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. 2022 Aug 5;23(15):8725.
doi: 10.3390/ijms23158725.

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

Sandra Brasil  1   2   3 , Mariateresa Allocca  3   4   5 , Salvador C M Magrinho  1   2   3   6 , Inês Santos  3   7 , Madalena Raposo  3   7 , Rita Francisco  1   2   3 , Carlota Pascoal  1   2   3 , Tiago Martins  3   7 , Paula A Videira  1   2   3 , Florbela Pereira  3   6 , Giuseppina Andreotti  4 , Jaak Jaeken  3   8 , Kristin A Kantautas  9 , Ethan O Perlstein  10 , Vanessa Dos Reis Ferreira  1   2   3
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Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

Sandra Brasil et al. Int J Mol Sci. .

Abstract

Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders' views on AI for therapy discovery in CDG.

Keywords: AI in drug discovery; biomarkers; congenital disorders of glycosylation; disease models; drug repositioning; orphan drugs.

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Conflict of interest statement

E.O.P. is CEO of Maggie’s Pearl, LLC and CEO of Perlara PBC. He holds an ownership stake in both companies. Other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of CDG-repositioned drugs in clinical pipelines. (A) acetazolamide, (B) epalrestat, (C) palovarotene, and (D) celastrol.
Figure 2
Figure 2
PRISMA flow diagram adapted from the study by Page et al. [38].
Figure 3
Figure 3
Schematic representation of the mechanism of action of drugs under testing in clinical trials for PMM2-CDG. Acetazolamide inhibits CaV2.1 calcium channels. Epalrestat inhibits sorbitol synthesis. Celastrol modulates PMM2 proteostasis. Adapted from Gámez et al., 2020 [85].
Figure 4
Figure 4
Schematic representation of the mechanism of action of palovarotene.
See this image and copyright information in PMC

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