RNS60 aids mitochondria health, protects motor neurons in ALS mice
Candidate has been granted orphan drug, fast track designations by FDA
A treatment candidate from Revalesio named RNS60 protected motor neurons from damage in a mouse model of amyotrophic lateral sclerosis (ALS) linked with accumulating toxic TDP-43 protein clumps.
It also showed it could improve the health of mitochondria, the cells’ powerhouses that are abnormal in ALS, and reduce the toxic activation of certain cell types in the brain. Motor neurons are nerve cells that control voluntary muscle movements and are progressively damaged in ALS.
“These exciting results suggest that RNS60 has potential to mitigate neurodegeneration due to TDP-43 pathology,” Mukesh Gautam, PhD, professor at Northwestern University Feinberg School of Medicine, said in a Revalesio press release. “Since TDP-43 pathology contributes to a large population of both familial and sporadic ALS patients, these results are particularly promising.”
Gautam shared the results during a presentation titled “Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis” at the Society for Neuroscience Annual Meeting, Oct. 5-9, in Chicago.
In about 97% of ALS cases, a misfolded version of the TDP-43 protein accumulates in motor neurons and causes damage, contributing to muscle weakness and a range of other symptoms that mark the disease.
The exact mechanisms through which the abnormal TDP-43 clumps cause toxicity aren’t fully known, but research has shown that some of the earliest disease-related events in people and mice that carry these aggregates are problems in mitochondria and the abnormal activation of astrocytes and microglia, two types of cells in the brain that normally support neuronal function. Astrocytes are star-shaped cells that help regulate ions and other chemical messengers, stabilize the blood-brain-barrier that protects the brain from harmful substances in the blood, and provide energy and structural support to neurons. Microglia are the resident immune cells in the brain that help eliminate microbes and death cells, and also clear harmful protein aggregates.
In ALS, however, these cells typically become dysregulated and end up contributing to further motor neuron damage and symptom progression. Improving the health of mitochondria can reduce the cells’ activation, it’s believed.
Promising preclinical findings with RNS60
RNS60 is an experimental therapy designed to boost the formation of new mitochondria and restore energy production in nerve cells. It also can modulate the activity of immune cells, easing ALS-related inflammation. In preclinical studies, RNS60 showed it could protect the integrity of neurons and other supporting cells in the brain and spinal cord, preventing cell damage and death.
Here, researchers used a mouse model of ALS with a mutation in TARDBP, the gene that carries instructions for producing TDP-43. The mice developed typical ALS-like symptoms, including progressive motor neuron degeneration, which caused walking impairments and muscle weakness.
The mice were treated with RNS60 or a placebo every other day for 60 days. The therapy significantly aided the health of mitochondria, as evidenced by improved mitochondria structure, and reduced microglia and astrocyte activation. It also resulted in healthier motor neurons and neuromuscular junctions, that is, the sites of communication between nerve and muscle cells, over a placebo.
“There is a great need for treatment options to slow the progression of ALS,” said Hande Ozdinler, PhD, professor at Feinberg and the study’s lead researcher. “These promising preclinical findings warrant further investigation of the potential role of RNS60 in protecting motor neurons and preserving mitochondrial function, key factors in the pathogenesis of ALS.”
RNS60 has been granted orphan drug and fast track status for ALS by the U.S. Food and Drug Administration. These designations are expected to support and accelerate the development and review of RNS60 for this indication.
Consistent with the preclinical findings, data from a previous investigator-sponsored Phase 2 clinical trial (NCT03456882) also showed a short course with RNS60 (weekly infusions for six months) resulted in a six-month extension in survival after about three years. The results weren’t significant, but may warrant more studies to investigate the benefits of long-term treatment.
“These results add to the growing body of preclinical and clinical evidence that RNS60 may provide neuroprotective effects in ALS,” said Bert van den Bergh, the executive chairman of Revalesio’s board of directors. “We are simultaneously advancing RNS60 in planned clinical trials for the treatment of patients with ALS and ischemic stroke with the goal of improving the lives of people with these devastating conditions.”
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