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In this phase 3 trial, among children with later-onset spinal muscular atrophy, those who received nusinersen had improvement in motor-function scores and those who underwent a sham procedure did not.

In this phase 3 trial, among infants with spinal muscular atrophy, those who received nusinersen were more likely to achieve major motor milestones and less likely to need permanent assisted ventilation than those who underwent a sham procedure.

In a phase 1–2 dose-escalation trial involving adults with ALS due to SOD1 mutations who received intrathecal tofersen (an antisense oligonucleotide) or placebo, the levels of mutant SOD1 in the CSF were 33 percentage points lower in the highest-dose tofersen group than in the placebo group.

In a phase 2b trial involving patients with hypertriglyceridemia, the use of olezarsen (which targets APOC3 mRNA) for 6 months reduced triglyceride levels by approximately 50% as compared with placebo.

Enoxaparin is used to prevent deep-vein thrombosis in patients undergoing total knee arthroplasty. In this study, an antisense oligonucleotide against factor XI was more effective than enoxaparin in preventing deep-vein thrombosis and caused less bleeding. Patients undergoing total knee arthroplasty are at risk for postoperative venous thromboembolism. Conventional therapies for the prevention of this complication involve inhibitors of factor Xa or thrombin, such as enoxaparin. These drugs are effective but are associated with a risk of bleeding. 1 The pathogenesis of venous thromboembolism after surgery is incompletely understood, but tissue factor exposed at the surgical site is thought to be the major driver through the extrinsic pathway of coagulation (Figure 1). 2 The role of the intrinsic pathway in this process is uncertain. Experimental data suggest that targeting factor XI, a key component of the intrinsic pathway, . . .

Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS. This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8–33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology. Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16–45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology. The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial. ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.

Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs ≥50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11·4 mmol/L (SD 3·6) in the mipomersen group and 10·4 mmol/L (3·7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (−24·7%, 95% CI −31·6 to −17·7) than with placebo (−3·3%, −12·1 to 5·5; p=0·0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. ISIS Pharmaceuticals and Genzyme Corporation.

The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme‐linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.

This study explored the safety, tolerability, and dystrophin-restoring effect of a single, intramuscular dose of an antisense oligonucleotide, PRO051, to induce specific exon skipping during messenger RNA splicing and to restore dystrophin expression in patients with Duchenne's muscular dystrophy. Four patients, selected on the basis of mutational status, muscle condition, and a positive exon-skipping response to PRO051 in vitro, received the drug. Intramuscular injection of this compound induced local dystrophin synthesis. This study explored the safety, tolerability, and dystrophin-restoring effect of an antisense oligonucleotide, PRO051, in patients with Duchenne's muscular dystrophy. Intramuscular injection of this compound induced local dystrophin synthesis. Duchenne's muscular dystrophy is a severely debilitating childhood neuromuscular disease that affects 1 in 3500 newborn boys. 1 Progressive weakness of the skeletal muscles, cardiomyopathy, and respiratory failure are the most prominent features, but the brain can also be affected. 2 , 3 Virtually all patients are wheelchair-dependent by the age of 12 years, and most die in early adulthood. Improved ventilation techniques and glucocorticoid treatment have substantially improved fitness and muscle strength, prolonged mobility, and extended the expected lifespan from less than 20 years to 25 to 35 years. 4 – 6 However, there has been no treatment to prevent the eventual fatal outcome. . . .

Hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH) is a rare disorder characterized by recurrent, potentially life-threatening swelling in various parts of the body, including the limbs, face, and airways Current treatments focus primarily on symptomatic relief and the management of acute attacks, without targeting the underlying genetic cause or the dysregulated bradykinin production. Donidalorsen, a novel antisense oligonucleotide, addresses a key driver of HAE-C1-INH by targeting prekallikrein (PKK) to reduce bradykinin levels. This meta-analysis evaluates the efficacy and safety of Donidalorsen versus placebo, focusing on two dosing regimens: 4-week and 8-week intervals. Data from two randomized controlled trials (110 patients) revealed that Donidalorsen significantly reduced the frequency of HAE-C1-INH attacks, with the 4-week regimen showing superior outcomes compared to the 8-week dosing. The 4-week group also experienced fewer moderate or severe attacks and a reduced need for on-demand therapy. Adverse events were comparable between the Donidalorsen and placebo groups. These findings suggest that more frequent dosing may optimize treatment outcomes in HAE-C1-INH.