It results in proximal spinal and bulbar muscle weakness and atrophy. . PolyQ disorders are a group of rare nine neurodegenerative diseases that include Huntington's disease, spinocerebellar ataxias . "Antisense oligonucleotide" or ASO, is a broad term, encompassing any relatively short string of nucleic acids. Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. Antisense oligonucleotides slow the progression of the pediatric neurodegenerative disorder Batten's disease by correcting mRNA splicing, paving the way for personalized medicine. DOI: 10.1126/scitranslmed . Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. Antisense Oligonucleotides Antisense oligonucleotides are composed of a strand of DNA or RNA as an initial structure that binds via Watson-Crick hybridization to its complementary RNA strand. Access to Document 10.1172/JCI25424 Other files and links Link to publication in Scopus Fingerprint Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. Learn about the mechanisms of action and potential uses of antisense oligonucleotide-based therapies in polyglutamine disorders. antisense oligonucleotides (asos) are single-stranded oligonucleotides of 8 to 50 bases in length that specifically bind to selected rna sequences and regulate the expression of genes by several mechanisms depending on their chemical properties and targets, which will affect protein synthesis at posttranscriptional processing or protein Abstract Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. Antisense oligonucleotide infusion can be regulated or stopped should there be any unforeseen side effects, a key consideration for human application. Med., University of Utah, professor and chair of neurology and a senior author . This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. JCI Insight. Antisense oligonucleotides (ASOs) affect protein expression by binding to pre-mRNA or mRNA to modulate processing of pre-mRNA to mRNA or translation of mRNA to protein. In neurology specifically, in 2020, FDA approved novel therapies for patients with Parkinson's disease, multiple sclerosis, spinal muscular atrophy, Duchenne muscular dystrophy, tuberous . Antisense oligonucleotide infusion can be regulated or stopped should there be any unforeseen side effects, a key consideration for human application. The resulting RNA-DNA hybrid can induce ribonuclease H1 (RNase H1) degradation of the targeted RNA, modulation of splicing, or blockade of translation. Both Huntington's disease and spinal muscular atrophy are rare forms of neurodegeneration, but if antisense oligonucleotides can be shown to work for these disorders, then it may be possible . Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). Drug: Nusinersen. The appeal of developing an antisense oligonucleotide to treat ALS and other neurodegenerative diseases is its simplicity, according to Dr. Watts, associate professor of RNA therapeutics and co-lead-author of the Nature Medicine study. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. This approach could greatly affect the frequency of treatment delivery to only a few times a year, contrary to the monthly delivery of ASOs to Huntington's disease patients being currently used . Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. There has been a recent revival of interest in the use of antisense oligonucleotides to treat neurodegenerative disorders. no treatment for these . There are currently no disease-modifying treatments for any adult human neurodegenerative disease. Intracellular accumulations of aSyn are pathological hallmarks of PD. Aghajan, M. et al. . . Antisense oligonucleotides (ASO) are short, modified single-stranded DNA, RNA, or hybrid DNA-RNA sequences that bind complementary cellular RNAs, such as (pre-)mRNAs, or noncoding RNAs, such as microRNAs, thereby influencing their further processing. Purpose of Review Expanding therapeutic targets from proteins to RNAs opens up new possibilities for neurodegenerative disorders therapeutics development. Well-established and sophisticated pump technology allows dosing to be adjusted noninvasively by remote signaling ( 11, 12 ). IMR Press is a leading publisher of open access peer-reviewed biomedical and life sciences journals. RNA-based drugs that include antisense oligonucleotides bear great therapeutic potential toward treatment of various diseases by altering RNA and/or reducing, restoring, and modifying protein expression through multiple molecular mechanisms. For many toxic gain-of-function proteins in neurologic diseases, the goal for therapy is to reduce levels of a pathologic protein (eg, -synuclein, tau, or huntingtin). News & Perspective Drugs & Diseases Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Antisense Drugs for Huntington's, ALS and Prion Diseases Could Meet the Dire Need for Brain Treatments. An ASO is a . A drug engineered to combat the gene that causes spinocerebellar ataxia type 2 (SCA2) might also be used to treat amyotrophic lateral sclerosis (ALS), researchers showed in two mice studies. Session N2: Neuroscience in the Clinic: Antisense Oligonucleotide (ASO) Therapy abstracts . ASOs are ideal candidates for the treatment of neurodegenerative diseases, given numerous advance- ments made to their chemical modications and delivery methods. Antisense oligonucleotides can be used to specifically inhibit unwanted gene expression and hence target the molecular basis of genetic diseases. Here is a short summary of the antisense technology presentations. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Gene therapy for motor neurone disease. The use of antisense oligonucleotides (ASOs) is a promising approach to gene silencing. Detailed Description: SPINRAZA (nusinersen) is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Antisense Oligonucleotides, or ASOs, are small single-stranded molecules of DNA with a great deal of potential to help patients with genetic disorders like ALS, commonly known as Lou Gehrig's disease. Antisense oligonucleotide infusion can be regulated or stopped should there be any unforeseen side effects, a key consideration for human application. Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is the most common dominantly inherited ataxia in the world and caused by an expansion of a polyglutamine-coding CAG repeat in the ATXN3 gene. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. 008 This is a PDF le of an unedited . The recent regulatory approval of ASO-based therapy for the pediatric motor neuron disease spinal muscular atrophy has Antisense oligonucleotides (ASOs) are small, single-stranded DNAs that can bind specific RNA sequences on precursor messenger RNAs (pre-mRNAs) and mRNAs. Well- established and sophisticated pump technology allows dosing to be adjusted noninvasively by remote signaling (11, 12). PHILADELPHIAA custom-crafted antisense oligonucleotide therapy (ASO) has brought hope, and perhaps effective treatment . The antisense mechanism invoked depends on both the ASO's binding location on the target RNA and the chemical modifications of the ASO ( 23 ). Currently, there is no cure nor effective treatment strategy for any repeat expansion diseases. 4(12):e126124. However, for many of these expansion diseases, splice-switching antisense oligonucleotides (AOs) may offer promise as a therapeutic strategy, as these compounds have already demonstrated efficacy in the treatment of other types of genetic disorders. In the case of oligonucleotide-based therapies, the sequence directs target recognition and the chemistry of the backbone and the vehicle determines tissue distribution and metabolism . Taken together, reduction of aSyn production may . Neurodegenerative diseases represent an ever-increasing societal and economic burden with WHO estimates indicating that they will replace cancer as the 2nd leading cause of death by 2040. Antisense oligonucleotides (ASOs) have been under intense investigation over recent years as gene silencing tools. Well-established and sophisticated pump technology allows dosing to be adjusted noninvasively by remote signaling ( 11, 12 ). In neurodege. Parkinson's disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Antisense oligonucleotides (ASOs) have the potential to reduce, restore, or modify RNA and protein expression and thus can target disease pathogenesis by altering the expression of mutant proteins (1). One approach for therapy has focused on CAG-repeat antisense oligonucleotides (ASOs) designed to bind CUG repeat RNA, thereby blocking RNA-protein . We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. Antisense means it is complementary to the mRNA strand, and therefore can bind to it. (APP,APP) ASOs are small synthetic single-stranded chains of nucleic acids that target. In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. During the American Academy of Neurology Meeting in Los Angeles, experts from multiple neurodegenerative diseases came together to give an overview of ASO therapy past and present. In 2017, FDA approved the enzyme replacement therapy, Brineura, which involves . Well-established and sophisticated pump technology allows dosing to be adjusted noninvasively by remote signaling ( 11, 12 ). Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modied protein expres- sion. Gene Therapy - Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1. Antisense oligonucleotide infusion can be regulated or stopped should there be any unfore- seen side effects, a key consideration for human application. Roon-Mom, Antisense oligonucleotides in therapy for neurodegenerative di sorders, Ad- vanced Drug Delivery Reviews (2015), doi: 10.1016/j.addr.2015.03. Baughn et al., "Antisense Oligonucleotide as a Potential Therapy for Amyotrophic Lateral Sclerosis with C9orf72 Expansion" Poster Presentation, Keystone Symposia, New Frontiers in Neurodegenerative Disease Research, Santa Fe, NM, Feb. 3-8, 2013. Consecutive impairments of respiratory muscles often lead to respiratory failure and reduced life expectancy. Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disease of motor neurons in which the average survival is 2 to 3 years from onset and for which substantially disease-modifying treatments are currently lacking. 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. Antisense oligonucleotides (ASOs) are single-stranded nucleic acid strings that can be used to selectively modify protein synthesis by binding complementary (pre-)mRNA sequences. However, ALS is a complex neurodegenerative disease. There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. There has been a recent revival of interest in the use of antisense oligonucleotides to treat several neurodegenerative disorders using different approaches to prevent disease onset or halt disease progression and the first clinical trials for spinal muscular atrophy and amyotrophic lateral sclerosis showing promising results. Spinal muscular atrophy (SMA) is a genetic autosomal-recessive disease with a progressive degeneration of alpha motor neurons. Abstract. "ASOs are essentially anti-messenger RNA agents. Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. . 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 SOD1 (SOD1 ALS). A second unusual feature of the DM1 mutation is that it leads to the production of a toxic RNA. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). . 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. Indeed, existing pipelines for the development of ASO therapies for . For this specific review, we focus only on those ASOs that are single-stranded sequences, 8-50 base pairs in length, and bind to the target RNA by means of standard Watson-Crick base pairing. More than 30 years of optimization of oligonucleotide modifications have generated molecules with characteristics amenable to the treatment of neurodegenerative diseases. Nusinersen, approved by the FDA for treatment of SMA in 2016, was approved by the Chinese National Medical Products Administration in 2019. . The protein produced by the SOD1 gene is responsible for around 2% of cases of . "Antisense oligonucleotide" or ASO, is a broad term, encompassing any relatively short string of nucleic acids. ASOs are small single-stranded pieces of DNA that bind via complementary base-pair binding to the intracellular mRNA transcript (Figure). Parkinson's disease is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. ASOs are small synthetic single-stranded chains of nucleic acids that target specific RNA transcripts through several mechanisms. We aim to facilitate the dissemination of high-quality research in the area of biomedical science. . Batten's disease remains a terminal disease with limited treatment options. Antisense oligonucleotide-based therapeutics involves downregulation of gene expression. The disease is also called "Motor Neuron Disease (MND)" and "Lou Gehrig's disease". Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and. Keywords Research shows it can be caused by a number of different mutations, varying from case . Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. The data from this study provide encouragement for further development of antisense oligonucleotides for the treatment of neurodegenerative diseases, although the small numbers of participants and low doses limit broader conclusions . A genetic therapy that increases or lowers levels of a protein raises hopes for a . Antisense oligonucleotides are synthetic single stranded strings of nucleic acids, between 8 and 50 nucleotides in length, that bind to RNA through standard Watson-Crick base pairing. For this specific review, we focus only on those ASOs that are single-stranded sequences, 8-50 base pairs in length, and bind to the target RNA by means of standard Watson-Crick base pairing. More information: Yingyao Shao et al, Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome, Science Translational Medicine (2021). Stefan M. Pulst, M.D., Dr. Oligo means 'small,' because ASOs are made up of relatively few (usually fewer than 25) nucleotides. Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. Sometimes, aberrant splicing can be fixed using a synthetic molecule called an antisense oligonucleotide, also called an 'oligo' or an ASO. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a . Disease presentation and classification of spinal muscular atrophy (SMA) The severe form of proximal spinal muscular atrophy, also called Werdnig-Hoffmann disease [122, 123, 316], is the most common monogenetic lethal pediatric neuromuscular disorder.A milder form of proximal spinal muscular atrophy also exists that originally has been considered as a distinct neurological disease []. 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. There are currently two main types of oligonucleotide therapeutics, antisense oligonucleotides (ASOs) and short interfering oligonucleotides (siRNA). Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. In a remarkable example of precision medicine, a researcher at Boston's Children Hospital led a team that developed an antisense oligonucleotide therapy for one girl with a rare variant of Batten disease in just four months. Antisense Oligonucleotide Therapy Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which targets motor neurons cells responsible for controlling involuntary muscles functions. 18,19 Interactions of CUG exp RNA with proteins are thought to underlie many symptoms of the disease. Antisense oligonucleotides (ASOs) are gene silencing tools with the potential to treat disorders of the CNS. Antisense Oligonucleotide Therapeutics in Polyglutamine Disorders. Antisense oligonucleotides (ASOs) have been under intense investigation over recent years as gene silencing tools. Methods: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or . About 12 to 15% of patients with ALS carry a disease-determining genetic mutation. Recently developed antisense oligonucleotides with the ability to inhibit the expression of anti-apoptotic proteins, including Bcl-2, Bcl-xL, FLIP and surviving, have been shown to facilitate tumor . Recently, a disease-modifying antisense oligonucleotide (ASO) agent was approved for spinal muscular atrophy, suggesting ASOs will fulfill their early promise and become a significant new therapeutic category for neurodegenerative disorders . The NIHR Sheffield BRC is supporting research into an experimental antisense oligonucleotide (ASO) gene therapy for patients with motor neurone disease linked to mutations in the SOD1 (copper-zinc superoxide dismutase 1) gene. The primary end point was the . P Duarte, Jean-Cosme Dodart, Rui Jorge Nobre, Luis Pereira de Almeida, Antisense oligonucleotide therapeutics in neurodegenerative diseases: the case of polyglutamine disorders, Brain, Volume 143, Issue 2, . AntiSense oligonucleotides (ASO): a New Innovative Therapy for The Treatment of Neurodegenerative Disorders Dr. Francesca Bertino , 6 months ago 0 4 min read Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis caused by a mutation in SOD1, suggesting that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins . Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. Skip to main content. In HD, ASOs prevent the transcription of mHtt. cancer, and neurodegenerative diseases. With a long tradition and wide readership, IMR Press is dedicated to making positive contributions to academics, corporate libraries as well as to readers and authors. The internalization of ASOs is not necessarily linked to a single pathway. There currently is no effective treatment for this relentlessly progressive and fatal disease. (2019) Antisense oligonucleotide treatment ameliorates IFN--induced proteinuria in APOL1-transgenic mice. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target . 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