Gene Therapy in Models of Severe Epilepsy due to Sodium Channelopathy

Goldberg, Ethan M.

doi:10.1177/1535759720930044

Cited by 4 publications

(5 citation statements)

References 15 publications

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“…Therefore, the simplicity of sgRNA production has made it possible to generate gene libraries, gain and loss of valuable function for genetic screens and genetic therapy, which can be applied for either human, mouse, and primates studies (Cong et al, 2013). This demonstrates that features of given genetic epilepsy can be treated or even prevented (Goldberg, 2020).…”

Section: Clustered Regularly Interspaced Short Palindromic Repeats/cas9mentioning

confidence: 99%

“…With successive innovations, the CRISPR/Cas9 system has become widely adopted for genome engineering and is increasingly regarded as a clinical intervention for specific genome editing ( Lee H. B. et al, 2016 ). The CRISPR technique is highly relevant to the field of genetic epilepsy as either dominant heterozygous pathogenic missense variation or small insertion/deletion could be targeted for correction using this technique ( Goldberg, 2020 ).…”

Section: Interventionmentioning

confidence: 99%

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Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

Godoy

Prizon

Rossignoli

et al. 2022

Front. Integr. Neurosci.

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Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.

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Section: Clustered Regularly Interspaced Short Palindromic Repeats/cas9mentioning

confidence: 99%

Section: Interventionmentioning

confidence: 99%

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

Godoy

Prizon

Rossignoli

et al. 2022

Front. Integr. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Gene editing methodologies, the most prominent of which is the CRISPR/Cas9 gene editing system, allow for direct correction of a genetic defect. Briefly, CRISPR/Cas9 is a gene editing approach in which DNA sequences called CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) allow the targeting and destruction of specific DNA targets by Cas (CRISPR-associated) proteins ( 74 ). CRISPR/Cas9 technology may be particularly important for genetic epilepsies since dominant heterozygous missense mutations or small insertion-deletions make up a large percentage of the known pathogenic variations.…”

Section: Therapies For Genetic Epilepsiesmentioning

confidence: 99%

“…CRISPR/Cas9 technology may be particularly important for genetic epilepsies since dominant heterozygous missense mutations or small insertion-deletions make up a large percentage of the known pathogenic variations. These variants make appealing targets for correction with CRISPR/Cas9 ( 74 ), but therapies have yet to emerge for clinical use.…”

Section: Therapies For Genetic Epilepsiesmentioning

confidence: 99%

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

2022

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Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.

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“…In fact, in one study Scn1a-dCas9A is conceived as a preventive treatment (perinatally in pups), while in the other it is delivered in 4-week-old mice, but poor effect on phenotypic manifestations was observed. Therefore, they leave still open the possibility that increasing Scn1a gene is not efficacious in treating the pathology in the chronic phase of the disease [57], when normalization of interneuron activity occurs [58] but seizures are still present.…”

Section: Suntag-c11orf46mentioning

confidence: 99%

CRISPR/dCas9 as a Therapeutic Approach for Neurodevelopmental Disorders: Innovations and Limitations Compared to Traditional Strategies

Ricci

Colasante

2021

Dev Neurosci

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Brain development is a complex process that requires a series of precise and coordinated events to take place. When alterations in some of those events occur, neurodevelopmental disorders (NDDs) may appear, with their characteristic symptoms, including cognitive, social motor deficits, and epilepsy. While pharmacologic treatments have been the only therapeutic options for many years, more recently the research is turning to the direct removal of the underlying genetic cause of each specific NDD. This is possible thanks to the increased knowledge of genetic basis of those diseases and the enormous advances in genome-editing tools. Together with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based strategies, there is a great development also of nuclease defective Cas9 (dCas9) tools that, with an extreme flexibility, allow the recruitment of specific protein functions to the desired genomic sites. In this work, we review dCas9-based tools and discuss all the published applications in the setting of therapeutic approaches for NDDs at the preclinical level. In particular, dCas9-based therapeutic strategies for Dravet syndrome, transcallosal dysconnectivity caused by mutations in C11orf46 gene, and Fragile X syndrome are presented and discussed. A direct comparison with other possible therapeutic strategies, such as classic gene replacement or CRISPR/Cas9-based strategies, is provided. We also highlight not only those aspects that constitute a clear advantage compared to previous strategies but also the main technical hurdles related to their applications that need to be overcome.

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Gene Therapy in Models of Severe Epilepsy due to Sodium Channelopathy

Abstract: [Box: see text]

Cited by 4 publications

References 15 publications

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

CRISPR/dCas9 as a Therapeutic Approach for Neurodevelopmental Disorders: Innovations and Limitations Compared to Traditional Strategies

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