Abstract Details

Title GNE Myopathy Biomarkers: Essential for Diagnosis and Response to Therapy

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-004

Objective Identify biomarkers for GNE myopathy subjects.

Background GNE myopathy is a rare adult onset muscle disease that presents with progressive weakness and atrophy leading to severe incapacitation and dependent care. It is caused by defects in the key enzyme of sialic acid (SA) biosynthesis, UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE). Sialylation-increasing therapies have proven beneficial in GNE myopathy mouse models, leading to clinical studies with SA itself, the SA precursor ManNAc, or IVIG (rich in SA). Establishment of reliable clinical endpoint has remained a challenge due to the slow progression of the disease, the still unknown pathomechanism, and limited availability of patients’ muscle tissue. Our ongoing Natural History Study yielded an innovative mathematical disease progression model that is being validated as clinical trial endpoint. Biochemically, we demonstrated sustained increased plasma SA after single doses of oral ManNAc, indicating that ManNAc was intracellular processed. Other biomarkers are still in the discovery or validation phase.

Design/Methods GNE myopathy patient and control tissues, including muscle, were collected baseline or after ManNAc treatment and used for biomarker assays. Previously suggested biomarkers were revisited (plasma desialylated versus sialylated Thomson-Friedenreich antigen (T/ST) ratios and serum KL-6 levels), new biomarker discovery was performed (protein, RNA, SA pathway intermediates) and different techniques were applied (antibody, lectin, ELISA, 2D gel analysis, LC-MSMS).

Results

Lectin histochemistry of muscle biopsies was informative (especially SNA lectin) for diagnosis and response to therapy/efficacy. Intracellular SA and CMP-SA levels in white blood cells validate SA pathway effects of ManNAc inside cells. Blood KL-6 and T/ST ratios need further method development and validation. Blood protein 2D gel analysis identified sialoproteins with an abnormal charge, size, and/or abundance, which are leads to new biomarkers.

Conclusions Identification of reliable biomarkers not only inform about diagnosis or response to therapy, but also help elucidate the disease pathomechanism of GNE myopathy.

Authors/Disclosures
May Christine Malicdan PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
Nuria Carrillo, MD	Dr. Carrillo has received personal compensation for serving as an employee of Dianthus Therapeutics. Dr. Carrillo has or had stock in Dianthus Therapeutics.Dr. Carrillo has or had stock in Moderna Therapeutics.
	No disclosure on file