The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

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The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

10.1101/2020.07.31.216721 ◽

2020 ◽

Cited By ~ 1

Author(s):

Paymaan Jafar-nejad ◽

Berit Powers ◽

Armand Soriano ◽

Hien Zhao ◽

Daniel A. Norris ◽

...

Keyword(s):

Motor Neurons ◽

Muscular Atrophy ◽

Neurological Diseases ◽

Cell Types ◽

Rnase H ◽

Central Administration ◽

Spinal Motor Neurons ◽

New Class ◽

Wide Range ◽

Therapeutic Development

ABSTRACTAntisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing the field to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal, and non-neuronal cells. Therefore, it is critically important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and robust activity throughout the CNS in neurons, oligodendrocytes, astrocytes, and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

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

eLife ◽

10.7554/elife.50848 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

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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Epigenetic Regulation of Cannabinoid-Mediated Attenuation of Inflammation and Its Impact on the Use of Cannabinoids to Treat Autoimmune Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22147302 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7302

Author(s):

Bryan Latrell Holloman ◽

Mitzi Nagarkatti ◽

Prakash Nagarkatti

Keyword(s):

Autoimmune Diseases ◽

Chronic Inflammation ◽

Cannabinoid Receptors ◽

T Regulatory Cells ◽

Neurological Diseases ◽

Suppressor Cells ◽

The Body ◽

New Class ◽

Wide Range ◽

Clinical Disorders

Chronic inflammation is considered to be a silent killer because it is the underlying cause of a wide range of clinical disorders, from cardiovascular to neurological diseases, and from cancer to obesity. In addition, there are over 80 different types of debilitating autoimmune diseases for which there are no cure. Currently, the drugs that are available to suppress chronic inflammation are either ineffective or overtly suppress the inflammation, thereby causing increased susceptibility to infections and cancer. Thus, the development of a new class of drugs that can suppress chronic inflammation is imperative. Cannabinoids are a group of compounds produced in the body (endocannabinoids) or found in cannabis (phytocannabinoids) that act through cannabinoid receptors and various other receptors expressed widely in the brain and immune system. In the last decade, cannabinoids have been well established experimentally to mediate anti-inflammatory properties. Research has shown that they suppress inflammation through multiple pathways, including apoptosis and inducing immunosuppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Interestingly, cannabinoids also mediate epigenetic alterations in genes that regulate inflammation. In the current review, we highlight how the epigenetic modulations caused by cannabinoids lead to the suppression of inflammation and help identify novel pathways that can be used to target autoimmune diseases.

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Establishment of a Human Induced Pluripotent Stem Cell-Derived Neuromuscular Co-Culture Under Optogenetic Control

10.1101/2020.04.10.036400 ◽

2020 ◽

Cited By ~ 1

Author(s):

Elliot W. Swartz ◽

Greg Shintani ◽

Jijun Wan ◽

Joseph S. Maffei ◽

Sarah H. Wang ◽

...

Keyword(s):

Motor Neurons ◽

Induced Pluripotent Stem Cell ◽

Cell Types ◽

Calcium Flux ◽

Electrode Arrays ◽

Spinal Motor Neurons ◽

Culture Model ◽

Skeletal Myotubes ◽

Induced Pluripotent

SummaryThe failure of the neuromuscular junction (NMJ) is a key component of degenerative neuromuscular disease, yet how NMJs degenerate in disease is unclear. Human induced pluripotent stem cells (hiPSCs) offer the ability to model disease via differentiation toward affected cell types, however, the re-creation of an in vitro neuromuscular system has proven challenging. Here we present a scalable, all-hiPSC-derived co-culture system composed of independently derived spinal motor neurons (MNs) and skeletal myotubes (sKM). In a model of C9orf72-associated disease, co-cultures form functional NMJs that can be manipulated through optical stimulation, eliciting muscle contraction and measurable calcium flux in innervated sKM. Furthermore, co-cultures grown on multi-electrode arrays (MEAs) permit the pharmacological interrogation of neuromuscular physiology. Utilization of this co-culture model as a tunable, patient-derived system may offer significant insights into NMJ formation, maturation, repair, or pathogenic mechanisms that underlie NMJ dysfunction in disease.

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Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

Journal of Experimental Neuroscience ◽

10.4137/jen.s33122 ◽

2016 ◽

Vol 10 ◽

pp. JEN.S33122 ◽

Cited By ~ 36

Author(s):

Saif Ahmad ◽

Kanchan Bhatia ◽

Annapoorna Kannan ◽

Laxman Gangwani

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Skeletal Muscle Atrophy ◽

Spinal Motor Neurons ◽

Low Levels ◽

Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

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Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease

Physiological Reviews ◽

10.1152/physrev.00036.2006 ◽

2007 ◽

Vol 87 (3) ◽

pp. 799-823 ◽

Cited By ~ 196

Author(s):

Mark F. Mehler ◽

John S. Mattick

Keyword(s):

Nervous System ◽

Rna Editing ◽

Neurological Diseases ◽

Cell Types ◽

State Transitions ◽

Long Term Memory ◽

Protein Coding ◽

Continuous State ◽

Wide Range

The progressive maturation and functional plasticity of the nervous system in health and disease involve a dynamic interplay between the transcriptome and the environment. There is a growing awareness that the previously unexplored molecular and functional interface mediating these complex gene-environmental interactions, particularly in brain, may encompass a sophisticated RNA regulatory network involving the twin processes of RNA editing and multifaceted actions of numerous subclasses of non-protein-coding RNAs. The mature nervous system encompasses a wide range of cell types and interconnections. Long-term changes in the strength of synaptic connections are thought to underlie memory retrieval, formation, stabilization, and effector functions. The evolving nervous system involves numerous developmental transitions, such as neurulation, neural tube patterning, neural stem cell expansion and maintenance, lineage elaboration, differentiation, axonal path finding, and synaptogenesis. Although the molecular bases for these processes are largely unknown, RNA-based epigenetic mechanisms appear to be essential for orchestrating these precise and versatile biological phenomena and in defining the etiology of a spectrum of neurological diseases. The concerted modulation of RNA editing and the selective expression of non-protein-coding RNAs during seminal as well as continuous state transitions may comprise the plastic molecular code needed to couple the intrinsic malleability of neural network connections to evolving environmental influences to establish diverse forms of short- and long-term memory, context-specific behavioral responses, and sophisticated cognitive capacities.

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CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review

Diagnostics ◽

10.3390/diagnostics11091522 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1522

Author(s):

Karsten Krause ◽

Maximilian Wulf ◽

Paula Sommer ◽

Katalin Barkovits ◽

Matthias Vorgerd ◽

...

Keyword(s):

Motor Neurons ◽

Muscular Atrophy ◽

Neurological Diseases ◽

Neuromuscular Disorders ◽

Disease Onset ◽

Neuromuscular Diseases ◽

Promising Alternative ◽

Alternative Techniques ◽

Subordinate Role ◽

Lateral Sclerosis

Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications.

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Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

Brain Sciences ◽

10.3390/brainsci11020152 ◽

2021 ◽

Vol 11 (2) ◽

pp. 152 ◽

Cited By ~ 1

Author(s):

Daisy Edmison ◽

Luyu Wang ◽

Swetha Gowrishankar

Keyword(s):

Motor Neurons ◽

Membrane Trafficking ◽

Neurological Diseases ◽

Cellular Component ◽

Diverse Group ◽

Microtubule Severing ◽

Spinal Motor Neurons ◽

Hereditary Spastic Paraplegias ◽

Spinal Motor ◽

Genes Encoding

Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer’s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models.

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