scholarly journals Antisense Oligonucleotide Therapies for Neurodegenerative Diseases

2019 ◽  
Vol 42 (1) ◽  
pp. 385-406 ◽  
Author(s):  
C. Frank Bennett ◽  
Adrian R. Krainer ◽  
Don W. Cleveland
Keyword(s):  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Great Promise ◽  
Disease Symptoms ◽  
Therapeutic Platform ◽  
Lateral Sclerosis

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.

scholarly journals Antisense oligonucleotides

2019 ◽  
Vol 5 (2) ◽  
pp. e323 ◽  
Author(s):  
Daniel R. Scoles ◽  
Eric V. Minikel ◽  
Stefan M. Pulst
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Target Sequence ◽  
Spinocerebellar Ataxias ◽  
Complementary Oligonucleotide ◽  
Disease Modifying ◽  
Lateral Sclerosis

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. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.

scholarly journals Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients

2021 ◽  
Vol 11 (3) ◽  
pp. 296
Author(s):  
Lars Hendrik Müschen ◽  
Alma Osmanovic ◽  
Camilla Binz ◽  
Konstantin F. Jendretzky ◽  
Gresa Ranxha ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Total Protein ◽  
Antisense Oligonucleotide ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Clinical Signs ◽  
Central Nervous System Disease ◽  
Oligoclonal Bands ◽  
System Disease

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

scholarly journals Wrangling RNA: Antisense oligonucleotides for neurological disorders

2019 ◽  
Vol 11 (511) ◽  
pp. eaay2069 ◽  
Author(s):  
Kevin Talbot ◽  
Matthew J. A. Wood
Keyword(s):  
Spinal Muscular Atrophy ◽  
Effective Treatment ◽  
Neurological Disorders ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Antisense Oligonucleotide Therapy

Effective treatment of spinal muscular atrophy with antisense oligonucleotide therapy opens the door to treating other neurological disorders with this approach.

scholarly journals Increased Chitotriosidase1 Concentration Following Nusinersen Treatment in Spinal Muscular Atrophy

2021 ◽  
Author(s):  
Maren Freigang ◽  
Petra Steinacker ◽  
Claudia Diana Wurster ◽  
Olivia Schreiber-Katz ◽  
Alma Osmanovic ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Communicating Hydrocephalus ◽  
Increased Risk ◽  
Treatment Naïve ◽  
Neuro Inflammation ◽  
The Impact

Abstract BackgroundStudies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum / CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen. MethodsIn this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.ResultsCHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.ConclusionsCHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.

scholarly journals Antisense Drugs Make Sense for Neurological Diseases

2021 ◽  
Vol 61 (1) ◽  
pp. 831-852
Author(s):  
C. Frank Bennett ◽  
Holly B. Kordasiewicz ◽  
Don W. Cleveland
Keyword(s):  
Neurodegenerative Diseases ◽  
Rna Splicing ◽  
Genetic Basis ◽  
Neurological Diseases ◽  
Intrathecal Injection ◽  
Long Term Effects ◽  
New Class ◽  
Therapeutic Platform ◽  
Lateral Sclerosis

The genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of drugs—antisense oligonucleotides (ASOs)—show promise as a therapeutic platform for treating neurological diseases. ASOs are designed to bind to the RNAs either by promoting degradation of the targeted RNA or by elevating expression by RNA splicing. Intrathecal injection into the cerebral spinal fluid results in broad distribution of antisense drugs and long-term effects. Approval of nusinersen in 2016 demonstrated that effective treatments for neurodegenerative diseases can be identified and that treatments not only slow disease progression but also improve some symptoms. Antisense drugs are currently in development for amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and Angelman syndrome, and several drugs are in late-stage research for additional neurological diseases. This review highlights the advances in antisense technology as potential treatments for neurological diseases.

scholarly journals Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Maren Freigang ◽  
Petra Steinacker ◽  
Claudia Diana Wurster ◽  
Olivia Schreiber-Katz ◽  
Alma Osmanovic ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Communicating Hydrocephalus ◽  
Increased Risk ◽  
Treatment Naïve ◽  
Neuro Inflammation ◽  
The Impact

Abstract Background Studies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen. Methods In this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed. Results CHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy. Conclusions CHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.

scholarly journals Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA)

2018 ◽  
Vol 8 (12) ◽  
pp. 212 ◽  
Author(s):  
Darija Šoltić ◽  
Melissa Bowerman ◽  
Joanne Stock ◽  
Hannah Shorrock ◽  
Thomas Gillingwater ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Spinal Muscular Atrophy ◽  
Calcium Binding ◽  
Bioinformatics Analysis ◽  
Muscular Atrophy ◽  
Molecular Pathways ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Therapeutic Development ◽  
Lateral Sclerosis

Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritized as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles and molecular pathways, including metabolism of proteins and vesicle-mediated transport—both of which converge on endoplasmic reticulum (ER)-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases.

scholarly journals Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Tai-Heng Chen ◽  
Jun-An Chen
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Cell Types ◽  
Spinal Motor Neurons ◽  
Potential Applications ◽  
The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

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