Antisense Mediated Splicing Modulation For Inherited Metabolic Diseases: Challenges for Delivery

Abstract

In the past few years, research in targeted mutation therapies has experienced significant advances, especially in the field of rare diseases. In particular, the efficacy of antisense therapy for suppression of normal, pathogenic, or cryptic splice sites has been demonstrated in cellular and animal models and has already reached the clinical trials phase for Duchenne muscular dystrophy. In different inherited metabolic diseases, splice switching oligonucleotides (SSOs) have been used with success in patients' cells to force pseudoexon skipping or to block cryptic splice sites, in both cases recovering normal transcript and protein and correcting the enzyme deficiency. However, future in vivo studies require individual approaches for delivery depending on the gene defect involved, given the different patterns of tissue and organ expression. Herein we review the state of the art of antisense therapy targeting RNA splicing in metabolic diseases, grouped according to their expression patterns-multisystemic, hepatic, or in central nervous system (CNS)-and summarize the recent progress achieved in the field of in vivo delivery of oligonucleotides to each organ or system. Successful body-wide distribution of SSOs and preferential distribution in the liver after systemic administration have been reported in murine models for different diseases, while for CNS limited data are available, although promising results with intratechal injections have been achieved.

Functional Characterization of the spf/ash Splicing Variation in OTC Deficiency of Mice and Man

“…Based on our previous work on antisense therapy for splicing defects [ 27 ], [ 28 ] one of our aims was to investigate the feasibility of correcting the spf/ash mutation and rescuing OTC expression by the use of AONs. The development of oligonucleotide therapeutics is progressing rapidly, with a large number of disease targets residing in the liver [ 29 ].…”

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

“…The present work also reports the efficacy of antisense oligonucleotide therapy for rescuing normal splicing of the cryptic splice site generated by GFM1 c.689+908G>A in patient fibroblasts. Easy to design and highly specific, antisense oligonucleotides have been used as RNA-modulators in cellular models of several genetic disorders [47] including ISCU myopathy [48]. The challenge is always to achieve the safe and efficient delivery of the therapeutic oligonucleotide to the required tissues.…”

Delivery is key: lessons learnt from developing splice‐switching antisense therapies

“…Our experience suggests that delivery reagents are necessary for the successful use of AON therapeutics in the liver, particularly targeting hepatocytes (e.g. for the treatment of hyperlipidaemia, hepatitis C or inherited metabolic disorders with major hepatic expression) (Disterer et al , ; Yilmaz‐Elis et al , ; Perez et al , ).…”