Nature, Journal Year: 2024, Volume and Issue: unknown
Published: Dec. 11, 2024
Language: Английский
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 14868 - 14884
Published: Aug. 28, 2024
Antibody–oligonucleotide conjugates (AOCs) are promising treatments for Duchenne muscular dystrophy (DMD). They work via induction of exon skipping and restoration dystrophin protein in skeletal heart muscles. The structure–activity relationships (SARs) AOCs comprising antibody–phosphorodiamidate morpholino oligomers (PMOs) depend on several aspects their component parts. We evaluate the SAR antimouse transferrin receptor 1 antibody (αmTfR1)–PMO conjugates: cleavable noncleavable linkers, linker location PMO, impact drug-to-antibody ratios (DARs) plasma pharmacokinetics (PK), oligonucleotide delivery to tissues, skipping. containing a stable with DAR9.7 were most effective PMO vehicles preclinical studies. demonstrate that αmTfR1-PMO induce muscles mdx mice. Our results show potentially approach treatment DMD.
Language: Английский
Citations
3
Biomolecules, Journal Year: 2023, Volume and Issue: 13(7), P. 1108 - 1108
Published: July 12, 2023
The progressive degeneration of the skeletal musculature in Duchenne muscular dystrophy is accompanied by reactive myofibrosis, fat substitution, and chronic inflammation. Fibrotic changes reduced tissue elasticity correlate with loss motor function this X-chromosomal disorder. Thus, although dystrophinopathies are due to primary abnormalities DMD gene causing almost-complete absence cytoskeletal Dp427-M isoform dystrophin voluntary muscles, excessive accumulation extracellular matrix proteins presents a key histopathological hallmark dystrophy. Animal model research has been instrumental characterization dystrophic muscles contributed better understanding complex pathogenesis dystrophinopathies, discovery new disease biomarkers, testing novel therapeutic strategies. In article, we review how mass-spectrometry-based proteomics can be used study components endomysium, perimysium, epimysium, such as collagens, proteoglycans, matricellular proteins, adhesion receptors. mdx-4cv mouse diaphragm displays severe making it an ideal system for large-scale surveys systematic alterations matrisome fibers. Novel biomarkers myofibrosis now tested their appropriateness preclinical clinical setting diagnostic, pharmacodynamic, prognostic, and/or monitoring indicators.
Language: Английский
Citations
7
JCI Insight, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 4, 2024
The Murphy Roths Large (MRL) mouse strain has "super-healing" properties that enhance recovery from injury. In mice, the DBA/2J intensifies many aspects of muscular dystrophy so we evaluated ability MRL to suppress in Sgcg null model limb girdle dystrophy. A comparative analysis mice versus strains showed greater myofiber regeneration with reduced structural degradation muscle strain. Transcriptomic profiling dystrophic indicated strain-dependent expression extracellular matrix (ECM) and TGF-β signaling genes. To investigate ECM, cellular components were removed sections generate decellularized myoscaffolds. Decellularized myoscaffolds protective had significantly less deposition collagen matrix-bound TGF-β1 TGF-β3 throughout matrix. Dystrophic background, but not enriched myokines like IGF-1 IL-6. C2C12 myoblasts seeded onto matrices Sgcg–/– muscles background induced myoblast differentiation compared Thus, imparts its effect through a highly regenerative which is active even
Language: Английский
Citations
2
Genes, Journal Year: 2024, Volume and Issue: 15(11), P. 1489 - 1489
Published: Nov. 20, 2024
Antisense oligonucleotide (ASO)-mediated exon-skipping is an effective approach to restore the disrupted reading frame of dystrophin gene for treatment Duchenne muscular dystrophy (DMD). Currently, four FDA-approved ASOs can target three different exons, but these therapies are mutation-specific and only benefit a subset patients. Understanding broad applicability approaches essential prioritizing development additional with greatest potential impact on DMD population. This review offers updated analysis all theoretical strategies their across patient population, specific focus DMD-associated mutations documented in UMD-DMD database. Unlike previous studies, this leverages inclusion phenotypic data each mutation, providing more comprehensive clinically relevant perspective.
Language: Английский
Citations
2
Nature, Journal Year: 2024, Volume and Issue: unknown
Published: Dec. 11, 2024
Language: Английский
Citations
2