RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement

Abu-Baker, Aida; Kharma, Nawwaf; Perreault, Jonathan; Grant, Alanna; Shekarabi, Masoud; Maios, Claudia; Dona, Michele; Néri, Christian; Parker, Alex; Varin, Luc; Rouleau, Guy

doi:10.1016/j.omtn.2019.02.003

Cited by 14 publications

(6 citation statements)

References 47 publications

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“…Although we detected a small but significant decrease in Becn1 RNA (Figure 6H) when Ct values from siPab samples were normalized to Ct values from siScr samples, there was no significant difference when compared to non-transfected cells (Supplementary Figure S6A) and no defect in autophagosome formation was detected in Pabpn1 knockdown cells (Figure 6I). Previous studies have suggested that a combination of exogenous recombinant PABPN1 and endogenous Pabpn1 knockdown is sufficient to rescue muscle phenotypes in A17.1 mice (Malerba et al, 2017;Abu-Baker et al, 2019;Malerba et al, 2019a). We transfected Pabpn1 +/+ and Pabpn1 +/A17 pharyngeal myoblasts with plasmids encoding FLAG-tagged human PABPN1 (FL-hsPABPN1) (Banerjee et al, 2019) or FL-hsPABPN1 along with siRNA targeting Exon 7 of murine Pabpn1.…”

Section: Resultsmentioning

confidence: 99%

Pharyngeal pathology in a mouse model of oculopharyngeal muscular dystrophy is associated with impaired basal autophagy in myoblasts

Zeuthen

Zhu

et al. 2022

Front. Cell Dev. Biol.

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Oculopharyngeal muscular dystrophy (OPMD) is a late-onset dominant disease that primarily affects craniofacial muscles. Despite the fact that the genetic cause of OPMD is known to be expansion mutations in the gene encoding the nuclear polyadenosine RNA binding protein PABPN1, the molecular mechanisms of pathology are unknown and no pharmacologic treatments are available. Due to the limited availability of patient tissues, several animal models have been employed to study the pathology of OPMD. However, none of these models have demonstrated functional deficits in the muscles of the pharynx, which are predominantly affected by OPMD. Here, we used a knock-in mouse model of OPMD, Pabpn1+/A17, that closely genocopies patients. In Pabpn1+/A17 mice, we detected impaired pharyngeal muscle function, and impaired pharyngeal satellite cell proliferation and fusion. Molecular studies revealed that basal autophagy, which is required for normal satellite cell function, is higher in pharynx-derived myoblasts than in myoblasts derived from limb muscles. Interestingly, basal autophagy is impaired in cells derived from Pabpn1+/A17 mice. Pabpn1 knockdown in pharyngeal myoblasts failed to recapitulate the autophagy defect detected in Pabpn1+/A17 myoblasts suggesting that loss of PABPN1 function does not contribute to the basal autophagy defect. Taken together, these studies provide the first evidence for pharyngeal muscle and satellite cell pathology in a mouse model of OPMD and suggest that aberrant gain of PABPN1 function contributes to the craniofacial pathology in OPMD.

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Section: Resultsmentioning

confidence: 99%

Pharyngeal pathology in a mouse model of oculopharyngeal muscular dystrophy is associated with impaired basal autophagy in myoblasts

Zeuthen

Zhu

et al. 2022

Front. Cell Dev. Biol.

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“… 5 Gene replacement in this case would require a codon-optimized transgene to avoid being silenced by the RNAi or antisense oligonucleotide treatment. This approach has proved beneficial for oculopharyngeal muscular dystrophy in preclinical mouse studies and in theory could be applied to any of the previously mentioned disease categories 31 …”

Section: Genetic Treatment Strategies Employed In Neuromuscular Medicinementioning

confidence: 99%

“…This approach has proved beneficial for oculopharyngeal muscular dystrophy in preclinical mouse studies and in theory could be applied to any of the previously mentioned disease categories. 31 Knockdown treatments are not yet clinically available for dominantly inherited myopathies. Several studies are currently in preclinical development for disorders such as facioscapulohumeral muscular dystrophy and centronuclear myopathy due to DNM2 mutations.…”

Section: Commentmentioning

confidence: 99%

Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies

Findlay¹,

Weihl²

2022

CONTINUUM: Lifelong Learning in Neurology

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PURPOSE OF REVIEW: This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy.RECENT FINDINGS: Gene therapies have become a reality for several neuromuscular disorders. Exon-skipping and (in Europe) ribosomal read-through approaches are currently available to a subset of patients with Duchenne muscular dystrophy. Microdystrophin gene replacement has shown promise and is nearing the final stages of clinical trials. Numerous gene-based therapies for other muscular dystrophies and congenital myopathies are progressing toward approval as well.SUMMARY: Muscular dystrophies and congenital myopathies are a heterogenous group of hereditary muscle disorders. Confirming a diagnosis with genetic testing is not only critical for guiding management, but also an actual prerequisite for current and future gene therapies. Recessive loss-of-function or dominant haploinsufficiency disorders may be treated with gene replacement strategies, whereas dominant negative and toxic gain-of-function disorders are best addressed with a variety of knockdown approaches. It is important to recognize that many therapeutics are mutation specific and will only benefit a subset of individuals with a specific disease.

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“…Concerning nucleic acid-based therapy, RNA therapy has shown promising results in treating several human malignances [ 98 , 99 , 100 ], including viral diseases [ 101 ]. There are different approaches to targeting RNA in the human body: antisense oligonucleotides (ASOs) [ 102 ], microRNAs (miRNAs) [ 103 ], small interfering RNAs (siRNAs) [ 104 ], RNA vaccines [ 105 , 106 ], and CRISPR/Cas systems [ 101 ], among others. Nevertheless, due to poor RNA stability inside the body [ 107 ], inefficient delivery to the target site, and low bioavailability [ 108 , 109 ], RNA delivery remains one of the biggest challenges in RNA therapy [ 104 , 110 ].…”

Section: The Landscape Of Nucleic Acid-based Therapies In Sars-cov-2mentioning

confidence: 99%

Transcriptomics and RNA-Based Therapeutics as Potential Approaches to Manage SARS-CoV-2 Infection

Arriaga-Canon

Contreras-Espinosa

Rebollar-Vega

et al. 2022

IJMS

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SARS-CoV-2 is a coronavirus family member that appeared in China in December 2019 and caused the disease called COVID-19, which was declared a pandemic in 2020 by the World Health Organization. In recent months, great efforts have been made in the field of basic and clinical research to understand the biology and infection processes of SARS-CoV-2. In particular, transcriptome analysis has contributed to generating new knowledge of the viral sequences and intracellular signaling pathways that regulate the infection and pathogenesis of SARS-CoV-2, generating new information about its biology. Furthermore, transcriptomics approaches including spatial transcriptomics, single-cell transcriptomics and direct RNA sequencing have been used for clinical applications in monitoring, detection, diagnosis, and treatment to generate new clinical predictive models for SARS-CoV-2. Consequently, RNA-based therapeutics and their relationship with SARS-CoV-2 have emerged as promising strategies to battle the SARS-CoV-2 pandemic with the assistance of novel approaches such as CRISPR-CAS, ASOs, and siRNA systems. Lastly, we discuss the importance of precision public health in the management of patients infected with SARS-CoV-2 and establish that the fusion of transcriptomics, RNA-based therapeutics, and precision public health will allow a linkage for developing health systems that facilitate the acquisition of relevant clinical strategies for rapid decision making to assist in the management and treatment of the SARS-CoV-2-infected population to combat this global public health problem.

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RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement

Cited by 14 publications

References 47 publications

Pharyngeal pathology in a mouse model of oculopharyngeal muscular dystrophy is associated with impaired basal autophagy in myoblasts

Pharyngeal pathology in a mouse model of oculopharyngeal muscular dystrophy is associated with impaired basal autophagy in myoblasts

Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies

Transcriptomics and RNA-Based Therapeutics as Potential Approaches to Manage SARS-CoV-2 Infection

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