AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)

Balakrishnan, Bijina; Altassan, Ruqaiah; Budhraja, Rohit; Liou, Willisa; Lupo, A.; Bryant, Simon M.; Mankouski, Anastasiya; Radenkovic, Silvia; Preston, Graeme; Pandey, Akhilesh; Boudina, Sihem; Kozicz, Tamás; Morava, Éva; Lai, Kent

doi:10.1016/j.trsl.2023.01.004

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…[ 64 ] Disorder of multiple glycosylation pathways: • PGM1-CDG Phosphoglucomutase 1 Protein N-glycosylation: • PMM2-CDG Phosphomannomutase 2 • MPI-CDG Phosphomannose isomerase Combined sugar supplementation therapy (UDP-glycans and D-galactose) WO2022272056A2 Compositions and methods for treating PGM1 deficiency (2022) AAV9 hPGM1 gene AAV9-hPGM1 gene replacement prevents cardiac dysfunction in Pgm2 cKO mice. [ 68 ] Disorder of multiple glycosylation pathways: • PGM1-CDG Phosphoglucomutase 1 Gene replacement therapy Recombinant adeno-associated virus (AAV) gene therapy EP3175859A1 EP3175859B1 N-acetyl mannosamine for the treatment of a kidney-disease (2008) N-acetyl mannosamine and derivatives Gne p.Met7l2Thr/p.Met7l2Thr , Gne p.Met7l2Thr/+ and Gne +/+ mice were used to test the drugs. N-acetyl mannosamine and derivatives were useful for treating myopathies, muscular atrophy and/or muscular dystrophy and kidney conditions and diseases (e.g., those involving proteinuria and hematuria).…”

Section: Resultsmentioning

confidence: 99%

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Congenital disorders of glycosylation: narration of a story through its patents

Monticelli,

D’Onofrio,

Jaeken

et al. 2023

Orphanet J Rare Dis

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Congenital disorders of glycosylation are a group of more than 160 rare genetic defects in protein and lipid glycosylation. Since the first clinical report in 1980 of PMM2-CDG, the most common CDG worldwide, research made great strides, but nearly all of them are still missing a cure. CDG diagnosis has been at a rapid pace since the introduction of whole-exome/whole-genome sequencing as a diagnostic tool. Here, we retrace the history of CDG by analyzing all the patents associated with the topic. To this end, we explored the Espacenet database, extracted a list of patents, and then divided them into three major groups: (1) Drugs/therapeutic approaches for CDG, (2) Drug delivery tools for CDG, (3) Diagnostic tools for CDG. Despite the enormous scientific progress experienced in the last 30 years, diagnostic tools, drugs, and biomarkers are still urgently needed.

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Section: Resultsmentioning

confidence: 99%

“…Gene therapy is also starting to be applied in CDG, as described for PGM1-CDG (WO2022272056A2, [ 68 ]).…”

Section: Resultsmentioning

confidence: 99%

Congenital disorders of glycosylation: narration of a story through its patents

Monticelli,

D’Onofrio,

Jaeken

et al. 2023

Orphanet J Rare Dis

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“…Jon K. Laerdahl 2 Paul H. Backe 2,3 Eva Morava 1,4,5 Click here to access the podcast for this paper.…”

Section: Silvia Radenkovicmentioning

confidence: 99%

“…This is crucial, as early phenotypic predictions, especially for cardiac involvement in PGM1-CDG, could be highly relevant in the upcoming era of gene therapies. 4 Research involving cardiacspecific disease models such as iPSC-cardiomyocytes will be essential to further elucidate the role of the two isoforms in the cardiac presentation of PGM1-CDG. Finally, these findings emphasize the importance of considering organ-specific transcript differences while assessing genotype-phenotype correlations in disorders where genotype-phenotype correlations are lacking, such as PGM1-CDG.…”

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confidence: 99%

“…In conclusion, these observations point towards a possible role of PGM1 isoform 2 in the clinical severity of PGM1‐CDG. This is crucial, as early phenotypic predictions, especially for cardiac involvement in PGM1‐CDG, could be highly relevant in the upcoming era of gene therapies 4 . Research involving cardiac‐specific disease models such as iPSC‐cardiomyocytes will be essential to further elucidate the role of the two isoforms in the cardiac presentation of PGM1‐CDG.…”

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The role of PGM1isoform 2 in PGM1‐CDG: One step closer to genotype–phenotype correlation?

Radenkovic

Laerdahl

Backe

et al. 2023

J of Inher Metab Disea

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Dysregulated proteome and N‐glycoproteome in ALG1‐deficient fibroblasts

Budhraja,

Joshi,

Radenkovic

et al. 2024

Proteomics

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Asparagine‐linked glycosylation 1 protein is a β‐1,4‐mannosyltransferase, is encoded by the ALG1 gene, which catalyzes the first step of mannosylation in N‐glycosylation. Pathogenic variants in ALG1 cause a rare autosomal recessive disorder termed as ALG1‐CDG. We performed a quantitative proteomics and N‐glycoproteomics study in fibroblasts derived from patients with one homozygous and two compound heterozygous pathogenic variants in ALG1. Several proteins that exhibited significant upregulation included insulin‐like growth factor II and pleckstrin, whereas hyaluronan and proteoglycan link protein 1 was downregulated. These proteins are crucial for cell growth, survival and differentiation. Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy‐related proteins, suggesting mitochondrial and cellular stress. N‐glycoproteomics revealed the reduction in high‐mannose and complex/hybrid glycopeptides derived from numerous proteins in patients explaining that defect in ALG1 has broad effects on glycosylation. Further, we detected an increase in several short oligosaccharides, including chitobiose (HexNAc2) trisaccharides (Hex‐HexNAc2) and novel tetrasaccharides (NeuAc‐Hex‐HexNAc2) derived from essential proteins including LAMP1, CD44 and integrin. These changes in glycosylation were observed in all patients irrespective of their gene variants. Overall, our findings not only provide novel molecular insights into understanding ALG1‐CDG but also offer short oligosaccharide‐bearing peptides as potential biomarkers.

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AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)

Cited by 10 publications

References 40 publications

Congenital disorders of glycosylation: narration of a story through its patents

Congenital disorders of glycosylation: narration of a story through its patents

The role of PGM1isoform 2 in PGM1‐CDG: One step closer to genotype–phenotype correlation?

Dysregulated proteome and N‐glycoproteome in ALG1‐deficient fibroblasts

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