Biomarkers Related to Bone in Pediatric Gaucher Disease

Pilot Study to Assess Immune Biomarkers and Growth Factors Related to Bone Pathology in Pediatric Patients With Gaucher Disease

Aims of the observational study is to establish novel blood-based biomarkers for grading bone disease in pediatric patients with Gaucher disease (GD). Patients with clinically confirmed GD: deficient GCase enzyme activity and corresponding genetic analysis will be eligible for enrollment. Levels of Lyso-Gb1, chitotriosidase, and CCL18 will be established for future bone biomarkers correlation analysis. Skeletal involvement will be assessed using standard clinical diagnostic tools, such as skeletal radiology and/or (DEXA). The comparator group will include age-matched healthy controls.

Clinically confirmed patients with GD will be stratified based on their disease severity (Gaucher disease type 1 and Gaucher disease type 3) and bone pathology findings. In addition, given that growth is a dynamic process during the pediatric age group, results will be ascertained with respect to phases of growth, i.e., early childhood, late childhood, adolescent, and young adult age groups. At the conclusion of the study, investigatirs expect to establish specific biomarkers of bone development and pathology in pediatric GD patients.

Study Overview

• Status: Recruiting
• Conditions: Bone Diseases; Gaucher Disease

Detailed Description

Gaucher disease (GD), the most common lysosomal storage disorder, is caused by a deficiency of the enzyme glucocerebrosidase. Clinically, there are three sub-types according to neurological involvement. Type 1 GD (GD1) is non-neuronopathic GD, and GD types 2 and 3 (GD2-3) are neuronopathic forms. Bone involvement includes skeletal structural abnormalities such as Erlenmeyer flask deformities, cystic changes, growth retardation, progressive kyphoscoliosis, osteonecrosis, bone density abnormalities, bone fragility, and pathological fractures occur at a spectrum in different GD clinical types.

While bone crises are rare (often referred to as Gaucher crises), avascular necrosis (AVN) may occur in the pediatric age group with long-term morbidity and is often associated with chronic pain and orthopedic deformities requiring multiple surgical interventions.

As known, the development of the skeleton development (longitudinal and bone mass growth) is subject to both environmental and genetic influences. During childhood, skeletal growth is characterized by rapid bone growth and continues to lengthen bones by adding bone tissue on the epiphyseal plate until adolescence. The thickening of long bones is processed by adding bony tissue to its surface. The process of bone remodeling and repair continues after birth and adulthood.

Bone marrow infiltration and bone remodeling defects termed "Erlenmeyer flask deformity" are the most common GD-related bone diseases. Without intervention directed at GD, bone involvement usually starts before puberty. Moreover, children with severe GD present retarded growth and delayed puberty (<5th percentile in 34% of children). However, the underlying mechanisms of regulation of bone development and related complications in the pediatric age group in GD are not yet fully known. Neither the bone-specific biomarkers nor their relationship regarding growth factors associated with normal bone turnover during the normal growth process have been studied in detail in GD in the pediatric age group. Abnormalities in skeletal growth and bone turnover may be related to the abnormal regulation of some growth factors, for example, the elevation of fibroblast growth factor 23 (FGF23) or inhibition of insulin-like growth factors (IGFs) resulting in bone growth impartment. Moreover, chronic inflammation leads to alterations in the function and differentiation of osteoclasts and osteoblasts, which participate in bone growth and remodeling.

Furthermore, the evaluation of bone involvement could be challenging for the pediatric age group. The marrow replacement due to GD that moves in the opposite direction with the expected disappearance of the red marrow makes it challenging to evaluate the bone marrow using MRI and requires experience and technical skills to interpret the imaging studies. In addition, the technique of bone density evaluation is still not uniform in children, especially for different age groups.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Margarita Ivanova, PhD; Phone Number: 5714592367; Email: mivanova@ldrtc.org
• Study Contact Backup: Name: Loren Noll, MS; Phone Number: 5714592367; Email: lnoll@ldrtc.org

Study Locations

• United States
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Recruiting
      • Lysosomal and Rare disorder research and treatment center
      • Contact: Margarita Ivanova, PhD; Phone Number: 703-261-6220; Email: mivanova@ldrtc.org
      • Contact: Ozlem M Goker-Alpan, MD; Phone Number: 7032616220; Email: ogokar-alpan@ldrtc.org
      • Sub-Investigator: Margarita M Ivanova, PhD
      • Principal Investigator: Ozlem Goker-Alpan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Patients with clinically confirmed GD: deficient GCase enzyme activity and corresponding genetic analysis will be eligible for enrollment. GD patients with and without bone abnormalities and growth retardation. The study population will comprise patients with Gaucher disease from Lysosomal & Rare Disorders Research & Treatment Center and who were referred to Lysosomal & Rare Disorders Research & Treatment Center who are 21 years or younger.

Description

Inclusion Criteria:

1. The parent or legal guardian and the participant who is eligible to provide assent are able and willing to provide informed consent and assent when applicable.
2. The participant is 5-21 years of age at the initial visit.
3. The participant has a confirmed diagnosis of GD type 1 or type 3 (biochemically and/or genetically).
4. In the investigator's opinion, the subject is capable of understanding and complying with protocol requirements.
5. The subject or, when applicable, the subject's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

Exclusion Criteria:

1. Any subject who does not meet any of the following criteria will not qualify for the study.
2. Any current active chronic infection such as HIV, Hepatitis B or C.
3. Pregnancy or breastfeeding for females.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
GD subjects with normal growth rate and no bone involvement; No drug interventions.
GD type 1 subjects with evidence of bone involvement; No drug interventions.
GD type 3 subjects; No drug interventions.
Non-GD age and gender-matched controls with normal growth rate and no known bone complications; No drug interventions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Growth factors and bone development, including bone age, skeletal maturation and bone development abnormalities	IGF-1, IGFBP-3, TGFbeta, BMP6, BMP9, FGF2, FGF18, FGF21, FGF23 concentration in plasma units/ml	24 months
Blood-based biomarkers that correlate with bone involvement in pediatric patients with GD.	DMP-1, Osteocalcin, DKK-1, BAP, RANKL, OPG, TRAP5b, CTX, SOST, SFRP1, PICP,PINP, CCL1, GM-CSF, Il-4, Il-5, Il-6, Il-10, TNFalpha concentrations units/ml	24 months

Collaborators and Investigators

• Sponsor: Lysosomal and Rare Disorders Research and Treatment Center, Inc.
• Investigators: Principal Investigator: Ozlem Goker-Alpan, MD, Lysosomal and Rare Disorders Research and Treatment Center

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2023
• Primary Completion (Estimated): October 25, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: October 30, 2023
• First Submitted That Met QC Criteria: November 2, 2023
• First Posted (Actual): November 3, 2023

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Bone Diseases; Gaucher Disease
• Other Study ID Numbers: 23-LDRTC-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No