Publications by authors named "R Ellerington"
Nucleic acid therapeutics require delivery systems to reach their targets. Key challenges to be overcome include avoidance of accumulation in cells of the mononuclear phagocyte system and escape from the endosomal pathway. Spherical nucleic acids (SNAs), in which a gold nanoparticle supports a corona of oligonucleotides, are promising carriers for nucleic acids with valuable properties including nuclease resistance, sequence-specific loading and control of receptor-mediated endocytosis.
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- Androgens, through their interaction with the androgen receptor (AR), play a significant role in muscle development and mass regulation, but the exact mechanisms remain unclear.
- This study reveals that AR collaborates with SMAD4 to promote muscle growth by modulating gene expression and chromatin dynamics, particularly in response to muscle wasting conditions.
- In models of spinal and bulbar muscular atrophy (SBMA), an elongated polyglutamine (polyQ) tract in AR disrupts this cooperative function, leading to muscle atrophy, but treatment with BMP7 can potentially mitigate these effects and offers a pathway for future therapies.
Although recent regulatory approval of splice-switching oligonucleotides (SSOs) for the treatment of neuromuscular disease such as Duchenne muscular dystrophy has been an advance for the splice-switching field, current SSO chemistries have shown limited clinical benefit due to poor pharmacology. To overcome limitations of existing technologies, we engineered chimeric stereopure oligonucleotides with phosphorothioate (PS) and phosphoryl guanidine-containing (PN) backbones. We demonstrate that these chimeric stereopure oligonucleotides have markedly improved pharmacology and efficacy compared with PS-modified oligonucleotides, preventing premature death and improving median survival from 49 days to at least 280 days in a dystrophic mouse model with an aggressive phenotype.
View Article and Find Full Text PDFThe vacuolar H-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in , the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals.
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- - Spinal and bulbar muscular atrophy (SBMA) is an adult-onset disease linked to a mutated androgen receptor (AR) protein that affects muscle function and has significant clinical challenges.
- - Recent research indicates that the abnormal transcriptional activity of the mutant AR is central to the disease's progression, suggesting that correcting this issue could lead to promising treatments.
- - The study explored the use of AR isoform 2, which is a shorter version of the AR that doesn't contain the problematic polyQ region, and found that introducing this isoform using a specific viral vector improved symptoms in mice with SBMA by normalizing the dysregulated transcriptional activity.