Pathogenesis, emerging therapeutic targets and treatment in sialidosis

Abstract

Introduction: Sialidosis is a neurosomatic, lysosomal storage disease (LSD) caused by mutations in the NEU1 gene, encoding the lysosomal sialidase neuraminidase 1 (NEU1). Deficient enzyme activity results in impaired processing/degradation of sialoglycoproteins, and accumulation of oversialylated metabolites. Sialidosis is considered an orphan disorder for which no therapy is currently available.

Areas covered: The review describes the clinical forms of sialidosis and the NEU1 mutations so far identified; NEU1 requirement to complex with the protective protein/cathepsin A for stability and activation; and the pathogenic effects of NEU1 deficiency. Studies of the molecular mechanisms of pathogenesis in animal models uncovered basic cellular pathways downstream of NEU1 and its substrates, which may be implicated in more common adult (neurodegenerative) diseases. The development of a Phase I/II clinical trial for patients with galactosialidosis may prove suitable for sialidosis patients with the attenuated form of the disease.

Expert opinion: Recently, there has been a renewed interest in the development of therapies for orphan LSDs, like sialidosis. Given the small number of potentially eligible patients, the way to treat sialidosis would be through the coordinated effort of clinical centers, which provide diagnosis and care for these patients, and the basic research labs that work toward understanding the disease pathogenesis.

Keywords:

• chaperone-mediated therapy
• lysosomal exocytosis
• lysosomal storage disease
• mechanisms of pathogenesis
• neuraminidase 1
• sialidosis

Acknowledgment

We apologize that we could not cite all the outstanding contributions to this field of research because of space constraints.

Declaration of interest

A D’Azzo holds the Jewelers for Children Endowed Chair in Genetics and Gene Therapy. This work was funded in part by NIH grants GM60905 and DK52025, the Assisi Foundation of Memphis, the American Lebanese Syrian Associated Charities (ALSAC) and the National Tay-Sachs & Allied Disease Association (NTSAD). A D’Azzo and I Annunziata are named as co-inventors on the patent application “Methods and compositions to detect the level of lysosomal exocytosis activity and methods of use”, number PCT/US2012/ 052629 based, in part, on the research reported herein. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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