Scientists Spear Out a New Strategy to Discover Drugs for ALS

Scientists use muscle to develop a new strategy to discover drugs for ALS. A microfluidic device containing nano-SPEARs detects electrical activity in the body wall of C. elegans. Subsequent experiments indicated that this activity is generated by muscles (green) of the body wall. The strategy may help scientists identify drugs for ALS, including those that help keep the motor neurons and muscles connected. [Rachel Barkan for Molecular Biology of the Cell. Reproduced under a CC-BY-NC-SA 3.0 license.]

A new tool may enable scientists to identify potential therapies for ALS in high-throughput screens. The microfluidic device, which contains nanoscale suspended electrode arrays (nano-SPEARS), records the electrical activity of body wall muscles in the roundworm C. elegans. The strategy is scalable, enabling the measurement of muscle activity of multiple worms multiple times simultaneously. The approach, unlike patch-clamp analysis, can be performed without dissection.

The device, developed by the laboratory of Rice University’s Jacob Robinson in Texas, is compatible with live fluorescence imaging, key in using this approach in high-content phenotypic screens. What’s more, changes in the electrical signature of the body wall muscles can be detected in a C.elegans model of SOD1 ALS, suggesting that this phenotype could be used to screen for drugs for the disease.

This is the first study to measure the electrical activity of muscle cells in the intact roundworm.

The study is published on April 17 in Nature Nanotechnology.

In future, Robinson’s team aims to shrink the device to enable the recording of the activity of motor neurons that connect to the muscles of the body wall. The strategy may facilitate the discovery of potential ALS drugs that reduce motor neuron hyperexcitability.

Meanwhile, researchers at Harvard Medical School and Massachusetts General Hospital in Boston are using a different electrophysiological approach to develop treatments for the disease. The strategy, developed by Brian Wainger and Clifford Woolf, involves the recording of the activity of multiple individual ALS patient-derived motor neurons in parallel using multi-electrode arrays (MEAs).

The technique enabled the Harvard-MGH team, using a candidate approach, to identify retigabine as a potential treatment strategy for the disease (Wainger et al., 2014). Retigabine, a Kv7 potassium channel activator, is one of two strategies currently being evaluated in the clinic that aims to reduce motor neuron hyperexcitability. Both strategies are at the phase 2 stage (see March 2016 and February 2017 news).

Now, the Harvard-MGH team is using this approach to identify potential ion channels that may malfunction in ALS, contributing to motor neuron hyperexcitability. The approach may facilitate the development of potential treatments for ALS that target specific ion channels in the disease.

References

Gonzales DL, Badhiwala KN, Vercosa DG, Avants BW, Liu Z, Zhong W, Robinson JT. Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays. Nat Nanotechnol. 2017 Apr 17. [PubMed]

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr 10;7(1):1-11. [PubMed]

 

 

disease-als hyperexcitability muscle topic-newmethods topic-preclinical
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