Fintepla protects myelin, limits brain inflammation in Dravet mice
Study in animal model supports array of benefits with therapy's use
“These results support clinical observations that [Fintepla] may have benefits beyond seizures,” its scientists wrote.
The article, “Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome,” was published in the journal Epilepsia Open.
Fintepla is an approved add-on therapy for seizure control with Dravet
A severe form of epilepsy, Dravet syndrome often is caused by mutations in the SCN1A gene, which carries instructions for a protein component of a sodium channel called NaV1.1. This channel, found on the surface of nerve cells, controls the influx of sodium ions, which activates cells and allows them to pass signals to other cells.
Such SCN1A mutations either reduce the number of channels or render them inactive, resulting in episodes of prolonged seizures starting in the first year of life. Other Dravet symptoms may include sleeping disorders, behavioral problems, developmental delays, cognitive impairment, and muscle weakness.
Fintepla is an approved add-on treatment for people with Dravet syndrome and is typically taken with other anti-epileptic therapies to reduce the frequency of seizures. Beyond its benefits in controlling seizures, clinical studies indicate that Fintepla can improve behavior, emotions, and cognitive abilities, as well as extend life.
“[Fintepla] has additional, potentially disease-modifying activities beyond seizure control,” according to the report’s six scientists, all current or former employees of UCB, which acquired Fintepla’s developer Zogenix in 2022.
To investigate further, the team conducted a detailed examination of Fintepla’s effect on brain tissue and survival in a Dravet mouse model created by mutating the Scn1a gene.
“Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of [Fintepla],” they wrote.
These mice received under-the-skin injections of fenfluramine at a dose of 15 mg/kg once daily, or a control vehicle, from seven days after birth to days 35-37.
Researchers first examined brain sections to detect damage to myelin — a protective insulating layer, or sheath, surrounding nerve fibers. They particularly focused on brain regions with high levels of NaV1.1, including the hippocampus and cortex.
Image analysis demonstrated that the level of degenerated myelin was significantly higher in the hippocampus and cortex of Dravet model mice compared with healthy mice. Treatment with Fintepla significantly reduced the level of myelin damage in the diseased mice compared with those given the control vehicle.
Lower neuroinflammation, signs of nerve cell death seen in treated animals
Microglia, which are resident immune cells of the brain, then were assessed for evidence of activation, a sign of neuroinflammation. In Dravet mice, activated cells were more enriched around the nerve fibers connecting the left and right brain hemispheres (the corpus callosum) and in the hippocampus. With Fintepla treatment, the levels of activated microglia fell significantly compared with untreated controls.
Researchers also detected significantly high levels of DNA fragmentation in the brain of Dravet model mice caused by nerve cell apoptosis, a form of programmed cell death. Most apoptosis was observed in the corpus callosum, and its degree was reduced upon Fintepla treatment compared with vehicle-treated mice.
About 55% of untreated Dravet mice died by days 35-37, beginning at day 21. Fintepla treatment lowered mortality to 24% over the same period. No deaths were observed in healthy mice given Fintepla or the control vehicle.
“Our study is the first to report that treatment of [Dravet syndrome] mice reduces neuroinflammation and demyelination — most notably in the hippocampus, corpus callosum, and parietal cortex — and increases survival,” the researchers wrote.
“Further studies are needed to determine whether the histopathological [disease-related tissue] changes following [Fintepla] are related to decrease in SUDEP [sudden unexpected death in epilepsy]-related mortality and whether pro-survival is solely secondary to seizure control, or whether additional mechanisms are involved,” they added.