Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications

Abstract

Objective: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. Methods: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. Results: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein Nglycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

“…Recently, sorbitol has emerged as a biomarker for PMM2-CDG as urinary sorbitol levels seem to correlate with disease severity in patients. It was also used to monitor the effect of epalrestat (a repurposed drug in trial for PMM2-CDG) treatment in a pediatric PMM2-CDG patient [ 76 ].…”

“…There was minimal improvement of the NPCRS and of the ICARS ataxia score. No adverse events were observed during the trial period [ 76 ]. A phase 3, prospective, single-center clinical trial designed to assess the safety, tolerability, metabolic improvement and probable benefit of oral epalrestat therapy in pediatric subjects with PMM2-CDG will be conducted ( NCT04925960, accessed on 24 March 2022).…”

Why rare disease needs precision medicine—and precision medicine needs rare disease

“…Subsequent n = 1 clinical trials have been extraordinarily successful in treating this child, and they have since led to the approval of a much larger trial for others with the same condition. 8 …”

A Community-Led Approach as a Guide to Overcome Challenges for Therapy Research in Congenital Disorders of Glycosylation

“…There are currently a total of six ongoing observational studies (NCT04201067, NCT02089789, NCT04198987, and NCT03404856), including two NHS (NCT03173300 and NCT01417533), and four therapeutic CTs (NCT04833322, NCT04679389, NCT03404869, and NCT03404856). In parallel, significant advances in disease model development and biomarker discovery have also occurred [ 8 , 13 , 14 , 15 , 16 ]. On the other hand, CDG therapy-driven biomedical and clinical research is anticipated to be hindered by several challenges, many common to other rare diseases [ 17 , 18 ].…”