Experimental drug LW-1017 reactivates the brain’s cellular waste clearance system and reduces Parkinson’s and Alzheimer’s pathology in aged mice
Experimental drug LW-1017 reactivates the brain’s cellular waste clearance system and reduces Parkinson’s and Alzheimer’s pathology in aged mice
US company Lysoway Therapeutics tested LW-1017, a small molecule that opens the TRPML1 channel in the membrane of lysosomes, the cell’s waste recycling compartments, and activates cellular waste clearance. In aged mice, LW-1017 almost halted alpha-synuclein accumulation and preserved neurons in a Parkinson’s model. In an Alzheimer’s model, it reduced amyloid and tau deposits and restored memory. The study was published on 11 September in Scientific Reports.
Cells continually clear their waste by breaking down damaged proteins in lysosomes, small compartments containing enzymes. This clearance becomes less effective with age. The resulting accumulation of waste, including aggregated alpha-synuclein in Parkinson’s disease and amyloid and tau in Alzheimer’s disease, is thought to contribute to neuronal death. The TRPML1 channel in the lysosomal membrane accelerates clearance by releasing calcium. This promotes the fusion of waste-containing vesicles with lysosomes and activates genes involved in making new lysosomes. Researchers have discussed this approach for more than fifteen years, but the TRPML1 binding pocket lies deep within the membrane, and earlier molecules could not combine high potency with effective brain penetration. A rare disease illustrates the channel’s importance: children with a mutation that disables it have developmental delays and become blind by adolescence. Variants that reduce the function of the same gene occur in some people with early-onset parkinsonism. In Alzheimer’s disease, TRPML1 activity in the brain is often reduced even without a mutation.
LW-1017 overcame this limitation: after oral administration, it reaches higher concentrations in the brain than in the blood. When compared at the same dose with a similar compound that enters the brain less effectively, only LW-1017 substantially reduced pathology. This comparison indicates that brain penetration determines the effect.
Conventional Parkinson’s and Alzheimer’s models induce disease by overexpressing mutant proteins and do not reproduce the main age-related defect, impaired waste clearance. The researchers therefore tested the drug in aged, 18-month-old mice. These mice had substantially lower levels of waste clearance proteins and two proteins involved in cellular resilience, progranulin and GPNMB, than young mice. After 15 days of LW-1017 treatment, all four measures returned to the levels seen in young mice. In humans, variants in the same genes increase the risk of both diseases. The drug thus restores this protective system in the brain, which weakens with age.
In the Parkinson’s model, mice received injections of alpha-synuclein aggregates into the brain. Untreated mice lost about 30% of their dopaminergic neurons and performed worse on a horizontal ladder test of motor coordination. LW-1017 almost halted protein accumulation in a dose-dependent manner and preserved 85–97% of neurons, compared with 70% without treatment. The highest dose also restored normal motor coordination.
In the Alzheimer’s model, mice received injections of amyloid oligomers into the hippocampus, a brain region involved in memory. Untreated mice lost a quarter of their hippocampal neurons and failed two memory tests, the Morris water maze and the Y-maze. At 10 мг/кг, the drug fully restored performance on both tests, reduced amyloid and tau, and preserved about 90% of neurons.
“This is the first evidence in living organisms that activating TRPML1 restores autophagy and lysosomal function and produces consistent benefits at the molecular, cellular and functional levels in aged models of both Parkinson’s and Alzheimer’s disease,” says Lysoway founder Yongchang Qiu.
LW-1017 is now in a phase one trial in healthy volunteers to assess safety and dosing. Other companies are pursuing related approaches: in April, London-based Endlyz began targeting two other lysosomal proteins in Parkinson’s disease, although it had no data from disease models.