Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease (LYSO-PROOF)

Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease: An International, Multicenter, Epidemiological Protocol

International, multicenter, epidemiological study to demonstrate the correlation and predictive value of lyso-Gb1 concentration with the clinical severity of naïve, initially non-ERT/SRT Gaucher disease type 1 and during the study ERT/SRT-newly started Gaucher type 1 patients and to correlate lyso-Gb1 concentration with the clinical improvement of ERT or SRT treated Gaucher type 1 and the clinical course of non-treated patients based on GD-DS3

Study Overview

• Status: Completed
• Conditions: Lysosomal Storage Diseases; Sphingolipidoses; Gaucher Disease

Detailed Description

Gaucher disease is an autosomal recessive inherited lysosomal storage disorder. The disease is caused by the hereditary deficiency of the glucocerebrosidase, a lysosomal enzyme that breaks down glucocerebroside into glucose and ceramide.

To date a definitive diagnosis of Gaucher's disease can only be made applying biochemical testing measuring the reduced enzymatic activity of the beta-glucosidase together with genetic confirmation. Since numerous different mutations may be the cause of a particular lysosomal storage disease the sequencing of the entire beta-glucosidase gene is applied in Gaucher's disease in order to confirm the genetic diagnosis.

The use of primary storage molecules as biomarker was assessed for glucosylceramide (Gb1) in plasma of Gaucher's disease patients and compared to the level of Gb1 in healthy individuals.

In order to establish a sensitive and specific biomarker for GD, we compared mass spectra of the plasma of healthy controls and GD patients using HPLC and tandem mass spectrometry. Mass spectra that differed most between patients and controls were analysed in more detail. The resulting biomarker, which was patented in June 2011 (PCT/EP2012/002409), was lyso - Gb1. We identified this compound as a reliable, sensitive and specific biomarker for GD in a cohort of GD patients. Furthermore, in a pilot study we evaluated whether lyso-Gb1 is related to the specific genotypes and is reliable for long-term monitoring of the efficiency of therapy.

The aim this study is therefore to investigate lyso-Gb1 as a long-term prognostic marker in naïve, non-ERT/SRT GD type 1 patients by monitoring over the course of 36 months.

• Study Type: Observational
• Enrollment (Actual): 299

Contacts and Locations

Study Locations

• Albania
  • Tirana, Albania, 10001
    • University Hospital Center Mother Teresa
• Greece
  • Thessaloniki, Greece, 54642
    • Aristotle University of Thessaloniki, Ippokration General Hospital
• India
  • Bangalore, India, 560100
    • Centre for Human Genetics
• Israel
  • Jerusalem, Israel, 9103 102
    • Shaare Zedek Medical Center
• Morocco
  • Rabat, Morocco, 10100
    • Children Hospital
  • Rabat, Morocco, 10100
    • Hopital d'Enfant
• Pakistan
  • Punjab
    • Lahore, Punjab, Pakistan, 54600
      • The Children's Hospital and the Institute of Child Health
• Spain
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge (planta 7.1)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Male or female patients aged 6 months or older with genetically confirmed diagnosis of Gaucher disease type 1 without treatment prior to enrollment or no treatment for more than 24 months ago

Description

Inclusion Criteria:

• Male or female patients aged 6 months or older
• Patients with genetically confirmed diagnosis of Gaucher disease type 1
• No prior treatment with enzyme replacement therapy or substrate reduction therapy ro no traetment for more than 24 months
• Signed informed consent by parents/legal guardian and patient

Exclusion Criteria:

• Male or female patients being younger than 6 months
• Patients without genetically confirmed diagnosis of Gaucher disease type 1
• Gaucher disease 2 or 3
• Patient is currently undergoing enzyme replacement therapy or substrate reduction therapy
• Missing signed informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Participants diagnosed with Gaucher disease; Participants with genetically confirmed diagnosis of Gaucher disease type 1 older than 6 months old

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demonstrating the correlation and predictive value of lyso-Gb1 concentration with the clinical severity of naïve, initially non-ERT/SRT Gaucher disease type 1 and during the study ERT/SRT-newly started Gaucher type 1 patients	lyso-Gb1 will be analzyed via Liquid Chromatography Multiple Reaction-monitoring Mass Spectrometry (LC/MRM-MS) and compared to merged control. The LC/MRM-MS is performed on an ABSciex 6500 triple quadrupole mass spectrometer, coupled with a Waters Acquity UPLC.	48 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlating lyso-Gb1 concentration with the clinical improvement of ERT or SRT treated Gaucher type 1 and the clinical course of non-treated patients based on GD-DS3.	lyso-Gb1 will be analysed over a period of 36 months via Liquid Chromatography Multiple Reaction-monitoring Mass Spectrometry (LC/MRM-MS) to demonstrate the course of the biomarker.	48 month

Collaborators and Investigators

• Sponsor: CENTOGENE GmbH Rostock
• Investigators: Study Chair: Peter Bauer, M.D., CENTOGENE GmbH Rostock

Publications and helpful links

General Publications

• Elstein D, Mellgard B, Dinh Q, Lan L, Qiu Y, Cozma C, Eichler S, Bottcher T, Zimran A. Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naive and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials. Mol Genet Metab. 2017 Sep;122(1-2):113-120. doi: 10.1016/j.ymgme.2017.08.005. Epub 2017 Aug 24.

Helpful Links

• CENTOGENE is a rare disease company focused on transforming clinical, genetic, and biochemical data into medical solutions for patients

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2018
• Primary Completion (Actual): January 15, 2021
• Study Completion (Actual): January 15, 2021

Study Registration Dates

• First Submitted: March 13, 2015
• First Submitted That Met QC Criteria: April 9, 2015
• First Posted (Estimate): April 15, 2015

Study Record Updates

• Last Update Posted (Actual): May 28, 2021
• Last Update Submitted That Met QC Criteria: May 27, 2021
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Lipid Metabolism Disorders; Lymphatic Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Gaucher Disease type 1
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Gaucher Disease; Sphingolipidoses
• Other Study ID Numbers: LP 06-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided