Antisense mediated splicing modulation for inherited metabolic diseases: challenges for delivery

Area of Science:

• Molecular biology
• Genetics
• Pharmacology

Background:

• Targeted mutation therapies, particularly antisense therapy, have advanced significantly for rare diseases.
• Antisense therapy, specifically splice switching oligonucleotides (SSOs), has demonstrated efficacy in correcting splicing defects in cellular and animal models.
• SSOs have shown success in clinical trials for Duchenne muscular dystrophy and in patient cells for inherited metabolic diseases.

Purpose of the Study:

• To review the current state of antisense therapy targeting RNA splicing in metabolic diseases.
• To analyze progress in in vivo oligonucleotide delivery for different tissue expression patterns (multisystemic, hepatic, CNS).
• To summarize recent advancements in applying SSO therapy to inherited metabolic disorders.

Main Methods:

• Review of existing literature on antisense therapy and splice switching oligonucleotides in metabolic diseases.
• Categorization of metabolic diseases based on tissue and organ expression patterns.
• Summary of studies reporting in vivo delivery of oligonucleotides to specific organs or systems.

Main Results:

• SSOs can correct enzyme deficiencies by forcing pseudoexon skipping or blocking cryptic splice sites, restoring normal transcripts and proteins.
• Successful body-wide and liver-specific distribution of SSOs achieved via systemic administration in murine models.
• Promising, though limited, data exists for CNS delivery of SSOs using intrathecal injections.

Conclusions:

• Antisense therapy targeting RNA splicing is a viable therapeutic strategy for inherited metabolic diseases.
• In vivo delivery of SSOs requires tailored approaches based on the specific gene defect and affected tissues.
• Further research into effective in vivo delivery, especially for CNS disorders, is crucial for clinical translation.