Antisense Oligonucleotides for the Study and Treatment of ALS

Boros, Benjamin D.; Schoch, Kathleen M.; Kreple, Collin J.; Miller, Timothy M

doi:10.1007/s13311-022-01247-2

Cited by 36 publications

(27 citation statements)

References 101 publications

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“…As few examples, other more specific strategies, such as gene and cell therapies are promising approaches for these diseases [ 302 , 303 , 304 ]. These approaches rely on the use of stem cells and of vectors conceived on the bases of the recently approved gene therapies adopted for SMA [ 305 ], as well as on the use of synthetic antisense oligonucleotides specifically targeting the mRNA transcript encoding the mutant protein responsible for a given MND [ 306 , 307 , 308 , 309 , 310 ]. The present limitation of their use is the capability to deliver the various vectors or nucleotides in the affected tissues in order to be taken up from cells involved in the disease.…”

Section: Discussionmentioning

confidence: 99%

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Tedesco

Ferrari

Cozzi

et al. 2022

IJMS

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Motoneuron diseases (MNDs) are neurodegenerative conditions associated with death of upper and/or lower motoneurons (MNs). Proteostasis alteration is a pathogenic mechanism involved in many MNDs and is due to the excessive presence of misfolded and aggregated proteins. Protein misfolding may be the product of gene mutations, or due to defects in the translation process, or to stress agents; all these conditions may alter the native conformation of proteins making them prone to aggregate. Alternatively, mutations in members of the protein quality control (PQC) system may determine a loss of function of the proteostasis network. This causes an impairment in the capability to handle and remove aberrant or damaged proteins. The PQC system consists of the degradative pathways, which are the autophagy and the proteasome, and a network of chaperones and co-chaperones. Among these components, Heat Shock Protein 70 represents the main factor in substrate triage to folding, refolding, or degradation, and it is assisted in this task by a subclass of the chaperone network, the small heat shock protein (sHSPs/HSPBs) family. HSPBs take part in proteostasis by bridging misfolded and aggregated proteins to the HSP70 machinery and to the degradative pathways, facilitating refolding or clearance of the potentially toxic proteins. Because of its activity against proteostasis alteration, the chaperone system plays a relevant role in the protection against proteotoxicity in MNDs. Here, we discuss the role of HSPBs in MNDs and which HSPBs may represent a valid target for therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Tedesco

Ferrari

Cozzi

et al. 2022

IJMS

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“…Moreover, preclinical trials have also been undertaken to ameliorate TDP-43 pathology via modulation of TDP-43-regulating proteins such as Ataxin-2 [63,64], which are now in Phase I clinical trials (ClinicalTrials.gov, Identifier# NCT04494256). Further identification of disease-relevant targets that are able to protect against neurodegeneration caused by TDP-43 dysfunction offers hope for development of additional improved therapeutics, potentially including antisense approaches, for ALS and FTD (55). Limitations Among the limitations of our work, we analysed a single timepoint of administration of the Chop ASO, namely two weeks prior to the removal of Dox from rNLS8 mice.…”

Section: Discussionmentioning

confidence: 99%

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

Luan

Wright

Brown-Wright

et al. 2022

Preprint

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TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however activation of cell stress pathways may contribute to pathogenesis. We therefore sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS/FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical ISR effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

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“…With the development of nusinersen, an ASO indicated for spinal muscular atrophy, the use of ASOs in CNS disorders has continued to expand, and several ASOs targeting genes implicated in neurodegenerative diseases are currently in clinical trial. For example, tofersen, a 2'-MOE ASO designed to target superoxide dismutase (SOD1) for amyotrophic lateral sclerosis (ALS) (Miller et al, 2020;Miller et al, 2022) and BIIB080, an ASO that targets human MAPT gene to prevent tau protein production for tauopathies including AD (Mummery et al, 2021). On the other hand, there are ASOs, which were not effective in human clinical trials resulting in the clinical trial halt.…”

Section: Discussionmentioning

confidence: 99%

“…Upon binding to target RNA, the resulting ASO:RNA pairing recruits the enzyme RNaseH to degrade the mRNA transcript. This strategy has been used to lower the production of disease-causing genes/proteins in several diseases including amyotrophic lateral sclerosis (Smith et al, 2006; Jiang et al, 2016; Boros et al, 2022), Huntington’s disease (Kordasiewicz et al, 2012; Lane et al, 2018; Kingwell, 2021), and spinal muscular atrophy (Wurster & Ludolph, 2018).…”

Section: Introductionmentioning

confidence: 99%

Evaluating the efficacy of commercially available antisense oligonucleotides to reduce mouse and human tauin vivo

Schoch

Miller

2022

Preprint

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Tauopathies, including Alzheimers disease (AD), are neurodegenerative diseases characterized by the accumulation of tau protein encoded by the MAPT (Microtubule Associated Protein Tau) gene. Various strategies targeting mechanisms to reduce tau pathology have been proposed and several tau-directed therapies are being investigated in clinical trials. Our lab previously developed a novel strategy to lower tau protein levels using antisense oligonucleotides (ASOs), showing that human tau (hTau) reduction in aged PS19 tauopathy mice reversed phosphorylated tau pathology, spared neurons, and prolonged survival. Currently, the tau-lowering ASO is being evaluated in the clinical trials with successful phase 1b results. Similarly, preclinical and clinical studies have demonstrated the use of other ASOs as effective therapeutic strategies. Acquiring ASOs for research purposes may be limited by partnerships with pharmaceutical companies. However, ASOs can be obtained through commercial vendors. The current study evaluates the efficacy of mouse and human tau-targeting ASOs obtained from a commercial vendor in various mouse models. We show that mice treated with purchased ASOs distribute among various brain cell types including neurons, microglia, and astrocytes. Mice treated with tau lowering ASOs show decreased mouse or human tau mRNA and protein levels. In addition, human tau lowering ASO-treated PS19 mice showed decreased phosphorylated tau (AT8) and gliosis relative to saline-treated PS19 mice. The results obtained in PS19 mice are consistent with data obtained from our previous study using a non-commercial tau-lowering ASO. Overall, the present study demonstrates the efficacy of commercially-available tau targeting ASOs in vivo to support their broad use by researchers.

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Antisense Oligonucleotides for the Study and Treatment of ALS

Cited by 36 publications

References 101 publications

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS/FTD

Evaluating the efficacy of commercially available antisense oligonucleotides to reduce mouse and human tauin vivo

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