Longitudinal measurement using a novel Western blot assay of glycosylation of alpha dystroglycan in patients with LGMD2I/R9 FKRP-related

Topic:

Clinical Trials

Poster Number: 140

Author(s):

Douglas Sproule, MD MSc, ML Bio Solutions, Nicholas Johnson, MD, Virginia Commonwealth University, Tahseen Mozaffar, MD, University of California, Irvine, Matthew Wicklund, MD, University of Colorado School of Medicine, Urvi Desai, MD, Neuroscience Institute, Atrium Health; Department of Neurology, Wake Forest U. School of Medicine, Doris Leung, MD, PhD, Kennedy Krieger Institution, Katherine Mathews, MD, FAAN, University of Iowa, Jeffrey Statland, MD, University of Kansas Medical Center, Carla Zingariello, DO, University of Florida, Conrad Weihl, MD, PhD, Washington University School of Medicine, John Vissing, MD, DMSci, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Linda Lowes, PT, PhD, Nationwide Children's Hospital, Peter Kang, MD, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Kameron Bates, MS, Virginia Commonwealth University, Lindsay Alfano, PT, DPT, PCS, Nationwide Children’s, Han Xie, PhD, Virginia Commonwealth University, Jessica St. Romain, Virginia Commonwealth University, GRASP Consortium, Virginia Commonwealth University, Thulashitha Rajasingham, MSc, Bridge Bio, Hector Rodriguez, PhD, BridgeBio PharmA, Tricia Blankenbiller, MS, ML Bio Solutions

Introduction: Limb-girdle Muscular Dystrophy (LGMD) Type 2I, also called LGMDR9 FKRP-related, is caused by bi-allelic partial loss-of-function of the fukutin-related protein (FKRP) gene. The FKRP enzyme performs a critical step in the glycosylation of alpha dystroglycan (αDG); impaired FKRP enzyme activity leads to the formation of dysfunctional hypoglycosylated αDG, resulting in chronic myocyte injury and muscular dystrophy.

Objectives: MLB-01-001 is a natural history and biomarker development study in patients with LGMD2I, designed to assess appropriate Clinical Outcome Assessments (COAs) and explore prognostic biomarkers for LGMD2I to facilitate clinical trial development for potential therapeutics.

Methods: MLB-01-001 is an ongoing, prospective, 12-month observational study of clinically affected and genetically defined LGMD2I participants aged 10 to 65 years enrolled at 11 international academic centers. Tibialis anterior muscle biopsies were obtained at baseline, month 6, and month 12 for evaluation of glycosylated ⍺DG levels by a novel Western blot assay.

Results: To date, 88 participants have completed 12 months of follow up. 57% were women with mean age 37 years, mean symptom onset at 15.9 years and mean duration since diagnosis of 10.4 years. 73% were homozygous for the c.826C>A (p.L276I) founder mutation. Preliminary data from 29 individuals with LGMD2I showed reduced levels of glycosylated αDG (~11% of healthy). Glycosylation of ⍺DG appears to mirror the severity of LGMD2I disease, with compound pathogenic heterozygotes showing reduced glycosylated ⍺DG protein levels (~3% of healthy) compared to c.826C>A homozygotes (~14% of healthy). Updated data will be provided at the time of the meeting.

Conclusions: Preliminary data from a natural history study of patients with LGMD2I suggest that a novel Western blot assay can be used to evaluate glycosylation of ⍺DG, which is central to the pathogenesis of LGMD2I. Measurement of ⍺DG glycosylation may provide a relevant approach to assess the impact of potential therapies for LGMD2I.