Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome

Miziak, Barbara; Czuczwar, Stanisław J.

doi:10.1080/17460441.2021.1857722

Cited by 11 publications

(8 citation statements)

References 101 publications

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“…Studies in patients aged 2 to 25 years with drug-resistant epilepsy, including DS, found a 50-99% reduction in seizures and an improvement in cognitive functions (reviewed in Ref. 105,106). In addition, various drugs regulating sodium channel activity are also potential future medicines for DS.…”

Section: Therapeutic Perspectives For Dsmentioning

confidence: 99%

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

et al. 2021

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Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug-resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up-to-date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families.

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Section: Therapeutic Perspectives For Dsmentioning

confidence: 99%

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

et al. 2021

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“…The TANGO strategy has been applied in the treatment of Dravet syndrome (DS), a rare autosomal dominant drug-resistant epilepsy that is caused by mutations in the SCN1A (Voltage-Gated Sodium Channel Alpha Subunit 1) gene. In a preclinical mouse model, the ASO, STK-001, prevented the inclusion of a mutated Scn1a gene exon leading to the increase of functional Scn1a mRNA concentration and restoring the pathology [ 39 ].…”

Section: Rna-based Therapymentioning

confidence: 99%

Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

Lee

Wang

2022

Biomedicines

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The development of new sequencing technologies in the post-genomic era has accelerated the identification of causative mutations of several single gene disorders. Advances in cell and animal models provide insights into the underlining pathogenesis, which facilitates the development and maturation of new treatment strategies. The progress in biochemistry and molecular biology has established a new class of therapeutics—the short RNAs and expressible long RNAs. The sequences of therapeutic RNAs can be optimized to enhance their stability and translatability with reduced immunogenicity. The chemically-modified RNAs can also increase their stability during intracellular trafficking. In addition, the development of safe and high efficiency carriers that preserves the integrity of therapeutic RNA molecules also accelerates the transition of RNA therapeutics into the clinic. For example, for diseases that are caused by genetic defects in a specific protein, an effective approach termed “protein replacement therapy” can provide treatment through the delivery of modified translatable mRNAs. Short interference RNAs can also be used to treat diseases caused by gain of function mutations or restore the splicing aberration defects. Here we review the applications of newly developed RNA-based therapeutics and its delivery and discuss the clinical evidence supporting the potential of RNA-based therapy in single-gene neurological disorders.

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“…Febrile seizure is a typical feature of the early stage (“febrile” phase) of DS. Patients usually have seizures (mostly clonic generalized and unilateral motor seizures) after a fever, vaccination, or warm bath in the first year of life (usually between 4 and 8 months) and often progress to status epilepticus ( 5 – 7 ). This phase is followed by the “worsening” phase at the age of 1–4 years, characterized by the presence of additional seizure types (such as generalized motor, atypical, myoclonic, and absence seizures) with cognitive, behavioral, and motor impairments in which thermogenic factors can still induce seizures ( 5 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Patients usually have seizures (mostly clonic generalized and unilateral motor seizures) after a fever, vaccination, or warm bath in the first year of life (usually between 4 and 8 months) and often progress to status epilepticus ( 5 – 7 ). This phase is followed by the “worsening” phase at the age of 1–4 years, characterized by the presence of additional seizure types (such as generalized motor, atypical, myoclonic, and absence seizures) with cognitive, behavioral, and motor impairments in which thermogenic factors can still induce seizures ( 5 – 8 ). Finally, the “worsening” phase is followed by the “stabilization” phase, in which the frequency of seizures is reduced compared with the febrile stage (generalized tonic–clonic seizures and tonic seizures are still observed), but cognitive and psychomotor disorders and ataxia are significantly aggravated in the previous phase ( 5 , 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…This phase is followed by the “worsening” phase at the age of 1–4 years, characterized by the presence of additional seizure types (such as generalized motor, atypical, myoclonic, and absence seizures) with cognitive, behavioral, and motor impairments in which thermogenic factors can still induce seizures ( 5 – 8 ). Finally, the “worsening” phase is followed by the “stabilization” phase, in which the frequency of seizures is reduced compared with the febrile stage (generalized tonic–clonic seizures and tonic seizures are still observed), but cognitive and psychomotor disorders and ataxia are significantly aggravated in the previous phase ( 5 , 7 – 9 ). In addition to difficult-to-control epilepsy, DS is often associated with some serious comorbidities, including cognitive impairment, premature death, autism, sleep disorders, hyperactivity, ataxia, and sudden unexpected death in epilepsy (SUDEP) ( Figure 1 ) ( 9 – 12 ), which seriously affect the quality of life of affected children and impose heavy burdens on society and family.…”

Section: Introductionmentioning

confidence: 99%

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Up to What Extent Does Dravet Syndrome Benefit From Neurostimulation Techniques?

Ding

Wang

et al. 2022

Front. Neurol.

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BackgroundDravet syndrome (DS) is a refractory developmental and epileptic encephalopathy (EE) with a variety of comorbidities, including cognitive impairment, autism-like behavior, speech dysfunction, and ataxia, which can seriously affect the quality of life of patients and impose a great burden on society and their families. Currently, the pharmacological therapy is patient dependent and may work or not. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), responsive neurostimulation (RNS), and chronic subthreshold cortical stimulation (CSCS), have become common adjuvant therapies for neurological diseases, but their efficacy in the treatment of DS is unknown.MethodsWe searched Web of Science, PubMed, and SpringerLink for all published cases related to the neuromodulation techniques of DS until January 15, 2022. The systematic review was supplemented with relevant articles from the references. The results reported by each study were summarized narratively.ResultsThe Web of science, PubMed and SpringerLink search yielded 258 items. A total of 16 studies published between 2016 and 2021 met the final inclusion criteria. Overall, 16 articles (109 cases) were included in this study, among which fifteen (107 patients) were involved VNS, and one (2 patients) was involved DBS. After VNS implantation, seizures were reduced to ≥50% in 60 cases (56%), seizure free were found in 8 cases (7.5%). Only two DS patients received DBS treatment, and the initial outcomes of DBS implantation were unsatisfactory. The seizures significantly improved over time for both DBS patients after the addition of antiepileptic drugs.ConclusionMore than half of the DS patients benefited from VNS, and VNS may be effective in the treatment of DS. However, it is important to note that VNS does not guarantee improvement of seizures, and there is a risk of infection and subsequent device failure. Although DBS is a safe and effective strategy for the treatment of refractory epilepsy, the role of DBS in DS needs further study, as the sample size was small. Thus far, there is no strong evidence for the role of DBS in DS.

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Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome

Cited by 11 publications

References 101 publications

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

Up to What Extent Does Dravet Syndrome Benefit From Neurostimulation Techniques?

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