Antisense therapy in Galactosemia

Posted by & filed under Part 07: CARBOHYDRATES, Treatment.

Mutational analysis of patients with galactosemia Portugal revealed the intronic variation c.820+13A>G as the second most prevalent mutation. Coelho et al. functionally characterized this intronic variation and studied its pathogenic mechanism.

Minigene splicing assays in two distinct cell lines and patients’ transcript analyses showed that the mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon (p.D274Gfs*17). Functional-structural studies showed that the truncated GALT lacks enzymatic activity and is prone to aggregation.

Antisense therapy was then used to correct this intronic mutation activating cryptic splice sites and successfully restored the constitutive splicing. Given the current diet-based treatment for classic galactosemia remains insufficient, antisense therapy as an alternative treatment strategy may be interesting to explore further.

Functional correction by antisense therapy of a splicing mutation in the GALT gene. Coelho et al. Eur J Hum Genet. 2014 Jul 23. PMID: 25052314

Posted by Yannis Trakadis, MD

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