A comprehensive approach to identifying repurposed drugs to treat <i><scp>SCN</scp>8A</i> epilepsy

Atkin, Talia A.; Maher, Chani M.; Gerlach, Aaron C.; Antonio, Brett; Santos, Sonia Carvalho; Padilla, Karen; Rader, Julie Ann; Krafte, Douglas S.; Fox, Matthew A.; Stewart, Gregory R.; Petrovski, Steve; Devinsky, Orrin; Might, Matthew; Petrou, Steven; Goldstein, David B.

doi:10.1111/epi.14037

Cited by 31 publications

(25 citation statements)

References 29 publications

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“…Interestingly, a recent study has shown that the sodium channel modulator GS967 might be an effective treatment of SCN8A ‐DEE in mice . In a high‐throughput drug screening study in an SCN8A GoF cell line, 90 drugs were found to significantly inhibit the sodium influx . Four drugs of potential clinical interest (amitriptyline, carvedilol, nilvadipine, and carbamazepine) were further investigated and demonstrated concentration‐dependent inhibition of the sodium channel currents.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

2019

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Pathogenic variants in SCN8A have originally been described in patients with developmental and epileptic encephalopathy (DEE). However, recent studies have shown that SCN8A variants can be associated with a broader phenotypic spectrum, including the following: (1) Patients with early onset, severe DEE, developing severe cognitive and motor regression, pyramidal/extrapyramidal signs, and cortical blindness. Severe SCN8A-DEE is characterized by intractable seizures beginning in the first months of life. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms (apnea, cyanosis, mydriasis), evolving to clonic or bilateral tonic-clonic manifestations. Spasm-like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. Electroencephalograms (EEGs) show progressive background deterioration and multifocal abnormalities, predominant in the posterior regions. (2) Sporadic and familial patients with mild-tomoderate intellectual disability, discrete neurological signs, and treatable epilepsy. EEG is abnormal in half of the cases, showing multifocal or diffuse epileptiform abnormalities. (3) Familial cases with benign infantile seizures, sometimes associated with paroxysmal dyskinesia later in life, with no other neurological deficits, normal cognition, and usually normal interictal EEG. (4) Patients without epilepsy but with cognitive and/or behavioral disturbances, or with movement disorders. Extrapyramidal features, such as dyskinesia, ataxia, and choreoathetosis are common in all groups. Early death has been reported in about 5% of the patients, most often in the subgroup of severe DEE. Premature death occurs during early childhood and often for causes other than sudden unexpected death in epilepsy. All epilepsy subgroups exhibit better seizure control with sodium channel blockers, usually at supratherapeutic doses in the severe cases. In severe SCN8A-DEE, ketogenic diet often has a good effect, whereas levetiracetam has a negative effect, if any. The familial SCN8A-related epilepsies show an autosomal dominant pattern of inheritance, whereas the vast majority of SCN8A-DEEs occur de novo.

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Section: Discussionmentioning

confidence: 99%

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

2019

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“…For instance, metformin has been tested in Mycobacterium tuberculosis infections [ 29 , 37 ] since, by activating the 5ʹ-adenosine monophosphate-activated protein kinase (MAPK), it interferes with the mitochondrial respiratory chain, inducing the production of reactive oxygen species and macrophage activation. Other repurposed drugs to treat epilepsy [ 38 ], peptic ulcers [ 39 ], cancer [ 40 ], anti-inflammatory drugs [ 41 , 42 , 43 , 44 , 45 , 46 ], antibodies [ 47 , 48 , 49 ], and hypoglycemic compounds [ 50 ] or sphingosine-1-phosphate receptor agonists [ 51 ] have been investigated.…”

Section: Nonantibiotic Based Therapiesmentioning

confidence: 99%

Postbiotic-Enabled Targeting of the Host-Microbiota-Pathogen Interface: Hints of Antibiotic Decline?

et al. 2020

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Mismanagement of bacterial infection therapies has undermined the reliability and efficacy of antibiotic treatments, producing a profound crisis of the antibiotic drug market. It is by now clear that tackling deadly infections demands novel strategies not only based on the mere toxicity of anti-infective compounds. Host-directed therapies have been the first example as novel treatments with alternate success. Nevertheless, recent advances in the human microbiome research have provided evidence that compounds produced by the microbial metabolism, namely postbiotics, can have significant impact on human health. Such compounds target the host-microbe-pathogen interface rescuing biotic and immune unbalances as well as inflammation, thus providing novel therapeutic opportunities. This work discusses critically, through literature review and personal contributions, these novel nonantibiotic treatment strategies for infectious disease management and resistance prevention, which could represent a paradigm change rocking the foundation of current antibiotic therapy tenets.

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“…For example, a fluorescence-based sodium flux assay for inhibitory activity in a SCN8A R1872Q mutant cell line identified 4 FDA-approved candidate drugs for SCN8Arelated epilepsy. 66 Based on the above considerations, we see as research priorities (1) the identification of mechanisms through which existing FDA-approved drugs affect epileptogenesis and (2) the study of existing FDA-approved drugs in a range of cellular and animal models of epileptogenesis. For example, existing immunomodulatory drugs used for multiple sclerosis may have unexplored antiepileptogenic potential and could be repurposed for epilepsy prevention.…”

Section: Repurposing Of Fda-approved Drugsmentioning

confidence: 99%

Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

et al. 2020

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Area II of the 2014 Epilepsy Research Benchmarks aims to establish goals for preventing the development and progression of epilepsy. In this review, we will highlight key advances in Area II since the last summary of research progress and opportunities was published in 2016. We also highlight areas of investigation that began to develop before 2016 and in which additional progress has been made more recently.

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A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy

Abstract: A comprehensive drug repurposing screen identified potential new candidates for the treatment of epilepsy caused by the R1872Q mutation in the SCN8A gene.

Cited by 31 publications

References 29 publications

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

Postbiotic-Enabled Targeting of the Host-Microbiota-Pathogen Interface: Hints of Antibiotic Decline?

Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

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