Sialic Acid Supplementation in N-Acetylneuraminic Acid Synthase (NANS) Deficiency

Study Overview
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Brief Summary
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This study is aimed at assessing the impact of short-term (3 days) exogenous sialic acid supplementation on endogenous biomarkers of sialic acid metabolism in NANS deficient patients.

Detailed Description
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NANS deficiency is a genetic disorder presenting clinically with intellectual development disorder, skeletal dysplasia and dysmorphic features. It has recently been described in 9 patients (4 children and 5 adults). Biallelic mutations in the NANS (N-Acetylneuraminic acid synthase) gene cause a block in the endogenous synthesis of sialic acid and accumulation of the precursor, N-acetyl mannosamine (ManNAc). In a cell culture model, this block results in hyposialylation of glycoproteins and glycolipids. It seems likely that in human, this enzyme deficiency impairs the sialylation of glycolipids and glycoproteins, known to be essential for brain development. Exogenously added sialic acid partially rescued the phenotype of NANS-deficient zebra fish. Currently there is no approved treatment for patients with NANS deficiency. The investigators concluded that exogenous sialic acid supplementation might be useful for NANS patients. Given that sialic acid is found as both, a free sugar and in a bound form in standard nutrition as well as in high quantities in breast milk, it can be considered as a safe nutritional ingredient; this notion is fully supported by animal toxicity studies. The use of sialic acid in NANS deficiency is in line with oral supplementation of specific sugars for treatment of other glycosylation and sialylation defects such as congenital disorders of glycosylation (CDG) and myopathy with mutation in the gene GNE. This novel monosaccharide therapy represents an opportunity to address fundamental biochemical questions about the relative contribution of endogenous and dietary sources on sialic acid metabolism and its potential role as a future therapy for NANS patients.

Official Title
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Sialic Acid Supplementation in NANS Deficiency: An Open-label, Proof of Concept, Two-centers Study

Conditions
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N-Acetylneuraminic Acid Storage Disease

Intervention / Treatment
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* Other: Neu5Ac supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for controls: 4 healthy adults aged 18 to 60 years (inclusion in Switzerland) Inclusion Criteria for subjects with NANS deficiency: 4 adults aged 18 to 60 years with genetically proven NANS deficiency (inclusion in Italy) 2 children aged 1 to 18 years with genetically proven NANS deficiency (inclusion in Switzerland) Exclusion Criteria for controls: Medication, Restrictive diet (e.g. lactose free diet), obesity or other co-morbidities (e.g. neurological disease, developmental delay) No exclusion Criteria for subjects

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open label individual patient clinical trial study of small sample size
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Experimental: sialic acid<br> | Other: Neu5Ac supplementation<br>* Sialic acid as N-Acetyl-neuraminic acid dehydrate (Neu5Ac) 150 mg/kg/d (max 12g/d) in three doses orally in subjects with NANS deficiency compared to controls<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolite concentration | The primary endpoint is the change of metabolite concentration after N-Acetyl-D neuraminic acid (Neu5Ac) supplementation from day 2 to day 4 and follow-up visit at day 5 | -30 min before ingestion of Neu5Ac at day 2. 120 min, 240 min and 360 min after Neu5Ac ingestion at day 2. 120 min after neu5Ac ingestion at day 3-4. With no Neu5Ac supplementation at day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine and plasma concentrations of N-acetyl mannosamine (ManNAc) | Change in ManNAc concentration from baseline and after exogenous sialic acid supplementation | 30 min before ingestion of Neu5Ac at day 2. 120 min, 240 min and 360 min after Neu5Ac ingestion at day 2. 120 min after neu5Ac ingestion at day 3-4. With no Neu5Ac supplementation at day 5 | 
| Urine and plasma concentrations of free sialic acid | Change in free sialic acid concentration from baseline and after exogenous sialic acid supplementation | 30 min before ingestion of Neu5Ac at day 2. 120 min, 240 min and 360 min after Neu5Ac ingestion at day 2. 120 min after neu5Ac ingestion at day 3-4. With no Neu5Ac supplementation at day 5 | 
| Urine and plasma concentrations of total sialic acid | Change in total sialic acid concentration from baseline and after exogenous sialic acid supplementation | 30 min before ingestion of Neu5Ac at day 2. 120 min, 240 min and 360 min after Neu5Ac ingestion at day 2. 120 min after neu5Ac ingestion at day 3-4. With no Neu5Ac supplementation at day 5 | 
| Urine and plasma concentrations of N-Acetyl-D neuraminic acid (Neu5Ac) | Change in Neu5Ac concentration from baseline and after exogenous sialic acid supplementation | 30 min before ingestion of Neu5Ac at day 2. 120 min, 240 min and 360 min after Neu5Ac ingestion at day 2. 120 min after neu5Ac ingestion at day 3-4. With no Neu5Ac supplementation at day 5 | 
| Urine and plasma metabolomic profile | Change in metabolomic profile from baseline and after exogenous sialic acid supplementation | 30 min before ingestion of Neu5Ac at day 2. 120 min, 240 min and 360 min after Neu5Ac ingestion at day 2. 120 min after neu5Ac ingestion at day 3-4. With no Neu5Ac supplementation at day 5 | 
| Blood pressure in mmHg | Measure of blood pressure (mmHg) supplementation | -30 min before Neu5Ac ingestion at day 2 to 4. With no Neu5Ac supplementation at day 5 | 
| Heart beat per minute (BPM) | Measure of heart BPM at baseline and after exogenous sialic acid supplementation | -30 min before Neu5Ac ingestion at day 2 to 4. With no Neu5Ac supplementation at day 5 | 
| Body weight (kg) | Measure of body weight at baseline and after exogenous sialic acid supplementation | -30 min before Neu5Ac ingestion at day 2 to 4. With no Neu5Ac supplementation at day 5 | 
| Dietary parameters | A self-reporting daily dietetic diary will be recorded for each participant. | 1x/day from day 1 to day 5 (end of the study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sialic acid, Monosaccharide