Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

Mosca, Rosario; Vlekkert, Diantha van de; Campos, Yvan; Fremuth, Leigh Ellen; Cadaoas, Jaclyn; Koppaka, Vish; Kakkis, Emil; Tifft, Cynthia J.; Toro, Camilo; Allievi, Simona; Gellera, Cinzia; Canafoglia, Laura; Visser, Gepke; Annunziata, Ida; d’Azzo, Alessandra

doi:10.3390/jcm9030695

Cited by 15 publications

(15 citation statements)

References 45 publications

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“…All patients had comprehensive clinical, molecular and biochemical investigations. Some of the molecular and biochemical information is described as part of a larger cohort study by Mosca et al 13 and is the subject of an additional sialidosis type I natural history study underway (Tifft and Toro in preparation).…”

Section: Resultsmentioning

confidence: 99%

A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot

et al. 2020

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AimTo describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated ‘macular cherry-red spot’.MethodsSeven patients with sialidosis type I (mutations in NEU1) and one with galactosialidosis (mutations in CTSA) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years.ResultsThe mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50)+0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to age-matched controls (p<0.0001).ConclusionMost of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear.Trial registration numberNCT00029965.

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Section: Resultsmentioning

confidence: 99%

A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot

et al. 2020

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“…44 Thus, GS may fall into the category of orphan diseases that are, in fact, more frequent than expected; in this case, the number of patients eligible for therapy could be greater than anticipated. In addition, there is now evidence that the activity of mutant NEU1 in the attenuated type I forms of sialidosis, 46 as well as in animal models mimicking type I sialidosis, 47 can be increased by exogenously incrementing PPCA levels. It is therefore conceivable that a rhPPCA therapeutic product could be used to treat both non-neuropathic GS and sialidosis patients.…”

Section: Discussionmentioning

confidence: 99%

Galactosialidosis: preclinical enzyme replacement therapy in a mouse model of the disease, a proof of concept

Cadaoas

Boyle

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Galactosialidosis is a rare lysosomal storage disease caused by a congenital defect of protective protein/cathepsin A (PPCA) and secondary deficiency of neuraminidase-1 and b-galactosidase. PPCA is a lysosomal serine carboxypeptidase that functions as a chaperone for neuraminidase-1 and b-galactosidase within a lysosomal multi-protein complex. Combined deficiency of the three enzymes leads to accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids and manifests in a systemic disease pathology with severity mostly correlating with the type of mutation(s) and age of onset of the symptoms. Here, we describe a proof-of-concept, preclinical study toward the development of enzyme replacement therapy for galactosialidosis, using a recombinant human PPCA. We show that the recombinant enzyme, taken up by patient-derived fibroblasts, restored cathepsin A, neuraminidase-1, and b-galactosidase activities. Long-term, bi-weekly injection of the recombinant enzyme in a cohort of mice with null mutation at the PPCA (CTSA) locus (PPCA -/-), a faithful model of the disease, demonstrated a dose-dependent, systemic internalization of the enzyme by cells of various organs, including the brain. This resulted in restoration/normalization of the three enzyme activities, resolution of histopathology, and reduction of sialyloligosacchariduria. These positive results underscore the benefits of a PPCA-mediated enzyme replacement therapy for the treatment of galactosialidosis.

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“…These compounds have not been administered in patients under controlled trials yet. However, this observation may also explain the potential differences among patients with the same genetic mutations that may be attributed to lifestyle, diet, and environmental factors, aside from genetic background [13].…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and Management of Type 1 Sialidosis: Clinical Insights from Long-Term Care of Four Unrelated Patients

et al. 2020

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Background: Sialidosis is a rare autosomal recessive disease caused by NEU1 mutations, leading to neuraminidase deficiency and accumulation of sialic acid-containing oligosaccharides and glycopeptides into the tissues. Sialidosis is divided into two clinical entities, depending on residual enzyme activity, and can be distinguished according to age of onset, clinical features, and progression. Type 1 sialidosis is the milder, late-onset form, also known as non-dysmorphic sialidosis. It is commonly characterized by progressive myoclonus, ataxia, and a macular cherry-red spot. As a rare condition, the diagnosis is often only made after few years from onset, and the clinical management might prove difficult. Furthermore, the information in the literature on the long-term course is scarce. Case presentations: We describe a comprehensive clinical, neuroradiological, ophthalmological, and electrophysiological history of four unrelated patients affected by type 1 sialidosis. The long-term care and novel clinical and neuroradiological insights are discussed. Discussion and conclusions: We report the longest follow-up (up to 30 years) ever described in patients with type 1 sialidosis. During the course, we observed a high degree of motor and speech disability with preserved cognitive functions. Among the newest antiseizure medication, perampanel (PER) was proven to be effective in controlling myoclonus and tonic–clonic seizures, confirming it is a valid therapeutic option for these patients. Brain magnetic resonance imaging (MRI) disclosed new findings, including bilateral gliosis of cerebellar folia and of the occipital white matter. In addition, a newly reported variant (c.914G > A) is described.

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Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

Cited by 15 publications

References 45 publications

A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot

A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot

Galactosialidosis: preclinical enzyme replacement therapy in a mouse model of the disease, a proof of concept

Diagnosis and Management of Type 1 Sialidosis: Clinical Insights from Long-Term Care of Four Unrelated Patients

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