nusinersen and Muscular-Dystrophy--Duchenne

Synthetic Antisense oligonucleotides (ASOs) are novel and efficient laboratory tools to regulate the expression of specific genes, and have only recently come into clinical use. These are synthetic single-stranded DNA analogs, whose sequence is complementary to a target nucleotide and alter protein synthesis by several mechanisms. We herein provide a primer on the topic for pediatricians, as this group of drugs is likely to see many more drugs for previously incurable diseases.

Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Morpholinos; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; Randomized Controlled Trials as Topic

Topics: Gene Expression; Humans; Morpholinos; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Oligonucleotides; RNA, Messenger; RNA, Small Interfering

This is the second part of a two-part document intended to discuss recent therapeutic progresses in genetic neuromuscular disorders. The present review is for diseases of motor neuron and skeletal muscle, some of which reached recently the most innovative therapeutic approaches. Nusinersen, an SMN2 mRNA splicing modifier, was approved as first-ever therapy of spinal muscular atrophy (SMA) by FDA in 2016 and by EMA in 2017. The orally administered small-molecule risdiplam, which increases SMN protein levels similarly but also in peripheral organs, is tested in ongoing phase 2 and 3 trials. After positive results with phase 1 treatment with AAV9-SMN, the first gene therapy for SMA, a phase 3 clinical trial is ongoing. Ataluren is the first approved drug for Duchenne muscular dystrophy (DMD) patients with premature stop codon mutations and its indication has been recently extended since the age of 2 years. Exon skipping technology was and is currently tested in many phase 3 trials, and eteplirsen received a conditional approval by FDA for patients amenable to exon 51 skipping, but not by EMA. Many other compounds with different mechanisms of action are now tested in DMD by phase 2 and 3 trials, including phase 1 gene therapy. Other innovative approaches are under investigation, i.e., gene therapy in X-linked myotubular myopathy and Pompe disease, and antisense oligonucleotides in myotonic dystrophy type 1. Positive evidences are discussed about lamotrigine and ranolazine in non-dystrophic myotonias, chaperons in Pompe disease, and nucleosides in mitochondrial DNA depletion induced by thymidine kinase 2 deficiency.

Topics: Genetic Therapy; Glycogen Storage Disease Type II; Humans; Mitochondrial Diseases; Muscular Atrophy, Spinal; Muscular Diseases; Muscular Dystrophy, Duchenne; Myopathies, Structural, Congenital; Myotonic Dystrophy; Neuromuscular Agents; Oligonucleotides; Oxadiazoles; SMN Complex Proteins

Inherited neuromuscular disorders encompass a broad group of genetic conditions, and the discovery of these underlying genes has expanded greatly in the past three decades. The discovery of such genes has enabled more precise diagnosis of these disorders and the development of specific therapeutic approaches that target the genetic basis and pathophysiological pathways. Such translational research has led to the approval of two genetic therapies by the US Food and Drug Administration: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy, which are both antisense oligonucleotides that modify pre-mRNA splicing. In this Review we aim to discuss new genetic therapies and ongoing clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, and other less common childhood neuromuscular disorders.

Topics: Child; Genetic Therapy; Humans; Morpholinos; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Neuromuscular Diseases; Oligonucleotides

Oligonucleotides (oligos) have been under clinical development for approximately the past 30 years, beginning with antisense oligonucleotides (ASOs) and apatmers and followed about 15 years ago by siRNAs. During that lengthy period of time, numerous clinical trials have been performed and thousands of trial participants accrued onto studies. Of all the molecules evaluated as of January 2017, the regulatory authorities assessed that six provided clear clinical benefit in rigorously controlled trials. The story of these six is given in this review.

Topics: Aptamers, Nucleotide; Clinical Trials as Topic; Cytomegalovirus Retinitis; Drug Approval; Hepatic Veno-Occlusive Disease; Humans; Hypercholesterolemia; Macular Degeneration; Morpholinos; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; Polydeoxyribonucleotides; Thionucleotides

During the past 10 years, antisense oligonucleotide-mediated exon skipping and splice modulation have proven to be powerful tools for correction of mRNA splicing in genetic diseases. In 2016, the US Food and Drug Administration (FDA)-approved Exondys 51 (eteplirsen) and Spinraza (nusinersen), the first exon skipping and exon inclusion drugs, to treat patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), respectively. The exon skipping of DMD mRNA aims to restore the disrupted reading frame using antisense oligonucleotides (AONs), allowing the production of truncated but partly functional dystrophin proteins, and slow down the progression of the disease. This approach has also been explored in several other genetic disorders, including laminin α2 chain-deficient congenital muscular dystrophy, dysferlin-deficient muscular dystrophy (e.g., Miyoshi myopathy and limb-girdle muscular dystrophy type 2B), sarcoglycanopathy (limb-girdle muscular dystrophy type 2C), and Fukuyama congenital muscular dystrophy. Antisense-mediated exon skipping is also a powerful tool to examine the function of genes and exons. A significant challenge in exon skipping is how to design effective AONs. The mechanism of mRNA splicing is highly complex with many factors involved. The selection of target sites, the length of AONs, the AON chemistry, and the melting temperature versus the RNA strand play important roles. A cocktail of AONs can be employed to skip multiples exons. In this chapter, we discuss the design of effective AONs for exon skipping.

Topics: Dystrophin; Exons; Genetic Therapy; Humans; Morpholinos; Muscular Atrophy, Spinal; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; RNA Splicing