Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS

Hirunagi, Tomoki; Sahashi, Kentaro; Leu, Angel; Nguyen, Michelle; Mukthavaram, Rajesh; Karmali, Priya; Chivukula, Padmanabh; Tohnai, Genki; Iida, Madoka; Onodera, Kazunari; Ohyama, Manabu; Okada, Yohei; Katsuno, Masahisa

doi:10.1016/j.omtn.2021.02.007

Cited by 19 publications

(10 citation statements)

References 44 publications

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“…The lipids can either be solid or liquid-crystalline or a combination hereof and are manufactured in well-defined combinations with surfactants and other components, including targeting ligands to increase their pharmacokinetic properties[ 73 ]. Due to their large size, LNPs do not cross the BBB on their own, but ICV injected LNPs have shown widespread distribution and gene knockdown in the CNS[ 74 , 75 ]. A drawback of LNPs is their potential toxicity and immunogenicity[ 76 ].…”

Section: Delivery Of Rna Drugs To the Cnsmentioning

confidence: 99%

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Holm

Hansen²,

Klitgaard³

et al. 2022

RNA Biology

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RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. Abbreviations 2’-MOE: 2’- O -(2-methoxyethyl); 2’- O -Me: 2’- O -methyl; 2’-F: 2’-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin

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Section: Delivery Of Rna Drugs To the Cnsmentioning

confidence: 99%

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Holm

Hansen²,

Klitgaard³

et al. 2022

RNA Biology

View full text Add to dashboard Cite

show abstract

“…Recently, we reported the therapeutic potential of lipid nanoparticle (LNP)-mediated delivery of siRNA targeting CAG expansions for allele selective suppression of polyQ-expanded proteins in the mouse CNS [ 50 ]. The siRNA that was fully complementary to the CAG repeats did not show allele selectivity, whereas the siRNA with a central mismatch and UNA substitutions (REPU910) achieved mutant-allele selective suppression of polyQ-expanded proteins.…”

Section: Nucleic Acid-based Therapeutic Approach For Sbmamentioning

confidence: 99%

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

Hirunagi

Sahashi

Meilleur

et al. 2022

Genes

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The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA.

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“…CAG-siRNA specifically silences the alleles of estrogen receptor with CAG repeats in fibroblasts, inhibits the generation of polyQ protein in the central nervous system to treat the SCA, spinal cord and medullary atrophy, HD, dentatered-globus pallidus atrophy, etc., ( Hirunagi et al, 2021 ). Intravenous siRNAs reduce the Axin-3 expression, alleviate the dyskinesia and improve the striatal and cerebellar lesions in SCA3 mice ( Conceição et al, 2016 ).…”

Section: Rna Interferencementioning

confidence: 99%

Combinational treatments of RNA interference and extracellular vesicles in the spinocerebellar ataxia

Ding

Zhang

Liu

2022

Front. Mol. Neurosci.

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Spinocerebellar ataxia (SCA) is an autosomal dominant neurodegenerative disease (ND) with a high mortality rate. Symptomatic treatment is the only clinically adopted treatment. However, it has poor effect and serious complications. Traditional diagnostic methods [such as magnetic resonance imaging (MRI)] have drawbacks. Presently, the superiority of RNA interference (RNAi) and extracellular vesicles (EVs) in improving SCA has attracted extensive attention. Both can serve as the potential biomarkers for the diagnosing and monitoring disease progression. Herein, we analyzed the basis and prospect of therapies for SCA. Meanwhile, we elaborated the development and application of miRNAs, siRNAs, shRNAs, and EVs in the diagnosis and treatment of SCA. We propose the combination of RNAi and EVs to avoid the adverse factors of their respective treatment and maximize the benefits of treatment through the technology of EVs loaded with RNA. Obviously, the combinational therapy of RNAi and EVs may more accurately diagnose and cure SCA.

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Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS

Cited by 19 publications

References 44 publications

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

Combinational treatments of RNA interference and extracellular vesicles in the spinocerebellar ataxia

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