Basic Science Research with Spider Venom Increases Understanding of Dravet Syndrome

A recent article by Richards and colleagues, “Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death,” examined the use of spider venom as a possible treatment of Dravet syndrome.

Purpose

• One of the mechanisms that helps maintain the balance between inhibition and excitation in the brain is a gene called SCN1A. This gene is essential for proper movement of sodium (Na+) ions in and out of neurons in the brain.
• The underlying cause of Dravet syndrome, a rare form of epilepsy, is a mutation in the SCN1A gene. This mutation causes problems in Na⁺ channel function.
• Dravet syndrome is characterized by multiple seizure types and developmental delay. People with Dravet syndrome also don’t respond to seizure medicines very well and have higher rates of early death.
• Since Dravet syndrome is caused by a change in one gene, this leads to the possibility of finding a specific cure that targets just the SCN1A gene. The promise of such a drug is that it may have fewer side effects.

Description of Study

• This study looked at a specific peptide (chain of amino acids) in spider venom, known as Hm1a.
• The scientists looked at the effects of Hm1a in in vitro assays (i.e., tests done in a petri dish or a test tube outside the body) and in mice that were genetically modified to simulate Dravet syndrome.
• They also looked at the structure and function of Hm1a peptide to better understand how it works.

Summary of Study Findings

• In vitro studies found that the peptide Hm1a regulates Na+ channel function or how sodium flows in and out of neurons. It also found that Hm1a affects inhibitory neurotransmission or how information sent in the brain is stopped. This can normalize the balance between cells that excite and those that inhibit, which is what goes awry in Dravet syndrome.
• Similar to the human condition, genetically modified mice with Dravet syndrome have many seizures and premature death.
  • Mice with Dravet syndrome given Hm1a had fewer seizures and were rescued from death.
  • Also, the brains of these mice had fewer epileptiform discharges (electrical activity that is characteristic of a seizure).

What does this mean?

• Although more research is needed, this study suggests that peptide Hm1a found in spider toxin may be a new way to treat Dravet syndrome because of its effects on Na⁺ channels.
• The in vitro studies showed that Hm1a affected inhibitory (and not excitatory) transmission in the brain. This could mean that when Hm1a is developed for use in humans, it may have fewer side effects.
• However, since Hm1a cannot cross the blood brain barrier and reach the central nervous system, a different way of getting this peptide into the brain will be needed.
• On the bright side, there are a number of other types of epilepsy that may have changes in SCN1A and inhibitory neurotransmission. Possibly, Hm1a could be developed as a novel therapy for an array of epilepsy syndromes in addition to Dravet syndrome.

Reference

Richards KL, Milligan CJ, Richardson RJ, Jancovski N, Grunnet M, Jacobson LH, Undheim EAB, Mobli M, Chow CY, Herzig V, Csoti A, Panyi G, Reid CA, King GF, Petrou S. Proceedings of the National Academy of Sciences (PNAS), August 21, 2018;115(34): E8077-E8085.