-
Biomedicine & Pharmacotherapy =... Jun 2024Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cancer, accounting for approximately 80% of all renal cell cancers. Due to its exceptional... (Review)
Review
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cancer, accounting for approximately 80% of all renal cell cancers. Due to its exceptional inter- and intratumor heterogeneity, it is highly resistant to conventional systemic therapies. Targeting the evasion of cell death, one of cancer's hallmarks, is currently emerging as an alternative strategy for ccRCC. In this article, we review the current state of apoptosis-inducing therapies against ccRCC, including antisense oligonucleotides, BH3 mimetics, histone deacetylase inhibitors, cyclin-kinase inhibitors, inhibitors of apoptosis protein antagonists, and monoclonal antibodies. Although preclinical studies have shown encouraging results, these compounds fail to improve patients' outcomes significantly. Current evidence suggests that inducing apoptosis in ccRCC may promote tumor progression through apoptosis-induced proliferation, anastasis, and apoptosis-induced nuclear expulsion. Therefore, re-evaluating this approach is expected to enable successful preclinical-to-clinical translation.
Topics: Humans; Carcinoma, Renal Cell; Apoptosis; Kidney Neoplasms; Animals; Antineoplastic Agents; Molecular Targeted Therapy
PubMed: 38781868
DOI: 10.1016/j.biopha.2024.116805 -
Molecular Neurobiology May 2024Non-coding CGG repeat expansions within the 5' untranslated region are implicated in a range of neurological disorders, including fragile X-associated tremor/ataxia... (Review)
Review
Non-coding CGG repeat expansions within the 5' untranslated region are implicated in a range of neurological disorders, including fragile X-associated tremor/ataxia syndrome, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. This review outlined the general characteristics of diseases associated with non-coding CGG repeat expansions, detailing their clinical manifestations and neuroimaging patterns, which often overlap and indicate shared pathophysiological traits. We summarized the underlying molecular mechanisms of these disorders, providing new insights into the roles that DNA, RNA, and toxic proteins play. Understanding these mechanisms is crucial for the development of targeted therapeutic strategies. These strategies include a range of approaches, such as antisense oligonucleotides, RNA interference, genomic DNA editing, small molecule interventions, and other treatments aimed at correcting the dysregulated processes inherent in these disorders. A deeper understanding of the shared mechanisms among non-coding CGG repeat expansion disorders may hold the potential to catalyze the development of innovative therapies, ultimately offering relief to individuals grappling with these debilitating neurological conditions.
PubMed: 38780719
DOI: 10.1007/s12035-024-04239-9 -
Small Methods May 2024Triple-negative breast cancer (TNBC) remains a significant challenge in terms of treatment, with limited efficacy of chemotherapy due to side effects and acquired drug...
Triple-negative breast cancer (TNBC) remains a significant challenge in terms of treatment, with limited efficacy of chemotherapy due to side effects and acquired drug resistance. In this study, a threose nucleic acid (TNA)-mediated antisense approach is employed to target therapeutic Akt genes for TNBC therapy. Specifically, two new TNA strands (anti-Akt2 and anti-Akt3) are designed and synthesized that specifically target Akt2 and Akt3 mRNAs. These TNAs exhibit exceptional enzymatic resistance, high specificity, enhance binding affinity with their target RNA molecules, and improve cellular uptake efficiency compared to natural nucleic acids. In both 2D and 3D TNBC cell models, the TNAs effectively inhibit the expression of their target mRNA and protein, surpassing the effects of scrambled TNAs. Moreover, when administered to TNBC-bearing animals in combination with lipid nanoparticles, the targeted anti-Akt TNAs lead to reduced tumor sizes and decreased target protein expression compared to control groups. Silencing the corresponding Akt genes also promotes apoptotic responses in TNBC and suppresses tumor cell proliferation in vivo. This study introduces a novel approach to TNBC therapy utilizing TNA polymers as antisense materials. Compared to conventional miRNA- and siRNA-based treatments, the TNA system holds promise as a cost-effective and scalable platform for TNBC treatment, owing to its remarkable enzymatic resistance, inexpensive synthetic reagents, and simple production procedures. It is anticipated that this TNA-based polymeric system, which targets anti-apoptotic proteins involved in breast tumor development and progression, can represent a significant advancement in the clinical development of effective antisense materials for TNBC, a cancer type that lacks effective targeted therapy.
PubMed: 38779741
DOI: 10.1002/smtd.202400291 -
Journal of Translational Internal... Apr 2024Huntington's disease (HD) is a devastating, autosomal-dominant inherited, neurodegenerative disorder characterized by progressive motor deficits, cognitive impairments,...
Huntington's disease (HD) is a devastating, autosomal-dominant inherited, neurodegenerative disorder characterized by progressive motor deficits, cognitive impairments, and neuropsychiatric symptoms. It is caused by excessive cytosine-adenine-guanine (CAG) trinucleotide repeats within the huntingtin gene (HTT). Presently, therapeutic interventions capable of altering the trajectory of HD are lacking, while medications for abnormal movement and psychiatric symptoms are limited. Numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. In this review, we update the latest advances on new promising molecular-based therapeutic strategies for this disorder, including DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. We mainly focus on the ongoing clinical trials and the latest pre-clinical studies to explore the progress of emerging potential HD therapeutics.
PubMed: 38779119
DOI: 10.2478/jtim-2023-0142 -
European Journal of Clinical... May 2024Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the... (Review)
Review
BACKGROUND
Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho-physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target.
RESULTS
However, approved lipid lowering therapies such as statins, ezetimibe or PCSK9 inhibitors have a neutral to modest effect on Lp(a) levels, thus prompting the development of new strategies selectively targeting Lp(a). These include antisense oligonucleotides and small interfering RNAs (siRNAs) directed towards apolipoprotein(a) [Apo(a)], which are in advanced phase of clinical development. More recently, additional approaches including inhibitors of Apo(a) and gene editing approaches via CRISPR-Cas9 technology entered early clinical development.
CONCLUSION
If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk.
PubMed: 38778431
DOI: 10.1111/eci.14254 -
Scientific Reports May 2024Antisense oligonucleotides (ASOs) are synthetic single-stranded oligonucleotides that bind to RNAs through Watson-Crick base pairings. They are actively being developed...
Antisense oligonucleotides (ASOs) are synthetic single-stranded oligonucleotides that bind to RNAs through Watson-Crick base pairings. They are actively being developed as therapeutics for various human diseases. ASOs containing unmethylated deoxycytidylyl-deoxyguanosine dinucleotide (CpG) motifs are known to trigger innate immune responses via interaction with toll-like receptor 9 (TLR9). However, the TLR9-stimulatory properties of ASOs, specifically those with lengths equal to or less than 20 nucleotides, phosphorothioate linkages, and the presence and arrangement of sugar-modified nucleotides-crucial elements for ASO therapeutics under development-have not been thoroughly investigated. In this study, we first established SY-ODN18, an 18-nucleotide phosphorothioate oligodeoxynucleotide with sufficient TLR9-stimulatory activity. We demonstrated that an unmethylated CpG motif near its 5'-end was indispensable for TLR9 activation. Moreover, by utilizing various sugar-modified nucleotides, we systematically generated model ASOs, including gapmer, mixmer, and fully modified designs, in accordance with the structures of ASO therapeutics. Our results illustrated that introducing sugar-modified nucleotides in such designs significantly reduces TLR9-stimulatory activity, even without methylation of CpG motifs. These findings would be useful for drug designs on several types of ASOs.
Topics: Toll-Like Receptor 9; Oligonucleotides, Antisense; Humans; CpG Islands; Animals; Mice; Nucleotides; Sugars; Oligodeoxyribonucleotides
PubMed: 38773176
DOI: 10.1038/s41598-024-61666-3 -
Nature Communications May 2024Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings...
Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15. Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA. Variant mRNA exhibits reduced METTL3 methyltransferase-mediated writing of N-methyladenosine (mA) and reduced reading by YTHDC1 and YTHDF1/3 required for efficient mRNA nuclear export and translation, respectively. In contrast to current models, the variant does not alter the sequence of mA target sites, but instead reduces their accessibility for modification. The defect was rescued by antisense morpholinos predicted to expose mA sites on target EPRS1 mRNA, or by mA modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor. Our bioinformatic analysis predicts widespread occurrence of SNVs associated with human health and disease that similarly alter accessibility of distal mRNA mA sites. These results reveal a new RNA-dependent etiologic mechanism by which SNVs can influence gene expression and disease, consequently generating opportunities for personalized, RNA-based therapeutics targeting these disorders.
Topics: Female; Humans; Male; Adenosine; Hereditary Central Nervous System Demyelinating Diseases; Homozygote; Methyltransferases; Mutation, Missense; Nerve Tissue Proteins; RNA Splicing Factors; RNA, Messenger; RNA-Binding Proteins
PubMed: 38769304
DOI: 10.1038/s41467-024-48549-x -
ACS Applied Materials & Interfaces Jun 2024Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it...
Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it is crucial to promptly explore and develop effective methodologies for bacterial infections. Herein, we propose a novel approach for synthesizing nanostructures based on antisense oligonucleotides (ASOs) through the coordination-driven self-assembly of Zn with ASO molecules. This approach aims to provide effective synergistic therapy for chronic wound infections caused by (). The resulting hybrid nanoparticles successfully preserve the structural integrity and biological functionalities of ASOs, demonstrating excellent ASO encapsulation efficiency and bioaccessibility. antibacterial experiments reveal that Zn-ASO NPs exhibit antimicrobial properties against , , and . This antibacterial ability is attributed to the high concentration of metal zinc ions and the generation of high levels of reactive oxygen species. Additionally, the ftsZ-ASO effectively inhibits the expression of the ftsZ gene, further enhancing the antimicrobial effect. antibacterial assays demonstrate that the Zn-ASO NPs promote optimal skin wound healing and exhibit favorable biocompatibility against infections, resulting in a residual infected area of less than 8%. This combined antibacterial strategy, which integrates antisense gene therapy and metal-coordination-directed self-assembly, not only achieves synergistic and augmented antibacterial outcomes but also expands the horizons of ASO coordination chemistry. Moreover, it addresses the gap in the antimicrobial application of metal-coordination ASO self-assembly, thereby advancing the field of ASO-based therapeutic approaches.
Topics: Staphylococcus aureus; Anti-Bacterial Agents; Zinc; Oligonucleotides, Antisense; Animals; Mice; Escherichia coli; Microbial Sensitivity Tests; Staphylococcal Infections; Bacillus subtilis; Humans; Wound Healing
PubMed: 38767982
DOI: 10.1021/acsami.4c01453 -
Drug Development Research Jun 2024Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded deoxynucleotide sequences composed of phosphate backbone-connected sugar rings. Designing of... (Review)
Review
Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded deoxynucleotide sequences composed of phosphate backbone-connected sugar rings. Designing of those strands is based on Watson-Crick hydrogen bonding mechanism. Thanks to rapidly advancing medicine and technology, evolving of the gene therapy area and ASO approaches gain attention. Considering the genetic basis of diseases, it is promising that gene therapy approaches offer more specific and effective options compared to conventional treatments. The objective of this review is to explain the mechanism of ASOs and discuss the characteristics and safety profiles of therapeutic agents in this field. Pharmacovigilance for gene therapy products is complex, requiring accurate assessment of benefit-risk balance and evaluation of adverse effects.
Topics: Oligonucleotides, Antisense; Humans; Genetic Therapy; Animals; Pharmacovigilance
PubMed: 38764172
DOI: 10.1002/ddr.22187 -
Archives of Pharmacal Research Jun 2024Huntington's disease (HD) is a paradigm of a genetic neurodegenerative disorder characterized by the expansion of CAG repeats in the HTT gene. This extensive review... (Review)
Review
Huntington's disease (HD) is a paradigm of a genetic neurodegenerative disorder characterized by the expansion of CAG repeats in the HTT gene. This extensive review investigates the molecular complexities of HD by highlighting the pathogenic mechanisms initiated by the mutant huntingtin protein. Adverse outcomes of HD include mitochondrial dysfunction, compromised protein clearance, and disruption of intracellular signaling, consequently contributing to the gradual deterioration of neurons. Numerous therapeutic strategies, particularly precision medicine, are currently used for HD management. Antisense oligonucleotides, such as Tominersen, play a leading role in targeting and modulating the expression of mutant huntingtin. Despite the promise of these therapies, challenges persist, particularly in improving delivery systems and the necessity for long-term safety assessments. Considering the future landscape, the review delineates promising directions for HD research and treatment. Innovations such as Clustered regularly interspaced short palindromic repeats associated system therapies (CRISPR)-based genome editing and emerging neuroprotective approaches present unprecedented opportunities for intervention. Collaborative interdisciplinary endeavors and a more insightful understanding of HD pathogenesis are on the verge of reshaping the therapeutic landscape. As we navigate the intricate landscape of HD, this review serves as a guide for unraveling the intricacies of this disease and progressing toward transformative treatments.
Topics: Huntington Disease; Humans; Animals; Huntingtin Protein; Oligonucleotides, Antisense; Genetic Therapy; Gene Editing; Neuroprotective Agents
PubMed: 38764004
DOI: 10.1007/s12272-024-01499-w