ATH-1105 protects against common ALS, FTD disease mechanisms

Therapy has been shown to extend lifespan, improve motor function in mice

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Athira Pharma’s experimental therapy ATH-1105 shows anti-inflammatory and neuroprotective effects, promoting neuron growth and reducing damage associated with mechanisms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a related condition.

The small molecule reduced inflammation and the buildup of a faulty version of TDP-43, a protein that’s thought to drive neuronal damage in both ALS and FTD.

That’s according to new data from preclinical studies in lab-grown cells and a mouse model of the two diseases that were shared in a poster at this year’s Alzheimer’s Association International Conference (AAIC), July 16-20, virtually and in person in Amsterdam, the Netherlands.

The poster was titled “ATH-1105, a small-molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP-43 protein pathology in ALS and frontotemporal dementia-relevant preclinical models.”

The findings add to previous evidence that ATH-115 extended lifespan and improved motor function in ALS mouse models.

“We are encouraged by the growing body of preclinical research supporting ATH-1105, which shows the molecule is protective against several [disease-causing mechanisms] common to ALS and FTD,” Kevin Church, PhD, Athira’s chief scientific officer, said in a company press release.

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Effects of ATH-1105 on ALS, FTD

Mutations in the TARDBP gene, which codes for TDP-43, have been linked to the risk of developing ALS. The mutations cause the protein to fold into the wrong shape and form toxic clumps.

Nearly everybody (97%) with ALS grow these TDP-43 aggregates in motor neurons, the nerve cells that control voluntary movement and are progressively lost with the disease. The damage results in muscle weakness and an inability to control movement. The aggregates also form in roughly half of people with FTD.

ATH-115 works as a positive modulator of the HGF/MET system, meaning it activates it. The HGF/MET system is a signaling pathway that helps safeguard neurons from damage by promoting their growth, repair, and survival.

“Positive modulation of the HGF/MET system has been shown to protect against several drivers of neurodegeneration in preclinical models, and this approach may represent a potential therapeutic strategy for ALS and FTD,” wrote the researchers, who tested ATH-115 in lab-grown neurons from the hippocampus of healthy rats. The hippocampus is a brain region linked to memory and learning, and TDP-43 clumps also build up there.

Neurons treated with ATH-115 grew about twice as many neurites, or projections that form connections with other neurons, and about three times more synapses, which are the points of contact between them.

The effect had about the same magnitude as treatment with HGF, the growth factor in the HGF/MET system.

ATH-1105 offers protection

The scientists then used four chemicals in amounts that were toxic to lab-grown rat cortical neurons, or neurons from the brain’s outermost layer. The chemicals were the neurotransmitter glutamate, bacteria-derived lipopolysaccharide (LPS), hydrogen peroxide, and 1-methyl-4-phenylpyridinium, a neurotoxin.

Each of them reduced the number of neurons that remained alive. However, when treated with ATH-1105 beforehand, the neurons were protected against their associated damage and didn’t die as much. In fact, almost all remained alive.

The researchers then analyzed the effects of ATH-1105 when added to LPS-exposed lab-grown human macrophages, a type of immune cell. LPS exposure increased the cells’ production of IL-6 and TNF-alpha, two pro-inflammatory signaling molecules, while ATH-1105 significantly reduced their levels.

Inflammation induced by LPS can cause cognitive impairment. In mice, this can be studied using a test called a T-maze. Compared with a placebo, ATH-1105 (given by mouth once daily for 14 days) eased cognitive impairment in LPS-exposed mice.

Finally, the researchers used a mouse model of ALS and FTD that produces a faulty version of human TDP-43. Some mice were given ATH-1105 by mouth once daily from 1-3 months of age. Others were given a placebo.

Similar to data from previous preclinical studies, ATH-1105 reduced blood IL-6 and TNF-alpha levels. It also reduced the levels of neurofilament light chain, a marker of neuronal damage.

Moreover, ATH-1105 reduced TPD-43 levels in the mice’s sciatic nerve by about three times, nearly reaching those seen in healthy mice. The sciatic nerve is a long nerve that runs from the lower back down the lower limbs.

“The consistency and breadth of these effects in reducing markers of inflammation, neurodegeneration, and TPD-43 protein pathology continue to support the broad therapeutic potential and continued advancement of ATH-1105,” Church said.