oxidative stress — the imbalance between the production of free radicals (natural byproducts of metabolism) and a cell’s ability to detoxify them, resulting in damage.

The preclinical study evaluated the impact of SBT-272 on mitochondrial function, structure, and ability to move in mice and motor neurons with a mutated TARDBP gene, which carries instructions for producing the TDP-43 protein.

Systemic administration of SBT-272 to mice led to sustained levels of the medicine in regions throughout the brain, confirming the compound crossed the blood-brain barrier — the highly specialized barrier that controls which substances enter or leave the brain.

Notably, the treatment in mice also protected against mitochondrial oxidative stress.

The movement of mitochondria, which was significantly impaired in TDP-43-mutated motor neuron cultures, improved in a dose-dependent manner. SBT-272’s use also reduced mitochondrial structural defects caused by faulty TDP-43.

In cultured TDP-43 neurons treated with SBT-272, improvements in structure and movement were associated with a greater outgrowth of nerve fibers (axons) from the nerve cell body.

Earlier preclinical work demonstrated that SBT-272 improved biomarkers of nerve damage, delayed the onset of neurological symptoms, and prolonged the life of an ALS mouse model. SBT-272 also eased symptoms in a Parkinson’s disease mouse model.

Stealth announced in early 2020 the launch of a Phase 1 trial into the therapy’s safety and tolerability in healthy volunteers. In November of that year, the company reported that a favorable safety profile was seen.

“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,” McCarthy said.