Tonus Therapeutics

Tonus Therapeutics
8210 Golden Oak Circle
Williamsville NY 14221

877-484-7673
info@tonustherapeutics.com

All cells respond to mechanical inputs and generate mechanical outputs. The inputs may be familiar from our conscious senses of touch and hearing and the outputs from from muscle activity, but there are many more. For example, blood pressure is regulated by mechanosensation as is muscle coordination. Cells also have a variety of internal sensors and motors that allow them to respond to external inputs, to transport materials internally, and to generate forces on their neighbors. Yet despite the omnipresence of these systems there are no drugs that available for influencing these systems.

sampleNMR Structure of GsMTx4 molecule

One of the key cell sensors are mechanosensitive ion channels located in the cell membrane that are activated by stress in the membrane. Discovered in 1983 by Dr. Sachs, these channels open when the cell membrane is stretched. When they are open they allow Na+, K+, and Ca2+ ions to cross the membrane as an ionic current. The influx of Ca2+ can affect many enzymes, notably calpain proteases that can cause atrophy of dystrophic muscle.  Mechanosensitive ion channels are unique drug targets that have not yet been addressed by drug companies.

However, Dr. Sachs’ lab with collaborators Drs. Suchyna and Gottlieb screened nature’s libraries of chemical compounds found in venoms, and found a small protein in a tarantula venom that inhibits the mechanosensitive channels and they named it GsMTx4. They solved the structure and found out how to synthesize it in the lab and then began to test it on mechanosensitive processes in cells.

The first test was for atrial fibrillation, a cardiac arrhythmia that affects over two million Americans. When the atria of the heart are stretched by overfilling, the heart starts to beat irregularly, or fibrillate, and may develop blood clots that can prove fatal. In collaboration with cardiologists, they were able to show that GsMTx4 reversibly inhibited atrial fibrillation. It had no effect on the normal heartbeat or the strength of contraction.  Later tests have shown that GsMTx4 is not toxic to animals.

A second test was muscular dystrophy where a genetic defect causes the membrane reinforcing network to fail. This failure leads to increased stress on the cell membrane and the opening of mechanosensitive ion channels. In collaboration with scientists in Australia who were familiar with muscular dystrophy, they tested GsMTx4 on dystrophic mice and found that it made muscles less sensitive to mechanical stress. GsMTx4 inhibited the stress induced Ca2+ uptake that is associated with muscle atrophy in dystrophy.

A Belgian lab found that GsMTx4 inhibited calpain activation in dystrophic muscle. In collaboration with Dr. Eric Hoffman of the Wellstone Muscular Dystrophy Center in Washington DC, the Sachs lab tested GsMTx4 in dystrophic mice using implanted pumps for over 40 days and found that the mice got stronger and that there was no toxicity. Thus, GsMTx4 may be a therapy for muscular dystrophy, and since it is not a genetic therapy but one that treats the symptoms, it may prove applicable to many forms of dystrophy.

If all these treatments are for mechanosensitivity, will you become numb and deaf? No. They key is that the specialized hearing and touch receptors are not affected by GsMTx4.