Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

By |2020-08-13T13:58:55-05:00August 13th, 2020|Categories: DSF Research Review|Tags: , , , |

Stoke Therapeutics published a paper in Nature Communications detailing the mechanism of action for their new TANGO (targeted augmentation of nuclear gene output) therapy that utilizes ASO (antisense oligonucleotide) technology. While the applications of this technology have been discussed in presentations and meetings, this is the first publication detailing how it was developed. Cells use [...]

GABRA2 is a genetic modifier of Dravet syndrome in mice

By |2020-05-12T21:51:07-05:00May 12th, 2020|Categories: DSF Research Review|Tags: , , |

In previous research reviews we have talked about “Dravet mice” – usually  that means mice which have been engineered to carry a deletion of one copy of the Scn1a gene. These mice exhibit the key features of Dravet syndrome, including febrile and spontaneous seizures, SUDEP, and cognitive and behavioral deficits. But these mice display varying [...]

Fenfluramine acts as a positive modulator of sigma-1 receptors

By |2020-04-07T10:35:31-05:00April 7th, 2020|Categories: DSF Research Review|Tags: , , |

In previous posts we have profiled fenfluramine as a recent promising add-on therapy for Dravet syndrome, which not only reduces seizures but also improves executive functioning (behavior, emotions, and cognition). Fenfluramine's known pharmacological profile is to bind at 5-HT receptors and enhance the release of serotonin. It is thought that this mechanism is probably insufficient [...]

The Glucagon-Like Peptide-1 Analogue Liraglutide Reduces Seizures Susceptibility, Cognition Dysfunction and Neuronal Apoptosis in a Mouse Model of Dravet Syndrome

By |2020-04-07T10:41:40-05:00April 7th, 2020|Categories: DSF Research Review|Tags: , , |

Glucagon-like peptide-1 (GLP-1) is a hormone that is secreted from intestinal cells after food ingestion, stimulates insulin secretion, and helps regulate blood sugar levels. It also binds to receptors in the brain and promotes satiety, thereby reducing food intake. For these reasons, GLP-1 analogs have become popular as second-line drugs to treat type 2 diabetes [...]

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

By |2020-03-10T10:43:51-05:00March 8th, 2020|Categories: DSF Research Review|Tags: , , |

This study used zebrafish to try to gain insights into the very earliest neurodevelopmental effects occurring in Dravet syndrome. In previous posts we have explained that appropriately mutated zebrafish are now an established and useful model for Dravet syndrome. The authors performed behavioral analysis, measured convulsions, and did extensive examination of the functional and [...]

SCN8A Antisense Oligonucleotide is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome

By |2020-04-07T10:49:03-05:00February 6th, 2020|Categories: DSF Research Review|Tags: , , |

Dravet Syndrome is caused by loss-of-function mutations affecting the NaV1.1 sodium channel.  In a July 2019 research summary, we pointed out that gain-of-function mutations in another sodium channel, called NaV1.6, can lead to severe epileptic conditions - suggesting that NaV1.1 and NaV1.6 exist in a balance that maintains proper nerve conduction.   This raised the possibility [...]

Early EEG and behavioral alterations in Dravet mice

By |2020-04-07T10:52:04-05:00February 6th, 2020|Categories: DSF Research Review|Tags: , , |

This study explored EEG characteristics over the life cycle of Dravet mice; that is, through the febrile, worsening, and stabilization stages. One common way to analyze EEG spectra is to compute the "power spectral density" (PSD) profile. The authors found that normal EEG patterns were observed at the febrile stage, however a marked reduction in [...]

Dravet syndrome: Treatment options and management of prolonged seizures

By |2020-04-07T10:58:38-05:00February 6th, 2020|Categories: DSF Research Review|Tags: , , |

The journal Epilepsia has devoted a Special Issue to "Dravet Syndrome and other Sodium Channel Related Encephalopathies".  It is Volume 60, Issue S3, and can be accessed online - it contains many good articles, all of which are Open Access. I will point out one here - a review by an international panel of distinguished [...]

Sexually Divergent Mortality and Partial Phenotypic Rescue after Gene Therapy in a Mouse Model of Dravet Syndrome

By |2020-04-07T10:58:11-05:00January 8th, 2020|Categories: DSF Research Review|Tags: , , |

Dravet syndrome is caused by a mutation in the SCN1A gene, which codes for the NaV1.1 sodium channel a subunit. As described in previous summaries, gene therapy is becoming a very promising approach for fixing genetic disorders, with the use of adeno-associated virus ("AAV") as the preferred delivery system - but the coding region of [...]

Profound Reduction in Seizure Frequency (≥75%) Leads to Improved Everyday Executive Function: Analysis From a Phase 3 Study of ZX008 (Fenfluramine HCl) in Children/Young Adults With Dravet Syndrome

By |2020-04-07T10:57:49-05:00January 8th, 2020|Categories: DSF Research Review|Tags: , , |

This month my literature survey returned a poster that was presented at the recent American Epilepsy Society meeting. Although this is not a peer-reviewed journal article, I include it because it is interesting, and I have no concerns about its legitimacy. In previous summaries, the story of fenfluramine has been presented; along with some results [...]