Enhanced Delivery of Ligand-Conjugated Antisense Oligonucleotides (C16-HA-ASO) Targeting Dystrophia Myotonica Protein Kinase Transcripts for the Treatment of Myotonic Dystrophy Type 1

Benichou, Siham Ait; Jauvin, Dominic; De-Serres-Berard, Thiery; Bennett, Frank; Rigo, Frank; Gourdon, Geneviève; Boutjdir, Mohamed; Chahine, Mohamed; Puymirat, Jack

doi:10.1089/hum.2022.069

Cited by 11 publications

(11 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Systemic treatment with IONIS-877864, but not a control LICA, improved these features by increasing the number of muscle satellite cells and regenerating muscle fibers in induced DM200 mice. We also observed that IONIS-877864 decreases DMPK mRNA expression in the heart by 78% compared to 65% for the unconjugated ASO following systemic administration in DMSXL mice [64], confirming the relevance of fatty-acid conjugated ASOs for treating cardiac tissues as well.…”

Section: Lipid-conjugated Asos Targeting Skeletal and Cardiac Musclessupporting

confidence: 68%

“…Notably, IONIS screened hundreds of cEt-modified gapmer ASOs in human skeletal muscle cells to identify sequences leading to DMPK mRNA knockdown, followed by in vivo evaluation of their tolerability in mice and rats [ 63 ]. These results led to the identification of IONIS 486178 (or ISIS 486178), which has been extensively investigated in DM1 mice models [ 64 , 65 , 66 , 67 ]. In vitro screening is an important step in the development of antisense therapy, which requires accurate models to identify the best drug candidates.…”

Section: In Vitro Models Of Dm1 For Asos Screeningmentioning

confidence: 99%

“…A 50% reduction of the toxic transcripts in the heart restored connexin 40 protein expression and corrected Atp2a1 exon 22 exclusion, which was related to the correction of cardiac electric activity. It is noteworthy that the reported DMPK mRNA silencing by unconjugated ASOs is generally lower in the heart (30–60%) than in muscles (50–90%) following systemic administration [ 63 , 64 , 66 , 67 ]. Increased ASO retention in the endosomes of cardiomyocytes compared to skeletal muscle cells may contribute to this phenomenon [ 109 ].…”

Section: Systemic Therapy For Dm1 With Naked Asosmentioning

confidence: 99%

“…Accordingly, systemic injection of a C16 fatty acid conjugated to an ASO targeting ACTA1 -CUG transcripts (IONIS-992948) in the bichromatic reporter HSA-TR mouse model followed by serial in vivo spectroscopy showed a 2-fold improved correction of mis-splicing in muscles compared to unconjugated ASOs with the same sequence [ 78 ]. We noted that subcutaneous injection of 25 mg/kg of IONIS 486178 conjugated to a C16 palmitic acid via an HA linker (IONIS-877864) in DMSXL mice results in a 90% reduction in human DMPK mRNAs in muscles compared to about 60% for the same dose of the unconjugated ASO [ 64 ]. Yadava et al investigated the effect of IONIS-877864 on muscle regeneration by inducing muscle damage with BaCl 2 in DM200 mice [ 103 ].…”

Section: Lipid-conjugated Asos Targeting Skeletal and Cardiac Musclesmentioning

confidence: 99%

See 3 more Smart Citations

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

Serres-Bérard

Benichou

Jauvin

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3′ UTR of the myotonic dystrophy protein kinase (DMPK) gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.

show abstract

Section: Lipid-conjugated Asos Targeting Skeletal and Cardiac Musclessupporting

confidence: 68%

Section: In Vitro Models Of Dm1 For Asos Screeningmentioning

confidence: 99%

Section: Systemic Therapy For Dm1 With Naked Asosmentioning

confidence: 99%

Section: Lipid-conjugated Asos Targeting Skeletal and Cardiac Musclesmentioning

confidence: 99%

See 2 more Smart Citations

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

Serres-Bérard

Benichou

Jauvin

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Currently, new approaches, improving AON delivery are being suggested. One of them is application of the peptide- or other ligand-conjugated oligonucleotides, which might improve AON delivery in skeletal and cardiac muscles [ 51 , 52 , 53 ].…”

Section: Therapeutic Targets In Dm1 and Dm2mentioning

confidence: 99%

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Timchenko

2022

IJMS

View full text Add to dashboard Cite

Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 and CNBP in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients’ cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).

show abstract

Update on Therapy for Myotonic Dystrophy Type 1

Ivanovic

Meola

Vukojevic

et al. 2023

Curr Treat Options Neurol

View full text Add to dashboard Cite

Enhanced Delivery of Ligand-Conjugated Antisense Oligonucleotides (C16-HA-ASO) Targeting Dystrophia Myotonica Protein Kinase Transcripts for the Treatment of Myotonic Dystrophy Type 1

Cited by 11 publications

References 46 publications

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Update on Therapy for Myotonic Dystrophy Type 1

Contact Info

Product

Resources

About