A link to reset your password has been sent to your e-mail address. By continuing you agree to the use of cookies.
In respiratory diseases they are emerging as a newer therapy.
Status of 4 ASO therapies described in the study. These results suggest that ASO reduction of SCN8A expression could be an effective therapy for patients with additional genetic epilepsies. The goal of ASO treatment for Dravet syndrome is to upregulate the wild-type allele, to compensate for the inactive mutant allele. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. The first neuromuscular disorder successfully treated with an ASO was spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by progressive muscle atrophy [8].
We also discuss the future perspectives and targets for oligonucleotides in the management of respiratory diseases. The authors contributed equally to preparation of the manuscript. A steric block ASO was designed to prevent inclusion of the poison exon (Fig. The ASO nusinersen is a general treatment for mutations of SMN1 in spinal muscular atrophy that corrects the splicing defect in the SMN2 gene. Meisler MH, Helman G, Hammer MF, Fureman BE, Gaillard WD, Goldin AL, et al. Antisense oligonucleotides (ASOs) are emerging as an exciting new approach to these challenging disorders [1]. These results suggest that ASOs reducing expression of SCN8A would be therapeutic in humans with SCN8A encephalopathy, if the negative consequences of very low expression can be avoided [27].
Thus far, ASO treatment has been limited to rare genetic diseases. We describe four examples of neurodevelopmental disorders that demonstrate the range of mutational mechanisms that can be corrected by targeted ASOs. Issue release date: September 2021, Number of Print Pages: 6 At the time of diagnosis, the patient was 6 years old and was experiencing developmental regression, ataxia, seizures, brain atrophy, and vision problems. Mice receiving two ASO treatments lived for 9 weeks, compared to the 2 week survival of untreated mice. The mutant allele contains an SVA retrotransposon in intron 6 that activates a cryptic splice site. Scn8a mutant mice were treated with ASO by ICV injection at postnatal day 2, prior to the onset of symptoms [26]. Corey DR. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. We hypothesized that reducing the expression of Scn8a in Dravet syndrome might compensate for the haploinsufficiency of Scn1a and restore the excitatory/inhibitory balance. Administration of the Scn8a ASO by ICV injection at postnatal day 2 rescued the Scn1a mutant mice, with no deaths or seizures up to 6 months of age [26]. Since RNaseH1 is active in both the nucleus and cytoplasm, gapmer ASOs can target nuclear RNAs, such as pre-mRNA and long noncoding RNA, as well as mature cytoplasmic mRNA. SCN8A encephalopathy is a DEE caused by de novo mutations of SCN8A, which encodes Nav1.6, a major neuronal voltage-gated sodium channel [23]. Meisler MH. Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and Dravet Syndrome. Han Z, Chen C, Christiansen A, Ji S, Lin Q, Anumonwo C, et al. A retrotransposon insertion into MFSD8 in the mutant allele in this patient generated a cryptic splice site resulting in a transcript with an in-frame stop codon (Fig. The overall frequency of SMA is approximately 1/10,000 [9]. 1b). Children with all 3 types of SMA have been demonstrated to benefit from treatment with nusinersen, with earlier treatment providing greater benefit [17-19].
Preclinical tests in 3 mouse models engineered to express the human SMN2 gene demonstrated an increase in the proportion of SMN2 transcripts containing exon 7 and improvement of SMA phenotypes [14, 15]. Early diagnosis and treatment are critical for treatment of Batten disease. ICV administration on postnatal day 1 increased body weight, motor performance, and longevity in a model of SMA type 1 [15]. They act by altering gene expression of an affected individual. The FDA has approved ASOs for treatment of ten genetic disorders, with many applications currently in the pipeline. 2c). The patient received escalating doses of ASO by intrathecal injection, followed by maintenance doses every 3 months. c Binding of steric block ASOs prevents interaction with splice factors, resulting in exon skipping, shown here, or redirection to an alternative splice site. ASO therapy can be personalized to target patient-specific mutations [2, 3]. Meisler MH, Hill SF, Yu W. Sodium channelopathies in neurodevelopmental disorders. Single-dose gene-replacement therapy for spinal muscular atrophy. Two major types of ASOs are gapmers, which target mRNA for degradation by RNAseH, and ASOs that bind pre-mRNA and alter splicing by steric hindrance.
Article
Based on the patients deterioration and the known clinical course of Battens disease, the FDA approved an Expanded Access Investigational New Drug application. The ASO blocks a splice enhancer, restoring normal splicing. Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, et al. 2019 Elsevier B.V. All rights reserved. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. 1a, b). PREV The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. Steric block ASOs contain the 2MOE and PS modifications throughout and are not substrates for RNaseH. McKay RA, Miraglia LJ, Cummins LL, Owens SR, Sasmor H, Dean NM.
Gene replacement requires only one treatment and is administered by intravenous rather than intrathecal infusion. This success demonstrates the importance of developing a standardized process for obtaining FDA approval for individualized ASOs. 2b). Lim KH, Han Z, Jeon HY, Kach J, Jing E, Weyn-Vanhentenryck S, et al. In addition, oligonucleotides also are extensively used for gene transfer in the form of polymeric, liposomal and inorganic carrier materials. Improved methods of systemic administration, such as packaging in nanoparticles that cross the blood-brain barrier, would facilitate broader application. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The sequence-specificity of ASO binding results in high specificity and a low level of side effects. The authors have no conflicts of interest to declare. The survival motor neuron (SMN) protein functions in splicing and assembly of ribonuclear proteins [11]. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Miriam H. Meisler, meislerm@med.umich.edu, Keywords: Antisense oligonucleotideGene therapySpinal muscular atrophyDravet syndromeSCN8A. 2b) [2]. Hoot NR. The ASO prevents inclusion of exon 20N and leads to increased production of full-length SCN1A protein.
Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, et al. In cultured cells, this ASO reduced the presence of the poison exon from 60% of transcripts to < 5% of transcripts [22]. Oligonucleotide-based therapies are advanced novel interventions used in the management of various respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). Lefebvre S, Brglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. ASO, antisense oligonucleotide; SMA, spinal muscular atrophy. Patient-customized oligonucleotide therapy for a rare genetic disease. Rigo F, Chun SJ, Norris DA, Hung G, Lee S, Matson J, et al. Complementary & Alternative Medicine (CAM), Talking to Others about Your Advanced Cancer, Coping with Your Feelings During Advanced Cancer, Emotional Support for Young People with Cancer, Young People Facing End-of-Life Care Decisions, Late Effects of Childhood Cancer Treatment, Tech Transfer & Small Business Partnerships, Frederick National Laboratory for Cancer Research, Milestones in Cancer Research and Discovery, Step 1: Application Development & Submission, National Cancer Act 50th Anniversary Commemoration, Supportive & Palliative Care Editorial Board, Levels of Evidence: Supportive & Palliative Care, Levels of Evidence: Screening & Prevention, Levels of Evidence: Integrative Therapies, U.S. Department of Health and Human Services. Other chemical modifications improve binding affinity, solubility, and in vivo stability [7]. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant Huntingtin. The quantitative level of elevated or reduced expression is another important consideration.
b Gapmer ASOs contain 2MOE modified bases at their termini (solid lines) and internal unmodified bases (dashed lines) that provide a substrate for degradation by RNaseH1.
Three weeks after treatment, Scn8a transcript levels were reduced to 50% of wild-type levels. Milasen is a patient-specific ASO that rescues splicing of CNL7 in Battens disease. Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression. Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing in the nervous system. Nusinersen was approved by the FDA in 2016 for treatment of SMA. One physician reported that prior to treatment his son was unable to lift his arms or legs and had lost the ability to swallow, but after treatment, he began to lift his head, roll over, and sit on his own, and at the age of 2 years he began to count and learn the alphabet [16]. Gain-of-function mutations result in elevated neuronal activity. ScienceDirect is a registered trademark of Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V. Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases. The chemical evolution of oligonucleotide therapies of clinical utility. Children and young adults with spinal muscular atrophy treated with nusinersen. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. Treatment of gain-of-function variants of SCN8A in DEE requires reduced gene expression, but haploinsufficiency is associated with another, less severe, disorder [26]. Early diagnosis and treatment are essential to prevent irreversible changes. Better methodologies and techniques are the need of the hour that can deliver these agents to tissues and cells in a target specific manner by which their maximum potential can be reached in the management of chronic inflammatory diseases. Shen W, De Hoyos CL, Migawa MT, Vickers TA, Sun H, Low A, et al. Children with type I SMA who receive treatment with nusinersen exhibit dramatic improvement. The survival motor neuron protein in spinal muscular atrophy. In cultured fibroblasts from the patient, the ASO produced a 3-fold increase in correctly spliced transcripts and corrected the enlarged lysosomes.
