New and potential strategies for the treatment of PMM2-CDG
Alejandra Gámez1, Mercedes Serrano2, Diana Gallego1
1Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain; Instituto de Investigación Sanitaria IdiPaZ, Madrid, Spain.
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.
