# Recovery of α-L-fucosidase in fucosidosis nonsense variants by readthrough stimulation and release factor degradation

## TL;DR

Researchers found a way to restore a missing enzyme in a rare fatal disease by using a combination of treatments in cell models.

## Contribution

Combining readthrough stimulation and eRF3a degradation enhances α-L-fucosidase recovery in fucosidosis nonsense variants.

## Key findings

- Aminoglycoside G418 induced partial recovery of α-L-fucosidase activity in nonsense variants.
- Combining G418 with CC-885 improved enzyme restoration in specific variants (p.Q82X and p.W188X).
- The approach shows potential for personalized therapy in fucosidosis patients with nonsense mutations.

## Abstract

Fucosidosis is an ultra-rare and fatal lysosomal storage disease caused by the impaired lysosomal degradation of fucosylated glycoconjugates due to a deficiency in the lysosomal tissue α-L-fucosidase (FUCA1). The accumulation of fucosylated metabolites within lysosomes leads to a range of severe, primarily neurological, symptoms, including cognitive impairment and progressive motor dysfunction. In this study, we explored a therapeutic approach using translational readthrough (TR) for patients with premature termination codons resulting from nonsense mutations in the FUCA1 gene. We ectopically expressed several clinically identified FUCA1 nonsense variants in a cell line with low endogenous FUCA1 expression. Treatment with the aminoglycoside G418 induced TR, leading to partial recovery of the full-length enzyme and FUCA1 activity. Moreover, combining aminoglycoside treatment with CC-885-induced degradation of the eukaryotic release factor subunit eRF3a further enhanced FUCA1 restoration in two variants (p.Q82X and p.W188X). This study lays the groundwork for individualized TR therapy for patients with fucosidosis with FUCA1 nonsense variants.

Summary: A combination of readthrough stimulation and release factor degradation can restore α-L-fucosidase function in cell reporter models of the lysosomal storage disease fucosidosis.