Potential Treatment of Mitochondria Seen to Delay Neurologic Symptoms in ALS Mouse Model

The experimental treatment SBT-272 delayed the onset of neurological symptoms, lowered levels of a biomarker of nerve damage, and prolonged the life of male mice in a model of amyotrophic lateral sclerosis (ALS).

Stealth BioTherapeutics, the company developing SBT-272, also announced plans to open a Phase 1 safety trial by year’s end.

Results of this animal study, “The cardiolipin-targeting compound SBT-272 attenuates neurodegeneration, delays the onset of neurological signs and extends lifespan in male SOD1 G93A transgenic mice,” was presented at recent the 18^th Annual Northeast Amyotrophic Lateral Sclerosis Consortium in Clearwater Beach, Florida.

Problems in the workings of mitochondria (a cell’s powerhouse or energy supplier) are associated with nerve cell death and ALS disease progression. SBT-272, Stealth’s lead pipeline product, is designed to improve mitochondrial function by targeting a specific lipid (fat) called cardiolipin that’s found in the inner membrane of these structures.

For this preclinical test, researcher used SOD1 G93A mice, which carry a mutation in the SOD1 gene. Up to 20% of hereditary cases of ALS are related to mutations in this gene, which contains instructions to produce a protein that breaks down toxic oxygen molecules in cells, preventing tissue damage, and participates in energy production to sustain body functions.

Animals of both sexes were given one of two doses of SBT-272 (0.5 mg/kg or 5.0 mg/kg) or a placebo via an injection into the abdomen (peritoneum). The therapy was administered daily for up to 10 weeks.

In male mice, treatment with the higher SBT-272 dose (5.0 mg/kg) significantly delayed the onset of neurological symptoms and increased their lifespan compared to placebo.

Also in male mice, blood levels of neurofilament light chain (NfL) — a proposed nerve cell damage biomarker for ALS and multiple sclerosis — significantly dropped after treatment at this higher dose, again compared to levels seen in mice given placebo.

No significant benefits were seen in female mice. The company noted that female SOD1 G93A mice have milder disease manifestations and lower NfL levels, a potential reason for the lack of improvements seen with SBT-272’s use.

“We are encouraged by these early signals suggesting that mitochondrial medicine may be a promising avenue for the treatment of ALS, and are working diligently to progress SBT-272 into the clinic later this year to evaluate its safety ahead of anticipated efficacy studies,” Reenie McCarthy, Stealth’s CEO, said in a press release.

“We are especially pleased to have identified a responsive biomarker [neurofilament light chain], which may help to inform our development efforts,” McCarthy added.