bims-meglyc 2024-07-28 papers

Issue of 2024–07–28
three papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2024 Jul 01. pii: S1096-7192(24)00415-3. [Epub ahead of print]143(1-2): 108531

In vitro treatment with liposome-encapsulated Mannose-1-phosphate restores N-glycosylation in PMM2-CDG patient-derived fibroblasts.

Teppei Shirakura, Lakshmipriya Krishnamoorthy, Preeti Paliwal, Geoffrey Hird, Kerryn McCluskie, Peter McWilliams, Miao He, Moulay Hicham Alaoui Ismaili.

PMM2-CDG is the most common congenital disorder of glycosylation (CDG). Patients with this disease often carry compound heterozygous mutations of the gene encoding the phosphomannomutase 2 (PMM2) enzyme. PMM2 converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P), which is a critical upstream metabolite for proper protein N-glycosylation. Therapeutic options for PMM2-CDG patients are limited to management of the disease symptoms, as no drug is currently approved to treat this disease. GLM101 is a M1P-loaded liposomal formulation being developed as a candidate drug to treat PMM2-CDG. This report describes the effect of GLM101 treatment on protein N-glycosylation of PMM2-CDG patient-derived fibroblasts. This treatment normalized intracellular GDP-mannose, increased the relative glycoprotein mannosylation content and TNFα-induced ICAM-1 expression. Moreover, glycomics profiling revealed that GLM101 treatment of PMM2-CDG fibroblasts resulted in normalization of most high mannose glycans and partial correction of multiple complex and hybrid glycans. In vivo characterization of GLM101 revealed its favorable pharmacokinetics, liver-targeted biodistribution, and tolerability profile with achieved systemic concentrations significantly greater than its effective in vitro potency. Taken as a whole, the results described in this report support further exploration of GLM101's safety, tolerability, and efficacy in PMM2-CDG patients.

Keywords: Congenital disorders of glycosylation; GLM101; Inherited metabolic disorders; Liposome; Phosphomannomutase 2-CDG/ (PMM2); Substrate replacement therapy

DOI: https://doi.org/10.1016/j.ymgme.2024.108531

J Biol Chem. 2024 Jul 24. pii: S0021-9258(24)02100-8. [Epub ahead of print] 107599

O-GlcNAc Transferase Congenital Disorder of Glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome.

Johnathan M Mayfield, Naomi L Hitefield, Ignacy Czajewski, Lotte Vanhye, Laura Holden, Eva Morava, Daan M F van Aalten, Lance Wells.

O-GlcNAc transferase (OGT) is the sole enzyme responsible for the post-translational modification O-GlcNAc on thousands of target nucleocytoplasmic proteins. To date, nine variants of OGT that segregate with OGT Congenital Disorder of Glycosylation (OGT-CDG) have been reported and characterized. Numerous additional variants have been associated with OGT-CDG, some of which are currently undergoing investigation. This disorder primarily presents with global developmental delay and intellectual disability (ID), alongside other variable neurological features and subtle facial dysmorphisms in patients. Several hypotheses aim to explain the etiology of OGT-CDG, with a prominent hypothesis attributing the pathophysiology of OGT-CDG to mutations segregating with this disorder disrupting the OGT interactome. The OGT interactome consists of thousands of proteins, including substrates as well as interactors that require noncatalytic functions of OGT. A key aim in the field is to identify which interactors and substrates contribute to the primarily neural-specific phenotype of OGT-CDG. In this review, we will discuss the heterogenous phenotypic features of OGT-CDG seen clinically, the variable biochemical effects of mutations associated with OGT-CDG, and the use of animal models to understand this disorder. Furthermore, we will discuss how previously identified OGT interactors causal for ID provide mechanistic targets for investigation that could explain the dysregulated gene expression seen in OGT-CDG models. Identifying shared or unique altered pathways impacted in OGT-CDG patients will provide a better understanding of the disorder as well as potential therapeutic targets.

Keywords: O-GlcNAc transferase (OGT); O-GlcNAcylation; O-linked N-acetylglucosamine (O-GlcNAc); histone modification; intellectual disability; neurodevelopment; post-translational modification (PTM); protein-protein interaction; transcription; transcription regulation

DOI: https://doi.org/10.1016/j.jbc.2024.107599

Genes (Basel). 2024 Jun 21. pii: 821. [Epub ahead of print]15(7):

Preparing for Patient-Customized N-of-1 Antisense Oligonucleotide Therapy to Treat Rare Diseases.

Harry Wilton-Clark, Eric Yan, Toshifumi Yokota.

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development and addresses some of the major limitations that previously hindered the development of therapies for rare diseases.

Keywords: N-of-1; antisense oligonucleotide; atipeksen; exon skipping; milasen; muscular dystrophy; personalized medicine; rare disease; splice switching; valeriasen

DOI: https://doi.org/10.3390/genes15070821