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1.
Genes (Basel) ; 15(7)2024 Jun 21.
Article in English | MEDLINE | ID: mdl-39062600

ABSTRACT

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development and addresses some of the major limitations that previously hindered the development of therapies for rare diseases.


Subject(s)
Oligonucleotides, Antisense , Rare Diseases , United States Food and Drug Administration , Humans , Rare Diseases/genetics , Rare Diseases/drug therapy , Rare Diseases/therapy , Oligonucleotides, Antisense/therapeutic use , United States , Genetic Therapy/methods , Precision Medicine/methods
2.
Drug Discov Today ; 29(8): 104074, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38950729

ABSTRACT

Pathogenic viruses are a profound threat to global public health, underscoring the urgent need for the development of efficacious antiviral therapeutics. The advent of RNA-targeting antiviral strategies has marked a significant paradigm shift in the management of viral infections, offering a potent means of control and potential cure. In this review, we delve into the cutting-edge progress in RNA-targeting antiviral agents, encompassing antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), small and bifunctional molecules. We provide an in-depth examination of their strategic molecular design and elucidate the underlying mechanisms of action that confer their antiviral efficacy. By synthesizing recent findings, we shed light on the innovative potential of RNA-targeting approaches and their pivotal role in advancing the frontiers of antiviral drug discovery.


Subject(s)
Antiviral Agents , Drug Design , Oligonucleotides, Antisense , RNA, Small Interfering , RNA, Viral , Virus Diseases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/pharmacology , Virus Diseases/drug therapy , Virus Diseases/virology , Animals , Drug Discovery/methods
4.
Molecules ; 29(11)2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38893532

ABSTRACT

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1. Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood-brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.


Subject(s)
Cell-Penetrating Peptides , Muscular Atrophy, Spinal , Oligonucleotides, Antisense , Cell-Penetrating Peptides/chemistry , Cell-Penetrating Peptides/pharmacology , Humans , Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/therapy , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/pharmacology , Animals , Oligonucleotides/chemistry , Oligonucleotides/pharmacology , Survival of Motor Neuron 2 Protein/genetics , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 1 Protein/metabolism , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects
5.
Int J Mol Sci ; 25(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38891760

ABSTRACT

Dysferlin is a large transmembrane protein involved in critical cellular processes including membrane repair and vesicle fusion. Mutations in the dysferlin gene (DYSF) can result in rare forms of muscular dystrophy; Miyoshi myopathy; limb girdle muscular dystrophy type 2B (LGMD2B); and distal myopathy. These conditions are collectively known as dysferlinopathies and are caused by more than 600 mutations that have been identified across the DYSF gene to date. In this review, we discuss the key molecular and clinical features of LGMD2B, the causative gene DYSF, and the associated dysferlin protein structure. We also provide an update on current approaches to LGMD2B diagnosis and advances in drug development, including splice switching antisense oligonucleotides. We give a brief update on clinical trials involving adeno-associated viral gene therapy and the current progress on CRISPR/Cas9 mediated therapy for LGMD2B, and then conclude by discussing the prospects of antisense oligomer-based intervention to treat selected mutations causing dysferlinopathies.


Subject(s)
Dysferlin , Genetic Therapy , Muscular Dystrophies, Limb-Girdle , Mutation , Humans , Muscular Dystrophies, Limb-Girdle/therapy , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/diagnosis , Dysferlin/genetics , Dysferlin/metabolism , Genetic Therapy/methods , Oligonucleotides, Antisense/therapeutic use , Animals
6.
Int J Biol Macromol ; 272(Pt 2): 132890, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38848829

ABSTRACT

The lack of more effective therapies for breast cancer has enhanced mortality among breast cancer patients. Recent efforts have established efficient treatments to reduce breast cancer-related deaths. The ever-increasing attraction to employing biocompatible polysaccharide-based nanostructures as delivery systems has created interest in various disease therapies, especially breast cancer treatment. A wide range of therapeutic cargo comprising bioactive or chemical drugs, oligonucleotides, peptides, and targeted biomarkers have been considered to comprehend their anti-cancer effects against breast cancer. Some limitations of naked agents or undesired constructs, such as no or low bioavailability, enzymatic digestion, short-range stability, low-cellular uptake, poor solubility, and low surface area, have lessened their effectiveness. However, nanoscale formulations of therapeutic ingredients have provided a promising platform to address the mentioned concerns. For instance, some capable polysaccharides, including cellulose, pectin, chitosan, alginate, and dextran, were developed as breast cancer therapeutics with great nanoparticle structures. This review carefully examines the characteristics of beneficial polysaccharides that are utilized in the formation of nanoparticles (NPs). It also highlights the applications of antisense oligonucleotides (ASOs), and NPs made from polysaccharides in the treatment of breast cancer and suggests ways to enhance these particles for future research.


Subject(s)
Breast Neoplasms , Nanostructures , Oligonucleotides, Antisense , Polysaccharides , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/therapy , Polysaccharides/chemistry , Female , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides, Antisense/therapeutic use , Nanostructures/chemistry , Drug Delivery Systems , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Carriers/chemistry , Nanoparticles/chemistry
7.
Drugs ; 84(6): 637-643, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38849700

ABSTRACT

Increasing evidence has implicated lipoprotein(a) [Lp(a)] in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in developing novel approaches to integrating Lp(a) into the setting of cardiovascular prevention. Current guidelines advocate universal measurement of Lp(a) levels, with the potential to influence cardiovascular risk assessment and triage of higher-risk patients to use of more intensive preventive therapies. In parallel, considerable activity has been undertaken to develop novel therapeutics with the potential to achieve selective and substantial reductions in Lp(a) levels. Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease.


Subject(s)
Cardiovascular Diseases , Lipoprotein(a) , Oligonucleotides, Antisense , Humans , Lipoprotein(a)/blood , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/drug therapy , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/pharmacology , Atherosclerosis/drug therapy , RNA Interference , Oligonucleotides/therapeutic use , Oligonucleotides/pharmacology , Animals
8.
Med ; 5(6): 493-494, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38878767

ABSTRACT

Reducing the synthesis of apoC-III reduces fasting triglycerides in individuals lacking lipoprotein lipase activity. Recently, Stroes et al.1 published a phase 3 trial on the effects of olezarsen, a third-generation antisense oligonucleotide that blocks apoC-III mRNA, on triglycerides and risk of acute pancreatitis.


Subject(s)
Apolipoprotein C-III , Hyperlipoproteinemia Type I , Oligonucleotides , Triglycerides , Humans , Apolipoprotein C-III/genetics , Apolipoprotein C-III/blood , Hyperlipoproteinemia Type I/genetics , Hyperlipoproteinemia Type I/blood , Oligonucleotides/pharmacology , Oligonucleotides/therapeutic use , Triglycerides/blood , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Pancreatitis/genetics , Benzimidazoles
9.
Kidney Int ; 106(1): 21-23, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38906653

ABSTRACT

Chronic hemodialysis patients exhibit an excessive cardiovascular risk and a marked increase in both thromboembolism and bleeding episodes. Factor XI inhibition may provide anticoagulation, with a low risk of bleeding, and several factor XI inhibitors, including fesomersen, an antisense oligonucleotide, are under development. Recently, a phase 2 study of fesomersen showed a good safety profile in chronic hemodialysis patients and suggested that clotting rates of the arteriovenous fistula and the dialysis circuit are lower.


Subject(s)
Anticoagulants , Factor XI , Hemorrhage , Renal Dialysis , Humans , Renal Dialysis/adverse effects , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Factor XI/antagonists & inhibitors , Factor XI/metabolism , Blood Coagulation/drug effects , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/adverse effects , Oligonucleotides, Antisense/administration & dosage , Thromboembolism/prevention & control , Thromboembolism/etiology , Arteriovenous Shunt, Surgical/adverse effects
10.
Curr Neurol Neurosci Rep ; 24(8): 255-264, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38861215

ABSTRACT

PURPOSE OF REVIEW: Huntington's disease (HD) is an autosomal-dominant disorder caused by a pathological expansion of a trinucleotide repeat (CAG) on exon 1 of the huntingtin (HTT) gene. HD is characterized by the presence of chorea, alongside other hyperkinesia, parkinsonism and a combination of cognitive and behavioural features. Currently, there are no disease-modifying therapies (DMTs) for HD, and the only intervention(s) with approved indication target the treatment of chorea. This article reviews recent research on the clinical development of DMTs and newly developed tools that enhance clinical trial design towards a successful DMT in the future. RECENT FINDINGS: HD is living in an era of target-specific drug development with emphasis on the mechanisms related to mutant Huntingtin (HTT) protein. Examples include antisense oligonucleotides (ASO), splicing modifiers and microRNA molecules that aim to reduce the levels of mutant HTT protein. After initial negative results with ASO molecules Tominersen and WVE-120101/ WVE-120102, the therapeutic landscape continues to expand, with various trials currently under development to document proof-of-concept and safety/tolerability. Immune-targeted therapies have also been evaluated in early-phase clinical trials, with promising preliminary findings. The possibility of quantifying mHTT in CSF, along with the development of an integrated biological staging system in HD are important innovations applicable to clinical trial design that enhance the drug development process. Although a future in HD with DMTs remains a hope for those living with HD, care partners and care providers, the therapeutic landscape is promising, with various drug development programs underway following a targeted approach supported by disease-specific biomarkers and staging frameworks.


Subject(s)
Huntington Disease , Humans , Huntington Disease/therapy , Huntington Disease/genetics , Huntington Disease/drug therapy , Oligonucleotides, Antisense/therapeutic use , Huntingtin Protein/genetics , Animals , Drug Development
12.
BioDrugs ; 38(4): 511-526, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38914784

ABSTRACT

Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].


Subject(s)
Drug Approval , Oligonucleotides, Antisense , United States Food and Drug Administration , Humans , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/pharmacology , United States , RNA, Messenger/genetics , RNA, Messenger/metabolism , Animals , RNA Splicing/drug effects
13.
Medicine (Baltimore) ; 103(26): e38767, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38941378

ABSTRACT

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.


Subject(s)
Amyloid Neuropathies, Familial , Polyneuropathies , Humans , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/therapy , Polyneuropathies/genetics , Oligonucleotides/therapeutic use , Oligonucleotides, Antisense/therapeutic use , Prealbumin/genetics , Quality of Life
14.
Int J Mol Sci ; 25(9)2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38732027

ABSTRACT

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.


Subject(s)
Motor Neuron Disease , Oligonucleotides, Antisense , Humans , Oligonucleotides, Antisense/therapeutic use , Motor Neuron Disease/genetics , Motor Neuron Disease/therapy , Animals , Muscular Atrophy, Spinal/therapy , Muscular Atrophy, Spinal/genetics , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/therapy
15.
Expert Rev Neurother ; 24(6): 549-553, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38758193

ABSTRACT

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients. AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed. EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.


Subject(s)
Amyotrophic Lateral Sclerosis , Superoxide Dismutase-1 , Humans , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Oligonucleotides/therapeutic use , Oligonucleotides, Antisense/therapeutic use , Biomarkers/blood
16.
Arch Pharm Res ; 47(6): 571-595, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38764004

ABSTRACT

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.


Subject(s)
Huntingtin Protein , Huntington Disease , Huntington Disease/therapy , Huntington Disease/genetics , Humans , Animals , Huntingtin Protein/genetics , Huntingtin Protein/antagonists & inhibitors , Huntingtin Protein/metabolism , Oligonucleotides, Antisense/therapeutic use , Genetic Therapy/methods , Gene Editing/methods , Neuroprotective Agents/therapeutic use
17.
Nat Rev Drug Discov ; 23(6): 421-444, 2024 06.
Article in English | MEDLINE | ID: mdl-38740953

ABSTRACT

RNA has sparked a revolution in modern medicine, with the potential to transform the way we treat diseases. Recent regulatory approvals, hundreds of new clinical trials, the emergence of CRISPR gene editing, and the effectiveness of mRNA vaccines in dramatic response to the COVID-19 pandemic have converged to create tremendous momentum and expectation. However, challenges with this relatively new class of drugs persist and require specialized knowledge and expertise to overcome. This Review explores shared strategies for developing RNA drug platforms, including layering technologies, addressing common biases and identifying gaps in understanding. It discusses the potential of RNA-based therapeutics to transform medicine, as well as the challenges associated with improving applicability, efficacy and safety profiles. Insights gained from RNA modalities such as antisense oligonucleotides (ASOs) and small interfering RNAs are used to identify important next steps for mRNA and gene editing technologies.


Subject(s)
Gene Editing , RNA , mRNA Vaccines , Animals , Humans , COVID-19 , COVID-19 Drug Treatment , Gene Editing/methods , Oligonucleotides, Antisense/therapeutic use , RNA/therapeutic use , RNA, Messenger/genetics , RNA, Small Interfering/therapeutic use , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , SARS-CoV-2/genetics , SARS-CoV-2/drug effects , mRNA Vaccines/therapeutic use
18.
N Engl J Med ; 391(1): 21-31, 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38819395

ABSTRACT

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).


Subject(s)
Angioedemas, Hereditary , Humans , Male , Female , Double-Blind Method , Angioedemas, Hereditary/drug therapy , Adult , Middle Aged , Injections, Subcutaneous , Young Adult , Oligonucleotides, Antisense/adverse effects , Oligonucleotides, Antisense/therapeutic use , Aged , Adolescent , Quality of Life
19.
Nucleic Acid Ther ; 34(3): 125-133, 2024.
Article in English | MEDLINE | ID: mdl-38800942

ABSTRACT

The ABCA4 gene, involved in Stargardt disease, has a high percentage of splice-altering pathogenic variants, some of which cause complex RNA defects. Although antisense oligonucleotides (AONs) have shown promising results in splicing modulation, they have not yet been used to target complex splicing defects. Here, we performed AON-based rescue studies on ABCA4 complex splicing defects. Intron 13 variants c.1938-724A>G, c.1938-621G>A, c.1938-619A>G, and c.1938-514A>G all lead to the inclusion of different pseudo-exons (PEs) with and without an upstream PE (PE1). Intron 44 variant c.6148-84A>T results in multiple PE inclusions and/or exon skipping events. Five novel AONs were designed to target these defects. AON efficacy was assessed by in vitro splice assays using midigenes containing the variants of interest. All screened complex splicing defects were effectively rescued by the AONs. Although varying levels of efficacy were observed between AONs targeting the same PEs, for all variants at least one AON restored splicing to levels comparable or better than wildtype. In conclusion, AONs are a promising approach to target complex splicing defects in ABCA4.


Subject(s)
ATP-Binding Cassette Transporters , Exons , Introns , Oligonucleotides, Antisense , RNA Splicing , Stargardt Disease , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/pharmacology , ATP-Binding Cassette Transporters/genetics , Humans , Introns/genetics , RNA Splicing/genetics , Exons/genetics , Stargardt Disease/genetics , Stargardt Disease/pathology , Mutation
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