Splice switching oligonucleotides to restore PHKG2 expression in glycogen storage disease IX

Unmet Need

Glycogen Storage Disease IX (GSD IX) is a rare inherited disorder primarily caused by mutations in the PHKG2 gene, leading to significant deficiencies in glycogen metabolism. Patients typically present with a variety of debilitating symptoms, including fasting hypoglycemia, hepatomegaly, and growth delay. Current diagnostic methods rely heavily on biochemical and genetic testing, which often fail to provide a complete diagnosis, particularly when pathogenic variants are present in non-coding regions or involve splicing defects. Approximately 10% of known pathogenic variants in rare diseases are associated with mRNA splicing errors, which can lead to loss-of-function mutations due to premature termination codons and subsequent nonsense-mediated decay (NMD) of mRNA. This creates a pressing need for improved diagnostic tools that can effectively analyze splicing defects and provide accurate genetic diagnoses for patients with GSD IX, enabling early therapeutic interventions and improved patient care.

Description of the Technology

Duke inventors have developed a novel approach to address the challenges of diagnosing and treating GSD IX through the development of splice-switching oligonucleotides (SSOs). This technology specifically targets and corrects splicing defects in the PHKG2 gene, restoring its expression and function. By utilizing systematic RNA analysis, this approach circumvents the limitations of traditional DNA sequencing in identifying pathogenic variants that affect splicing. The invention is underpinned by the creation of a new model of GSD IX using precise genome editing in HEK293T cells, where a single nucleotide splice variant was introduced to study its functional effects on glycogen metabolism. This model allows for the exploration of therapeutic options for GSD IX and other diseases caused by splicing errors. The SSOs developed in this study have shown promise in facilitating proper gene expression and correcting splicing defects, positioning them as a potential therapeutic strategy for patients suffering from GSD IX and similar conditions.

Advantages

• Direct detection of splicing defects enhances diagnostic capabilities for GSD IX.

• Enables timely therapeutic strategies, improving patient outcomes.

• The novel cell model can be used to study other diseases and test SSO therapeutics.

• Provides comprehensive insights into non-coding variants, addressing limitations of traditional methods.