Oral small molecule WTX-A seen to prevent toxic clumps in early study
Wavebreak's inhibitor may have potential to treat Parkinson's in its early stages
WTX-A, a small molecule in the pipeline of Wavebreak, was able to reduce the formation of toxic clumps of the alpha-synuclein protein, a hallmark of Parkinson’s disease, in cells and mouse models of the disease.
While it’s still too early to tell if WTX-A can stop the symptoms of Parkinson’s from progressing, data from these preclinical studies suggest that it may be a candidate to treat the disease from its early stages.
“These data add to the growing body of preclinical evidence supporting the disease-modifying profile of Wavebreak’s small-molecule inhibitors,” John Thomson, PhD, Wavebreak’s chief scientific officer, said in a press release.
Researchers believe that these orally available small-molecule inhibitors may “interrupt the molecular mechanisms at the source of toxic oligomer formation with high precision and specificity,” Thomson added.
The data were shared in a poster at this year’s MDS International Congress of Parkinson’s Disease and Movement Disorders, which took place Aug. 27-31 in Copenhagen, Denmark.
The poster, “Small molecule inhibitors for precise inhibition of [alpha]-synuclein oligomer generation in Parkinson’s disease,” was presented by Andrew Cridland, PhD, principal scientist at Wavebreak, formerly Wren Therapeutics.
In Parkinson’s, single units of alpha-synuclein begin to assemble into short-lived clumps of just a few units. These clumps, known as oligomers, can spread from one nerve cell (neuron) to another and grow to form long, thread-like fibers called fibrils.
Alpha-synuclein oligomers are thought to cause death of dopaminergic neurons
Alpha-synuclein oligomers are thought to be the drivers of cellular toxicity and cause the death of dopamine-producing (dopaminergic) neurons in Parkinson’s. Dopamine is a chemical messenger that allows nerve cells to communicate and is gradually lost in Parkinson’s disease.
However, there’s little information about oligomers and, because they’re transient, it’s been a challenge to develop a way to target and measure them.
Wavebreak’s technology platform has addressed this challenge by gaining an understanding of how oligomers are formed and then discovering small molecules that can quell these mechanisms with precision. One such small-molecule inhibitor is WTX-A.
The company has also developed an antibody-based biomarker test that can distinguish oligomers from single units of alpha-synuclein and fibrils, which may be useful for both preclinical and future clinical research.
In the lab, WTX-A was shown to inhibit up to 93% of primary nucleation, a mechanism that forms oligomers from single units of protein, and up to 95% of secondary nucleation, whereby existing aggregates act as seeds or templates, facilitating the formation of new aggregates.
This was specific for alpha-synuclein. Oligomers of tau and amyloid-beta proteins, which undergo similar changes in Alzheimer’s, were not affected.
WTX-A led to drop in oligomer levels
Using induced pluripotent stem cells — specialized cells that have been reprogrammed to have the ability to develop into various types of cells in the body — the researchers made dopaminergic neurons, which they grew in the lab.
When exposed to human fibrils, these dopaminergic neurons formed oligomers. However, in the presence of WTX-A, there was a dose-dependent drop in oligomer levels. This means that more WTX-A led to more reduction.
The researchers detected similar reductions in oligomer levels in lab-grown neurons from both healthy mice and a mouse model of Parkinson’s caused by mutations in the SNCA gene, which provides instructions for making alpha-synuclein.
In another model of Parkinson’s, dubbed M83, mice were given an injection of the A53T mutant form of human alpha-synuclein, which is known to more easily form toxic clumps, into the brain.
In these mice, WTX-A was able to reduce the formation of oligomers by about 70% compared with a placebo, outperforming a first-generation small molecule that was previously tested by the company.
“A significant reduction in oligomers is expected to halt disease progression,” the researchers wrote, adding that they’re “preparing to initiate a biomarker-driven clinical development program with the initial trials in [Parkinson’s disease].”
Thomson said: “We are excited by the findings from these latest studies.”