Dravet syndrome is a severe developmental and epileptic encephalopathy. Fenfluramine and gene therapy are promising

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Nuclear Gene ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Phase Iii ◽  
Preclinical Research ◽  
Cardiovascular Side Effects ◽  
Phase Iii Trials ◽  
Negative Effect ◽  
Disease Specific ◽  
Specific Impact

Dravet syndrome is a severe developmental and epileptic encephalopathy related to SCN1A. Resistant epilepsy despite polypharmacy will soon have new therapeutic options.In 2019, the treatment range was broadened to include cannabidiol after 2 phase III trials showed dramatically decreased seizure frequency. However, the results are slightly less convincing than for stiripentol or fenfluramine, and thus far no disease-specific impact appears (yet). Fenfluramine, formerly used to treat obesity, was authorized in 2020 by the Food and Drug Administration (FDA) to treat seizures in Dravet's syndrome. Fenfluramine was extremely successful in 2 randomized, placebo-controlled Phase III trials (one without stiripentol, one with stiripentol). It was generally well-tolerated-with a small drop in appetite being the most prevalent negative effect. No cardiovascular side-effects have been detected. While the anticonvulsant mechanism is not well known, it seems largely serotonergic. Preclinical research showed indications of disease-specific and potential disease-modifying impact on Dravet syndrome. The latter would support fenfluramine usage beyond its anticonvulsant properties, and needs additional research. Studies with additional serotonergic compounds (clemizole and lorcaserine) began. Unfortunately, existing medications do not target Dravet's syndrome's underlying genetic etiology and hence have no substantial influence on patient cognition or other comorbidities. Therapies focusing on amplifying Nav 1.1 channels based on TANGO technology (anti-sense oligonucleotides; "targeted increase in nuclear gene output") will begin shortly (phase I and II studies). This technology seems promising and marks the beginning of an interesting therapeutic phase for Dravet syndrome patients.

Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome

2020 ◽  
Vol 12 (558) ◽  
pp. eaaz6100 ◽  
Author(s):  
Zhou Han ◽  
Chunling Chen ◽  
Anne Christiansen ◽  
Sophina Ji ◽  
Qian Lin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Antisense Oligonucleotides ◽  
De Novo ◽  
Nuclear Gene ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Unexpected Death ◽  
Α Subunit ◽  
Gene And Protein Expression ◽  
Electrographic Seizures

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human cell lines, as well as in mouse brain. We show that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-Scn1a+/− × C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein was confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

Metal-Protein Attenuating Compounds in Neurodegenerative Diseases

2016 ◽  
Author(s):  
Peng Lei ◽  
Scott Ayton ◽  
Ashley I. Bush
Keyword(s):  
Neurodegenerative Diseases ◽  
Drug Targets ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Alternative Drug ◽  
Phase Iii Trials ◽  
Specific Proteins ◽  
Copper Zinc ◽  
Lateral Sclerosis ◽  
Disease Specific

Neurodegenerative disorders including Alzheimer’s (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are progressive diseases of the aging population with currently few therapeutic options. While aggregation and deposition of disease-specific proteins link the pathologies of these diseases, targeting these aggregating proteins with therapeutics has not yet been successful in clinical trial. This chapter profiles metals (copper, zinc, and iron) as alternative drug targets for neurodegeneration. Complex changes to metals occur in these neurodegenerative diseases. Accumulating evidences have demonstrated that perturbations to metal homeostasis contribute to the progression of neuronal dysfunction and death. Importantly, several phase II trials have shown that correcting metal dyshomeostasis improves clinical outcomes; the chapter argues that it is now time to explore the therapeutic utility of metal-based drugs in larger, phase III trials.

Clinical implications and outcomes of the ORION Phase III trials

2020 ◽  
Author(s):  
Julia Brandts ◽  
Kausik K Ray
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Phase Iii ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density Lipoprotein Cholesterol ◽  
Clinical Safety ◽  
Phase Iii Trials ◽  
Phase Ii And Iii ◽  
Ongoing Phase

Inclisiran is a siRNA inhibiting hepatic PCSK9 synthesis. As a first-in-class therapy, inclisiran has been assessed within the ORION trial program for its low-density lipoprotein cholesterol (LDL-C) lowering efficacy and clinical safety. Phase II and III trials have shown that inclisiran lowers LDL-C by about 50% with an infrequent dosing schedule in patients with established atherosclerotic cardiovascular disease and those at high risk, including patients with heterozygous familial hypercholesterolemia. Ongoing Phase III trials will provide evidence on longer-term safety and effectiveness, and inclisiran’s efficacy in patients with homozygous familial hypercholesterolemia. Furthermore, the ORION-4 trial will assess inclisiran’s impact on cardiovascular outcomes.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

Interaction of neurovascular protection of erythropoietin with age, sepsis, and statin therapy following aneurysmal subarachnoid hemorrhage

2010 ◽  
Vol 112 (6) ◽  
pp. 1235-1239 ◽  
Author(s):  
Ming-Yuan Tseng ◽  
Peter J. Hutchinson ◽  
Peter J. Kirkpatrick
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Statin Therapy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Potential Interaction ◽  
Repeated Measurements ◽  
Unfavorable Outcome ◽  
Phase Iii ◽  
Neurovascular Protection ◽  
Phase Iii Trials

Object In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy. Methods The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-β or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or ≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements. Results Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 × 109/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO. Conclusions Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

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