A lot is happening in the Huntington’s disease (HD) field right now. Emory research reports on a pig HD model and on CRISPR/Cas9 gene editing are just part of the wave.
Let’s step back and review the technologies now available to treat this neurodegenerative disease, caused by a gene producing a toxic protein. Antisense approaches, under development for decades and now in clinical trials, shut off the problematic gene. However, this type of treatment would need to be regularly delivered to nervous system tissues. Gene editing — not in the clinic yet — could actually remove the gene from somatic cells in affected individuals.
Emory researchers developed the pig HD model in collaboration with colleagues in Guangzhou, and anticipate it will be a practical way to test treatments such as gene editing. In comparison with mice, delivery to affected nervous system tissues can be better tested in pigs, because their size is closer to that of humans. The pig model of HD, published yesterday in Cell, also more closely matches the symptoms of the human disease. This research was covered by Chinese media organizations.
Imagine the game of pick up sticks. It’s hard to extract one stick from the pile without moving others. The same problem exists, in a much more complex way, in the brain. Pulling on one gene or neurotransmitter often nudges a lot of others.
Andrew Escayg, PhD
That’s why a recent paper from Andrew Escayg’s lab is so interesting. He studies genes involved in epilepsy. Several years ago, he showed that mice with mutations in the SCN8A gene have absence epilepsy, while also showing resistance to induced seizures. SCN8A is one of those sticks that touches many others. The gene encodes a voltage-gated sodium channel, involved in setting the thresholds for and triggering neurons’ action potentials. Mutating the gene in mice modifies sleep and even enhances spatial memory.
Escayg’s new paper, with first author Jennifer Wong, looks at the effect of “knocking down” SCN8A in the hippocampus in a mouse model of mesial temporal lobe epilepsy. This model doesn’t involve sodium channel genes; it’s generated by injection of a toxin (kainic acid) into the brain. The finding suggests that inhibiting SCN8A may be applicable to other forms of epilepsy. Escayg notes that mesial temporal lobe epilepsy is one of the most common forms of treatment-resistant epilepsy in adults.
Knocking down SCN8A in the hippocampus 24 hours after injection could prevent the development of seizures in 90 percent of the treated mice. “It is likely that selective reduction in Scn8a expression would have directly decreased neuronal excitability,” the authors write. It did not lead to increased anxiety levels or impaired learning/memory.
Currently, no available drugs target Scn8a specifically. However, antisense approaches for neurodegenerative diseases have been gaining ground – perhaps epilepsy could fit in.