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

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ClinicalTrials.gov Identifier: NCT03545568
Recruitment Status : Completed
First Posted : June 4, 2018
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
University of Modena and Reggio Emilia
Information provided by (Responsible Party):
Christel Tran, University of Lausanne

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
N-Acetylneuraminic Acid Storage Disease Other: Neu5Ac supplementation Not Applicable

Detailed Description:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open label individual patient clinical trial study of small sample size
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sialic Acid Supplementation in NANS Deficiency: An Open-label, Proof of Concept, Two-centers Study
Actual Study Start Date : May 1, 2018
Actual Primary Completion Date : October 15, 2018
Actual Study Completion Date : October 15, 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: sialic acid Other: Neu5Ac supplementation
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


Outcome Measures
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Primary Outcome Measures :
  1. Metabolite concentration [ Time Frame: -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 ]
    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


Secondary Outcome Measures :
  1. Urine and plasma concentrations of N-acetyl mannosamine (ManNAc) [ Time Frame: 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 ]
    Change in ManNAc concentration from baseline and after exogenous sialic acid supplementation

  2. Urine and plasma concentrations of free sialic acid [ Time Frame: 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 ]
    Change in free sialic acid concentration from baseline and after exogenous sialic acid supplementation

  3. Urine and plasma concentrations of total sialic acid [ Time Frame: 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 ]
    Change in total sialic acid concentration from baseline and after exogenous sialic acid supplementation

  4. Urine and plasma concentrations of N-Acetyl-D neuraminic acid (Neu5Ac) [ Time Frame: 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 ]
    Change in Neu5Ac concentration from baseline and after exogenous sialic acid supplementation

  5. Urine and plasma metabolomic profile [ Time Frame: 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 ]
    Change in metabolomic profile from baseline and after exogenous sialic acid supplementation

  6. Blood pressure in mmHg [ Time Frame: -30 min before Neu5Ac ingestion at day 2 to 4. With no Neu5Ac supplementation at day 5 ]
    Measure of blood pressure (mmHg) supplementation

  7. Heart beat per minute (BPM) [ Time Frame: -30 min before Neu5Ac ingestion at day 2 to 4. With no Neu5Ac supplementation at day 5 ]
    Measure of heart BPM at baseline and after exogenous sialic acid supplementation

  8. Body weight (kg) [ Time Frame: -30 min before Neu5Ac ingestion at day 2 to 4. With no Neu5Ac supplementation at day 5 ]
    Measure of body weight at baseline and after exogenous sialic acid supplementation

  9. Dietary parameters [ Time Frame: 1x/day from day 1 to day 5 (end of the study) ]
    A self-reporting daily dietetic diary will be recorded for each participant.


Eligibility Criteria
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Ages Eligible for Study:   1 Year to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03545568


Locations
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Italy
Struttura Semplice Dipartimentale di Genetica Clinica
Reggio Emilia, Italy, 42123
Switzerland
Lausanne University Hospital
Lausanne, Vaud, Switzerland, 1011
Sponsors and Collaborators
University of Lausanne
University of Modena and Reggio Emilia
More Information
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Responsible Party: Christel Tran, Principal investigator, University of Lausanne
ClinicalTrials.gov Identifier: NCT03545568    
Other Study ID Numbers: 2018-00284
First Posted: June 4, 2018    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Christel Tran, University of Lausanne:
Sialic acid
Monosaccharide
Additional relevant MeSH terms:
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Sialic Acid Storage Disease
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
 Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases