Strides in STXBP1 May
So, what was new in May of 2025?
Encoded Therapeutics published a paper on the development and animal testing of their STXBP1 gene therapy approach. Their approach is to introduce a working copy of the STXBP1 gene into neurons using an AAV vector while simultaneously decreasing off-target effects in areas like the liver and dorsal root ganglia, tissues where AAV has previously been shown to be damaging. They designed their vector in a way that the STXBP1 gene would only function in the excitatory and inhibitory neurons located in the brain but not in liver or dorsal root ganglion cells. They tested their vector by injecting it directly into a brain ventricle (a space in the brain containing cerebral spinal fluid) in a Stxbp1 mouse model and were able to correct several neurological impairments, including hyperactivity, memory deficits, and seizures. They also injected the vector into the brain ventricle of monkeys and found the injections were well tolerated, that the STXBP1 gene was expressed in several brain regions but much less so in the dorsal root ganglia.
A researcher from the University of Arkansas published a paper discussing therapies for Lennox-Gastaut syndrome (LGS). LGS is a severe childhood epilepsy that has a characteristic EEG pattern and is often difficult to treat. A genetic cause for LGS can be identified in about 30% - 40% of individuals, and among these genetic causes is STXBP1-RD. The paper reviewed how therapies designed to treat various genetic disorders, like STXBP1-RD, could be used to treat LGS in these population groups. Among the treatments discussed for STXBP1-RD were 4-phenylbutyrate, cannabidiol, levetiracetam, medications targeting serotonin receptors, and antisense oligonucleotide therapies. The same researcher, together with several colleagues at different institutions, wrote a similar review article discussing the emergence of precision therapies (i.e. gene-specific therapies) for the treatment of developmental and epileptic encephalopathies, including STXBP1.
A group in Sweden published a paper looking at how different genetic epilepsies respond to a ketogenic diet. They found that seizures caused by 31 different genes decreased in response to a ketogenic diet with the 4 best gene responses being SLC2A1, SCN1A, PAFAH1B1, and STXBP1. Of the 4 patients with STXBP1-RD, all had decreased seizures out to 1 year and 3/4 had reduced seizures out to 2 years. They also found that seizures caused by 17 different genes had no response to the ketogenic diet. The group concluded that genes involved in neuronal communication responded positively to the ketogenic diet whereas genes involved in other neuronal functions generally did not respond to the diet.
The effects of the anti-seizure medication, fenfluramine (FFA), was examined in a retrospective study of 54 patients in Spain, 17 of which had Dravet syndrome (DS), 20 of which had LGS, and 17 who had various genetic developmental epileptic encephalopathies (DEE), including STXBP1-RD. The researchers examined medical records to determine if FFA reduced seizure frequency by at least 50% over a 6-month period. They found that 94% of DS patients showed a reduction in seizure frequency compared to 50% of LGS patients and 47% of DEE patients. FFA reduced seizure frequency in all types of seizure examined and was particularly effective in reducing tonic-clonic seizures. It also demonstrated minor benefits in improving cognition, behavior, and sleep.
