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Medicine Jun 2024Hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis), known as Corino de Andrade disease, is a rare neurodegenerative disorder with a significant global... (Review)
Review
Hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis), known as Corino de Andrade disease, is a rare neurodegenerative disorder with a significant global impact characterized by the misfolding of transthyretin (TTR) protein leading to amyloid aggregation, ATTRv amyloidosis, especially with polyneuropathy, poses a considerable challenge in managing its rapid progression and debilitating effects. This mini-review focuses on the recent advancements in the treatment landscape for ATTRv amyloidosis with polyneuropathy, specifically the RNA interference therapeutic Vutrisiran and the ligand-conjugated antisense oligonucleotide Eplontersen. We aim to provide a comprehensive overview of the mechanisms, current evidence from clinical trials, and future directions for these novel therapeutic agents. Vutrisiran and Eplontersen have demonstrated significant clinical efficacy in improving neuropathic impairment, quality of life, and serum TTR levels in various trials. The distinct mechanistic approaches of these therapies, coupled with their acceptable safety profiles, offer promising avenues for addressing the complexities of ATTRv amyloidosis with polyneuropathy. The introduction of Vutrisiran and Eplontersen marks a pivotal moment in the quest for effective therapies against ATTRv amyloidosis with polyneuropathy. While clinical evidence is promising, ongoing research is crucial to deepen mechanistic understanding and address research gaps. Future perspectives include the potential expansion of therapeutic options and a more inclusive approach to cater to the diverse needs of individuals globally. This mini-review provides valuable insights into the evolving landscape of ATTRv amyloidosis management and sets the stage for further exploration in this challenging domain.
Topics: Humans; Amyloid Neuropathies, Familial; Polyneuropathies; Oligonucleotides; Oligonucleotides, Antisense; Prealbumin; Quality of Life
PubMed: 38941378
DOI: 10.1097/MD.0000000000038767 -
JACC. Advances Sep 2023In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol levels) trial, atorvastatin (80 mg/d) was compared to placebo in patients with recent stroke or...
BACKGROUND
In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol levels) trial, atorvastatin (80 mg/d) was compared to placebo in patients with recent stroke or transient ischemic attack (TIA) and no known coronary artery disease.
OBJECTIVES
This study aimed to assess the contribution of lipoprotein(a) [Lp(a)] to subsequent cerebrovascular and cardiovascular events in stroke/TIA survivors.
METHODS
Lp(a) levels and apolipoprotein(a) [apo(a)] isoform size were determined by liquid-chromatography mass spectrometry in samples collected at baseline from 2,814 SPARCL participants (1,418 randomized to atorvastatin and 1,396 to placebo). Within each treatment arm, patients in the highest quartile (≥84.0 nmol/L) were compared with those in the lowest quartiles of Lp(a) concentrations. Patients in the lowest quartile (≤25.9 Kringle IV domains) of apo(a) isoform sizes were compared with those in the highest quartiles. Multivariable-adjusted HRs were calculated using Cox proportional regression models.
RESULTS
There was no significant association between Lp(a) concentrations or apo(a) isoform sizes and the risk of recurrent stroke, the primary outcome of SPARCL, or cerebrovascular events in patients randomized to atorvastatin or placebo. In contrast, in patients randomized to atorvastatin, elevated Lp(a) concentrations and short apo(a) isoforms were positively and independently associated with an increased risk of coronary events (HR: 1.607 [95% CI: 1.007-2.563] and HR: 2.052 [95% CI: 1.303-3.232]). No such association was found in patients randomized to placebo (HR: 1.025 [95% CI: 0.675-1.555] and HR: 1.097 [95% CI: 0.735-1.637]).
CONCLUSIONS
Lp(a) contributes to the residual coronary artery disease risk of statin-treated stroke/TIA survivors, paving the way for use of therapies targeting Lp(a) in this population with stroke. (Lipitor In The Prevention Of Stroke, For Patients Who Have Had A Previous Stroke [SPARCL]; NCT00147602).
PubMed: 38939496
DOI: 10.1016/j.jacadv.2023.100557 -
Cell Reports Jun 2024GGGGCC (GC) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic...
GGGGCC (GC) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded GC repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded GC repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of GC repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.
PubMed: 38935506
DOI: 10.1016/j.celrep.2024.114375 -
Molecular Therapy. Nucleic Acids Jun 2024Locked nucleic acids (LNAs) are a subtype of antisense oligonucleotides (ASOs) that are characterized by a bridge within the sugar moiety. LNAs owe their robustness to... (Review)
Review
Locked nucleic acids (LNAs) are a subtype of antisense oligonucleotides (ASOs) that are characterized by a bridge within the sugar moiety. LNAs owe their robustness to this chemical modification, which as the name suggests, locks it in one conformation. This perspective includes two components: a general overview on ASOs from one side and on delivery issues focusing on lipid nanoparticles (LNPs) on the other side. Throughout, a screening of the ongoing clinical trials involving ASOs is given, as well as a take on the versatility and challenges of using LNAs. Finally, we highlight the potential of LNPs as carriers for the successful delivery of LNAs.
PubMed: 38933259
DOI: 10.1016/j.omtn.2024.102224 -
Antioxidants (Basel, Switzerland) May 2024Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular... (Review)
Review
The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect.
Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson-Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference. Here, we review ASO inhibitor/activator strategies to modulate transcription and translation that control the expression of enzymes, transcription factors, and intracellular sensors of DNA damage. Several small-interfering RNA (siRNA) drugs with N-acetyl galactosamine moieties for the liver have recently been approved. Preclinical studies using short-activating RNAs (saRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acids (LNAs) are at the forefront of proof-in-concept therapeutics. Future research targeting intracellular OxS-related pathways in the liver may help realize the promise of precision medicine, revolutionizing the customary approach to caring for and treating individuals afflicted with liver-specific conditions.
PubMed: 38929116
DOI: 10.3390/antiox13060678 -
Advanced Science (Weinheim,... Jun 2024Multidrug resistance (MDR) is a major obstacle limiting the effectiveness of chemotherapy against cancer. The combination strategy of chemotherapeutic agents and siRNA...
Multidrug resistance (MDR) is a major obstacle limiting the effectiveness of chemotherapy against cancer. The combination strategy of chemotherapeutic agents and siRNA targeting drug efflux has emerged as an effective cancer treatment to overcome MDR. Herein, stimuli-responsive programmable tetrahedral DNA-RNA nanocages (TDRN) have been rationally designed and developed for dynamic co-delivery of the chemotherapeutic drug doxorubicin and P-glycoprotein (P-gp) siRNA. Specifically, the sense and antisense strand sequences of the P-gp siRNA, which are programmable bricks with terminal disulfide bond conjugation, are precisely embedded in one edge of the DNA tetrahedron. TDRN provides a stimuli-responsive release element for dynamic control of functional cargo P-gp siRNA that is significantly more stable than the "tail-like" TDN nanostructures. The stable and highly rigid 3D nanostructure of the siRNA-organized TDRN nanocages demonstrated a notable improvement in the stability of RNase A and mouse serum, as well as long-term storage stability for up to 4 weeks, as evidenced by this study. These biocompatible and multifunctional TDRN nanocarriers with gold nanocluster-assisted delivery (TDRN@Dox@AuNC) are successfully used to achieve synergistic RNAi/Chemo-therapy in vitro and in vivo. This programmable TDRN drug delivery system, which integrates RNAi therapy and chemotherapy, offers a promising approach for treating multidrug-resistant tumors.
PubMed: 38923806
DOI: 10.1002/advs.202404112 -
Neurology International Jun 2024Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy...
Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is to describe the efficacy and safety of nusinersen in treating spinal muscular atrophy in 20 pediatric and 18 adult patients across six treatment centers in Kuwait. Functional motor assessments (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module) were used to assess changes in motor function following nusinersen treatment. The safety assessment involved clinical monitoring of adverse events. The results demonstrate clinically meaningful or considerable improvement in motor performance for nearly all patients, lasting over 4 years in some cases. A total of 70% of patients in the pediatric cohort and 72% of patients in the adult cohort achieved a clinically meaningful improvement in motor function following nusinersen treatment. Additionally, nusinersen was well-tolerated in both cohorts. These findings add to the growing body of evidence relating to the clinical efficacy and safety of nusinersen.
PubMed: 38921951
DOI: 10.3390/neurolint16030047 -
Annals of the Academy of Medicine,... Feb 2024Ribonucleic acid (RNA) therapeutics hold great potential for the advancement of dermatological treatments due to, among other reasons, the possibility of treating... (Review)
Review
Ribonucleic acid (RNA) therapeutics hold great potential for the advancement of dermatological treatments due to, among other reasons, the possibility of treating previously undruggable targets, high specificity with minimal side effects, and ability to include multiple RNA targets in a single product. Although there have been research relating to RNA therapeutics for decades, there have not been many products translated for clinical use until recently. This may be because of challenges to the application of RNA therapeutics, including the dearth of effective modes of delivery to the target, and rapid degradation of RNA in the human body and environment. This article aims to provide insight on (1) the wide-ranging possibilities of RNA therapeutics in the field of dermatology as well as (2) how key challenges can be addressed, so as to encourage the development of novel dermatological treatments. We also share our experience on how RNA therapeutics have been applied in the management of hypertrophic and keloid scars.
Topics: Humans; Keloid; Cicatrix, Hypertrophic; RNA; Dermatology; Skin Diseases; Genetic Therapy
PubMed: 38920235
DOI: 10.47102/annals-acadmedsg.2023316 -
Journal of Scleroderma and Related... Jun 2024Systemic sclerosis is a rare disease with a high mortality rate. It is a multisystem connective tissue disease due to endothelial autoimmune activation along with tissue...
Systemic sclerosis is a rare disease with a high mortality rate. It is a multisystem connective tissue disease due to endothelial autoimmune activation along with tissue and vascular fibrosis, inducing vasculopathy, with an angiogenesis wasting. The endothelial damage provokes platelet activation and immune cell adhesion. The detachment of endothelial cells leads to the interaction of platelets and collagen present in the exposed subendothelial layer. This provokes the activation of several coagulative factors, inducing a pro-thrombotic condition by thrombin generation, which converts fibrinogen into fibrin. Moreover, thrombin has other functions, such as the induction of hyperplasia in smooth muscle cells and fibroblasts, thereby favouring fibrosis. An increased risk of venous thromboembolism has been found in systemic sclerosis, whereas pulmonary hypertension may be due to the obstruction of small pulmonary arteries. Pulmonary veno-occlusive disease may also occur. Warfarin showed inconsistent results, while the outcomes of a randomised, placebo-controlled clinical trial on apixaban versus placebo are still awaited. A new anticoagulation strategy based on anti-factor XI drugs is being developed, with the aim of achieving optimal anticoagulation along with a low risk of bleeding. The molecule types under investigation in this category include monoclonal antibodies, small molecules, natural inhibitors, antisense oligonucleotides, and aptamers. Patients with systemic sclerosis may be ideal candidates for clinical trials planned to analyse the efficacy and safety of these molecules.
PubMed: 38910594
DOI: 10.1177/23971983241256250 -
The Journal of Allergy and Clinical... Jun 2024The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, suggesting that blocking SARS-CoV-2 infection...
BACKGROUND
The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Down-regulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed based on sequence data, require no delivery system, and can be administered locally.
OBJECTIVE
We sought to design ASOs that can block SARS-CoV-2 by down-regulating ACE2 in human airway.
METHODS
ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASOs pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels.
RESULTS
ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore they efficiently suppressed virus replication of three different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also down-regulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathological changes in lungs, and they increased survival of mice.
CONCLUSION
ACE2-targeting ASOs can effectively block SARS-COV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.
PubMed: 38909634
DOI: 10.1016/j.jaci.2024.06.007