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The New England Journal of Medicine Sep 2022The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in ( ALS).
METHODS
In this phase 3 trial, we randomly assigned adults with ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).
RESULTS
A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.
CONCLUSIONS
In persons with ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).
Topics: Adult; Amyotrophic Lateral Sclerosis; Biomarkers; Double-Blind Method; Humans; Injections, Spinal; Neurofilament Proteins; Oligonucleotides, Antisense; Recovery of Function; Superoxide Dismutase-1
PubMed: 36129998
DOI: 10.1056/NEJMoa2204705 -
The Lancet. Neurology Jul 2022Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this... (Review)
Review
Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.
Topics: Humans; Huntingtin Protein; Huntington Disease; Neurodegenerative Diseases; Oligonucleotides; Oligonucleotides, Antisense; RNA Splicing
PubMed: 35716694
DOI: 10.1016/S1474-4422(22)00121-1 -
Nucleic Acids Research Apr 2023Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides... (Review)
Review
Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the diseases targeted by this new class of drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne muscular dystrophy, hereditary transthyretin-mediated amyloidosis, familial chylomicronemia syndrome, acute hepatic porphyria, and primary hyperoxaluria. Chemical modification of DNA and RNA was central to making drugs out of oligonucleotides. Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2'-fluoro-RNA, 2'-O-methyl RNA and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2'-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.
Topics: Humans; Morpholinos; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; RNA; RNA Interference
PubMed: 36881759
DOI: 10.1093/nar/gkad067 -
Molecular Therapy : the Journal of the... Dec 2021Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the... (Review)
Review
Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; Dependovirus; Genetic Therapy; Humans; Oligonucleotides, Antisense
PubMed: 33839324
DOI: 10.1016/j.ymthe.2021.04.008 -
The Journal of Biological Chemistry 2021Antisense technology is beginning to deliver on the broad promise of the technology. Ten RNA-targeted drugs including eight single-strand antisense drugs (ASOs) and two... (Review)
Review
Antisense technology is beginning to deliver on the broad promise of the technology. Ten RNA-targeted drugs including eight single-strand antisense drugs (ASOs) and two double-strand ASOs (siRNAs) have now been approved for commercial use, and the ASOs in phase 2/3 trials are innovative, delivered by multiple routes of administration and focused on both rare and common diseases. In fact, two ASOs are used in cardiovascular outcome studies and several others in very large trials. Interest in the technology continues to grow, and the field has been subject to a significant number of reviews. In this review, we focus on the molecular events that result in the effects observed and use recent clinical results involving several different ASOs to exemplify specific molecular mechanisms and specific issues. We conclude with the prospective on the technology.
Topics: Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Discovery; Humans; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 33600796
DOI: 10.1016/j.jbc.2021.100416 -
Annual Review of Neuroscience Jul 2019Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases.... (Review)
Review
Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.
Topics: Animals; Brain; Humans; Muscular Atrophy, Spinal; Neurodegenerative Diseases; Oligonucleotides; Oligonucleotides, Antisense; Tissue Distribution
PubMed: 31283897
DOI: 10.1146/annurev-neuro-070918-050501 -
Developmental Neuroscience 2021Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing in the nervous system. The FDA has approved ASOs for... (Review)
Review
Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing in the nervous system. The FDA has approved ASOs for treatment of ten genetic disorders, with many applications currently in the pipeline. We describe the molecular mechanisms of ASO treatment for four neurodevelopmental and neuromuscular disorders. The ASO nusinersen is a general treatment for mutations of SMN1 in spinal muscular atrophy that corrects the splicing defect in the SMN2 gene. Milasen is a patient-specific ASO that rescues splicing of CNL7 in Batten's disease. STK-001 is an ASO that increases expression of the sodium channel gene SCN1A by exclusion of a poison exon. An ASO that reduces the abundance of the SCN8A mRNA is therapeutic in mouse models of developmental and epileptic encephalopathy. These examples demonstrate the variety of mechanisms and range of applications of ASOs for treatment of neurodevelopmental disorders.
Topics: Animals; Disease Models, Animal; Humans; Mice; Muscular Atrophy, Spinal; NAV1.1 Voltage-Gated Sodium Channel; Neurodevelopmental Disorders; Oligonucleotides, Antisense; RNA Splicing
PubMed: 34412058
DOI: 10.1159/000517686 -
Neurotherapeutics : the Journal of the... Jul 2022Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease mechanisms and genetics in combination with innovations in gene modulation strategies creates promising new options for the development of ALS therapies. In recent years, six gene modulation therapies have been tested in ALS patients. These target gain-of-function pathology of the most common ALS genes, SOD1, C9ORF72, FUS, and ATXN2, using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs). Here, we review the latest clinical and preclinical advances in gene modulation approaches for ALS, including gene silencing, gene correction, and gene augmentation. These techniques have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease.
Topics: Humans; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; C9orf72 Protein; Oligonucleotides, Antisense; MicroRNAs
PubMed: 36068427
DOI: 10.1007/s13311-022-01285-w -
Neurotherapeutics : the Journal of the... Jul 2022Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.
Topics: Humans; Amyotrophic Lateral Sclerosis; Oligonucleotides, Antisense; C9orf72 Protein; Superoxide Dismutase-1; Neurodegenerative Diseases
PubMed: 35653060
DOI: 10.1007/s13311-022-01247-2 -
EMBO Molecular Medicine Apr 2021Nucleic acid-based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the... (Review)
Review
Nucleic acid-based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid-based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid-based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide-based therapeutics.
Topics: Gene Expression; Nanoparticles; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 33821570
DOI: 10.15252/emmm.202013243