New and potential strategies for the treatment of PMM2-CDG.

Abstract

BACKGROUND:

Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5'-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic.

SCOPE OF REVIEW:

This review covers the latest advances in the search for a treatment for PMM2-CDG.

MAJOR CONCLUSIONS:

Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins.

GENERAL SIGNIFICANCE:

The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.

• Authors: Alejandra Gámez, Mercedes Serrano, Diana Gallego, Alicia Vilas, Belén Pérez
• Journal: Biochimica et biophysica acta. General subjects (Biochim Biophys Acta Gen Subj) Vol. 1864 Issue 11 Pg. 129686 (11 2020) ISSN: 1872-8006 [Electronic] Netherlands
• PMID: 32712172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Antisense Elements (Genetics)
• Enzyme Inhibitors
• Phosphotransferases (Phosphomutases)
• phosphomannomutase 2, human
• Mannose

Topics

• Animals
• Antisense Elements (Genetics) (therapeutic use)
• Congenital Disorders of Glycosylation (drug therapy, genetics, metabolism, therapy)
• Drug Discovery
• Enzyme Inhibitors (chemistry, therapeutic use)
• Glycosylation (drug effects)
• Humans
• Mannose (analogs & derivatives, therapeutic use)
• Phosphotransferases (Phosphomutases) (deficiency, genetics, metabolism)