LW-1017, an oral drug that switches the brain’s cleanup system back on, reduced Parkinson’s and Alzheimer’s pathology in aged mouse models.
Inside almost every cell there are small compartments called lysosomes, and they work a bit like a recycling plant. Worn-out parts and clumps of junk get broken down there and reused. Lysoway Therapeutics, a Cambridge, Massachusetts company, is betting that turning that system back up could help in two of the best-known brain diseases, Parkinson’s and Alzheimer’s.
Its lead candidate, LW-1017, has now been described in a paper in Scientific Reports, a Nature Portfolio journal. The results come from mice, so they need to be read with that in mind; they are still worth a look [1].
LW-1017 is a small-molecule drug that activates a protein called TRPML1, which sits on the surface of lysosomes and acts like a gate. Opening it releases calcium and sets off a chain of events. In the company’s cell experiments, this sent a group of regulatory proteins into the nucleus, which in turn switched on a set of genes involved in cleanup and in building more lysosomes. When the cells lacked TRPML1, the effects disappeared, which the company says confirms the drug works through its intended target.
The drug also has to get into the brain to be useful there. Oral dosing gave what the company calls robust brain exposure, along with sustained changes in markers of the cell’s self-cleaning process (known as autophagy) across the doses tested.
What happened in the mice
The animals were aged models of each disease, which fits conditions that mostly show up later in life. According to the company’s illustration, memory was checked with a water maze in the Alzheimer’s mice and movement with a ladder-rung walking test in the Parkinson’s mice. In the Parkinson’s models, LW-1017 reduced the abnormal alpha-synuclein protein that clumps in the disease, preserved dopamine-producing neurons and improved movement. In the Alzheimer’s models, it reduced amyloid and tau pathology (the two protein problems most closely tied to Alzheimer’s), decreased brain inflammation and improved cognition.
The release doesn’t give numbers for any of these effects, so how large the improvements were is a question for the paper itself, which is open access.
“This study provides the first in vivo evidence that pharmacological activation of TRPML1 restores autophagy–lysosomal function and produces coordinated molecular, cellular, and functional benefits in aged models of both Parkinson’s and Alzheimer’s diseases,” said Dr Yongchang Qiu, founder and CEO of Lysoway Therapeutics. “LW-1017 achieved robust, sustained central target engagement at oral doses as low as 3 mg/kg – notably, in a head-to-head test at 30 mg/kg, a less brain-penetrant but equally potent comparator failed to match the same level of benefit, underscoring that high brain penetrance is not only critical for giving us an adequate safety margin, since TRPML1 is expressed throughout the body – but also important for in vivo efficacy.”
The second half of that quote is the practical part. TRPML1 is found throughout the body, so a drug that gets into the brain efficiently leaves a better safety margin, according to Qiu. He also says brain access mattered for benefit, since the less brain-penetrant comparator fell short in a head-to-head test at 30 mg/kg.
From mice to people
Now the caution. Plenty of ideas have worked well in mice and then stalled in people, and neurodegeneration is well known for it. The “first in vivo evidence” claim in Qiu’s quote is the company’s own framing. And the trial LW-1017 is in right now doesn’t involve patients. It’s a Phase I single ascending dose and multiple ascending dose study in healthy volunteers, designed to look at safety, tolerability and pharmacokinetics (how the body absorbs and clears the drug). Whether it helps anyone with Parkinson’s or Alzheimer’s is a much later question.
The research was supported in part by grants from the Michael J Fox Foundation for Parkinson’s Research and The Silverstein Foundation for Parkinson’s with GBA. The company says it is developing modulators of TRPML1 and of a second lysosomal protein, TMEM175, all aimed at restoring the cell’s cleanup function.
Lysoway describes its focus as age-related neurodegenerative diseases, which is where the longevity link sits. The idea behind LW-1017 is to restore the cell’s housekeeping, and in these mice that reached several different pathologies at once. Parkinson’s and Alzheimer’s involve different clumped proteins, yet both models responded to the same underlying push. If cleanup capacity really does matter this much in aging brains, supporting it might matter beyond these two conditions. That’s a hypothesis for now, and the healthy-volunteer study is an early step toward finding out whether it holds up in humans.
