Sortilin protein inhibition shows promise as Batten disease treatment
Reduction of cellular waste product accumulation seen in mouse models
A small molecule inhibitor of the sortilin protein reduced cellular waste product accumulation and eased neuroinflammation in mouse models of late-infantile and juvenile forms of Batten disease in a recent study.
The treatment also completely eliminated tremors in a model of late-infantile Batten, also known as CLN2 disease.
“These findings reveal sortilin inhibition as a novel and highly efficacious therapeutic modality for the treatment of multiple forms of Batten disease,” the researchers wrote, noting it may also offer broader potential for a range of diseases with related cellular underpinnings.
The study, “Sortilin inhibition treats multiple neurodegenerative lysosomal storage disorders,” was published as a preprint on bioRxiv. That means it’s a complete, but unpublished manuscript that hasn’t yet been peer reviewed.
All forms of Batten disease are considered lysosomal storage disorders, wherein dysfunction of the organelles responsible for clearing cellular waste (lysosomes) results in the toxic accumulation of cellular waste products. Each type is caused by mutations in a different member of the CLN gene family, which encode the production of proteins needed for lysosome function.
While the underlying cause is different, the downstream effects are similar, including the buildup of waste products called lipofuscins in the brain, which drives neuroinflammation and neurodegeneration. Symptoms vary in severity, but include motor and cognitive dysfunction, vision problems, and seizures.
Targeting sortilin protein in Batten disease
An optimal therapy would target lysosome dysfunction and lipofuscin buildup as well as neuroinflammation, according to the authors.
Research indicates activating a protein called transcription factor EB (TFEB), which regulates the generation of new lysosomes, can boost lysosome function and clear waste products in the brain, but it doesn’t adequately address inflammation. On the other hand, anti-inflammatory molecules can ease neuroinflammation, but don’t address lysosomal dysfunction.
Researchers think sortilin, a protein widely distributed in various brain cell types and which factors in lysosome protein sorting, could address both disease features.
A small molecule sortilin inhibitor, AF38469, was evaluated for its effects in cultured nerve cells from five different Batten disease mouse models, each caused by a different CLN gene.
AF38469 reduced waste product buildup and prevented the accumulation of dysfunctional lysosomes across most of the cell lines. It also stimulated TFEB activity and its downstream targets. Moreover, AF38469 increased the activity of the TPP1 and PPT1 enzymes, which are dysfunctional in CLN2 and CLN1 disease, respectively.
The effects of continuous treatment with AF38469 over several weeks were evaluated in a mouse model of severe CLN2 disease, where early-onset neurodegeneration leads to severe tremors and early mortality.
A low dose of the therapy was associated with improved lysosome function and signs of reduced neuroinflammation in the brain, “suggesting an overall reduction of disease burden,” the researchers wrote.
The dose also led to a reversal in tremors, returning the animals to levels comparable to healthy mice. The treatment wasn’t associated with toxic side effects.
In a mouse model of juvenile Batten disease, or CLN3 disease, which is less severe than the CLN2 model, continuous AF38469 led to reductions in waste accumulation and improved lysosome function, along with evidence of reduced neuroinflammation.
The molecule also boosted lysosome function and eased neuroinflammation in healthy mice, suggesting sortilin inhibition may have benefits, “even in the absence of severe disease,” said the researchers, who noted certain indicators of neuroinflammation returned to near normal with the sortilin inhibitor in the thalamus, a brain region implicated in Batten disease that’s appeared resistant to improvements with current gene therapy candidates.
While the way it works therapeutically haven’t been fully worked out, the findings suggest sortilin inhibition offers, “utility for the treatment of a wide variety of conditions characterized by lysosomal dysfunction,” wrote the researchers, who noted lysosome dysfunction goes beyond Batten disease and “lies at the heart of a wide variety of disease conditions.” They said the approach could show promise for Parkinson’s, Fabry or Pompe diseases, among others.