AI Article Synopsis
- * The most notable success is nusinersen for SMA, which improves symptoms and slows progression, while tofersen is aimed at ALS but hasn't shown benefits for all patients.
- * This review summarizes current ASO research in MNDs, highlighting both successful and unsuccessful outcomes, discussing the strengths and weaknesses of existing studies, and suggesting future research directions for better treatments.
Article 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 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11083842 | PMC |
| http://dx.doi.org/10.3390/ijms25094809 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Influence of Length and Sequence of Complementary Oligonucleotides on the Spectral and Time-Resolved Fluorescence Properties of an H-Type Excitonic Dimer-Bearing Antisense Oligonucleotide.
J Phys Chem B
January 2025
OncoImmunin, Inc., 207A Perry Parkway, Suite 6, Gaithersburg, Maryland 20877, United States.
We have previously found that the presence of an H-type excitonic dimer formed by two fluorophores covalently bound to an oligonucleotide allows the delivery of such a polymer into live cells without inducing toxicity. We are now using time-resolved fluorescence measurements in solution to understand the molecular dynamics of an antisense probe and how pairing with complementary sense strands of various lengths and degrees of complementarity affects the antisense strand's properties. We report that a DNA strand composed of 30 residues and labeled with an H-type excitonic Cyanine-5/Cyanine-5 dimer shows a predominant 1.
View Article and Find Full Text PDFMetabolic Stability and Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics Beyond The Liver.
J Med Chem
January 2025
Regeneron Genetic Medicines, Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, United States.
Oligonucleotides have emerged as a formidable new class of nucleic acid therapeutics. Fully modified oligonucleotides exhibit enhanced metabolic stability and display successful clinical applicability for targets formerly considered "undruggable". Accumulating studies show that conjugation to targeting modalities of stabilized oligonucleotides, especially small interfering RNAs (siRNAs), has enabled robust delivery to intended cells/tissues.
View Article and Find Full Text PDFEndosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids.
Molecules
December 2024
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Therapeutic nucleic acids (TNAs) including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) have emerged as promising treatment strategies for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological agents, including the ability to target previously "undruggable" genes. Despite this promise, several biological barriers severely limit their clinical efficacy.
View Article and Find Full Text PDFSequence-Specific Free Energy Changes in DNA/RNA Induced by a Single LNA-T Modification in Antisense Oligonucleotides.
Int J Mol Sci
December 2024
Konan Laboratory for Oligonucleotide Therapeutics (KOLOT), 7-1-20 Minatojima-Minamimachi, Kobe 650-0047, Japan.
2',4'-methylene bridged nucleic acid/locked nucleic acid (2',4'-BNA/LNA; LNA) is a modified nucleic acid that improves the function of antisense oligonucleotide therapeutics. In particular, LNA in the DNA strand increases its binding affinity for the target RNA. Predicting the binding affinities of LNA-containing antisense oligonucleotides and RNA duplexes is useful for designing antisense oligonucleotides.
View Article and Find Full Text PDFRescue of Aberrant Splicing Caused by a Novel Complex Deep-intronic Allele.
Genes (Basel)
November 2024
Institute of Medical Molecular Genetics, University of Zurich, 8952 Schlieren, Switzerland.
Stargardt disease (STGD1) is an autosomal recessive disorder caused by pathogenic variants in that affects the retina and is characterised by progressive central vision loss. The onset of disease manifestations varies from childhood to early adulthood. Whole exome (WES), whole gene, and whole genome sequencing (WGS) were performed for a patient with STGD1.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!