A compound found in anemone venom could soon be the first line treatment for people with multiple sclerosis.
Over a decade ago US researchers first described a compound called ShK in venom of the Carribean sea anemone Stichodactyla helianthus. This toxin exerts its effects by selectively blocking potassium channels, which are abundant voltage-gated channels found in most cell types and involved in a wide variety of cellular functions.
Since the discovery of the ShK toxin, Monash University researcher Ray Norton and his colleagues have been studying its 3D structure and how its analogues can block a specific subset of potassium channels, which are dysfunctional in autoimmune diseases such as multiple sclerosis (MS). The team’s long-term research has recently borne fruit as they’ve received the exciting news that their ShK-based MS treatment has been approved for human clinical trials.
The most important characteristic of their ShK analogue is that it specifically targets potassium channels made up of Kv1.3 subunits. These channels are found predominantly on T-cells, a white blood cell population that plays a central role in cell-mediated immunity.
“It turns out that blocking this specific subclass of Kv1.3-rich T-cells effectively shuts down those T-cells, which happen to be the ones that cause damage in a range of autoimmune diseases,” explains Norton.
“Some of the ShK analogues that have led to the main compounds to be tested in the clinical trial were a combination of luck and good management,” says Norton. “Some analogues had been developed for other reasons and then we were able to understand their structure and how they bind to the potassium channel. We then rationalised how they worked and improved on them from there.”
There is a definite urgency in developing a powerful and reliable treatment for patients with autoimmune diseases. “There are no drugs on the market that work in this way — by shutting down this channel,” says Norton. “There are other drugs that work on MS but many of them are not particularly effective and a lot of people experience disease progression even when on these treatments.”
So far the ShK analogue has been tested in several animal models, including primates, and the trials coming up will be the first clinical testing in humans. The phase 1 clinical trials will be carried out on a cohort of MS patients in the Netherlands and, due to extensive preclinical investigations, the researchers are hopeful that this phase will be a success. The next step will be to further test the drug, and the dosages required in phase 2 trials, which will evaluate the therapeutic effect in patients who suffer from MS.
Norton explains that, although current testing is focussed on the effect of ShK on people with MS, there is promising preclinical data supporting the hope that the same strategy will work against rheumatoid arthritis, lupus and other autoimmune diseases, such as Type-1 diabetes.
Source: Monash University