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NCT Number: NCT07448779

Investigating the Pathogenic Role of N-glycosylation in AL Amyloidosis: Molecular Bases, Diagnosis, and Treatment

Immunoglobulin light chain (AL) amyloidosis is caused by a typically small, minimally proliferating bone marrow plasma cell clone secreting a patient-unique, unstable, aggregation-prone, toxic light chain (LC). The amyloidogenicity of LCs is encrypted in their sequence, yet molecular determinants of LC pathogenicity remain obscure. N-glycosylation has been long suspected to be a determinant of LC amyloidogenicity based on anecdotal reports of individual AL patients with a clonal LC displaying this post-translational modification. It is hypothesized that N-glycosylation fundamentally contributes to determining the amyloidogenicity of immunoglobulin LCs in a subset of patients with AL and might influence its clinical phenotype. It is further proposed that the synthesis and secretion of unstable LCs that also have to be N-glycosylated might reverberate on the biology of the plasma cell clone, possibly modulating the sensitivity toward different drugs and might represent itself a therapeutic target.

The objective of our study is now to elucidate the molecular role of LC N-glycosylation in AL amyloidosis, exploit it for risk assessment, and define its potential impact on the biology of the underlying plasma cell clone and its drug sensitivity.

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Key information

Conditions

AL Amyloidosis Amyloidosis Blood Protein Disorders Cardiovascular Diseases Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders Hemostatic Disorders Immune System Diseases Immunoglobulin Light-chain Amyloidosis Immunoproliferative Disorders Lymphoproliferative Disorders MGUS Metabolic Diseases Monoclonal Gammopathies Multiple Myeloma Neoplasms Neoplasms by Histologic Type Neoplasms, Plasma Cell Nutritional and Metabolic Diseases Paraproteinemias Proteostasis Deficiencies Vascular Diseases

Age range

18 year–99 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, PV, 27100, Italy

Location status: Recruiting

Location contact

Alice Nevone, PhD

CONTACT

[email protected]

+390382502967

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Diagnosis of monoclonal gammopathy (e.g. AL amyloidosis, MGUS, MM, others)
  • Planned peripheral blood sampling +/- bone marrow aspiration
  • Age > 18 years
  • Willingness to allow use of clinical data and diagnostic leftovers of clinical specimens for research purposes through signing a written informed consent.

Exclusion criteria

  • Lack of monoclonal gammopathy
  • Patients fulfilling the criteria for complete hematologic response after anti-clonal therapy
  • Age <18 years
  • Failure to show willingness to allow use of clinical data and diagnostic leftovers of clinical specimens for research purposes.

Treatment and study plan

Primary outcomes

  1. Dataset of full-length LC variable region sequences

    Time frame: two years

    Generation of a clinically annotated dataset of full-length immunoglobulin light chain (LC) variable region sequences derived from the largest reported series of patients with AL and MGUS, including clonal characterization and clinical annotation.

Secondary outcomes

  1. Clinical correlates of LC N-glycosylation

    Time frame: two years

    Identification of clinical features associated with LC N-glycosylation; evaluation of the impact of LC N-glycosylation on current assays for M-protein identification/quantification and amyloid typing; exploration of potential corrective measures if assay interference is demonstrated.

  2. Refinement of sequence-based prediction of LC amyloidogenicity

    Time frame: two years

    Validation of existing algorithms/scoring systems for predicting LC amyloidogenicity using newly generated sequences; development of an improved prediction algorithm incorporating sequence and structural/spatial features associated with LC N-glycosylation.

  3. Biologic and pharmacologic correlates of LC N-glycosylation

    Time frame: two years

    Comparative transcriptional profiling of plasma cell clones expressing unglycosylated versus N-glycosylated LCs; assessment of differential sensitivity to anti-plasma cell drugs and small-molecule inhibitors targeting N-glycosylation pathways.

Sponsors and collaborators

Lead sponsor

Fondazione IRCCS Policlinico San Matteo di Pavia

Other

Registry information

Acronym: GlycAL

Important dates

Study start
2025
Primary completion
2027
Study completion
2027
First posted
Mar 4, 2026
Registry last updated
Mar 4, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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