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Zebrafish and C. elegans in ALS: tightening the bench-to-clinic gap

While advances in molecular imaging, high-throughput screening, genomics and techniques like CRISPR-Cas9 gene editing have dramatically enhanced our understanding of the human body and disease, the pace of advancing new treatments for those diseases has lagged behind significantly.

One way to shorten the time between laboratory discoveries and available new drugs is to use animal models that can effectively reproduce the genetic, cellular and organismal environment of humans. Using better models can reduce the uncertainty—and need for additional testing—that’s now necessary to advance drug candidates. Few diseases illustrate that need as strongly than amyotrophic lateral sclerosis (ALS), popularly known as Lou Gehrig’s disease.

ALS is a devastating neuromuscular disorder marked by sudden adult onset, progressive degradation of muscular activity (including breathing, limb movement, and swallowing). Nearly all victims of ALS die within five years. The disease’s mechanism of pathology is yet unknown, though oxidative stress and genetic mutations appear to play a strong role. Today, only two medications are approved to treat ALS. One is Riluzole, which only slows down its progress, has an average survival benefit of just two months. The other is Edaravone, which significantly slows the rates of dysfunction but did not halt the disease’s progress, and had a survival rate of 40 percent after five years.

Canadian researchers Pierre Drapeau and Alexander Parker summarized their team’s research efforts in ALS treatments in Expert Opinion in Drug Discovery, looking at C. elegans, Zebrafish and Drosophila.  The researchers cited Zebrafish and C. elegans as ideal models because they were easily genetically manipulated, reproduced quickly, had short life spans, had a wide range of transgenic strain, and had neurotransmitters that largely paralleled those seen mammals and humans.

The researchers looked at four genes that appear to lie behind half of ALS cases: SOD1, TARDBP, FUS, and C9ORF72, all of which have zebrafish, C. elegans and Drosophila models.

  • C. elegans expressing mutant SOD1 are sensitive to oxidative stress and have locomotor defects as well as presynaptic dysfunction similar to ALS. The team also developed models to study ALS with TARDBP and FUS mutations, as well as a loss-of-function model for C9ORF72.
  • Zebrafish have also been modeled for SOD1 and the other three ALS-related genes. Loss of function has been enabled by CRISPR-Cas, ZFN and TALENS, and knock-in point mutations using CRISPR also have been incorporated into a Zebrafish animal model. Zebrafish studies have shown for the first time that early changes in neuron structure could arise after expression of mutant proteins associated with SOD1.

“The selection of the most relevant animal model to achieve research goals is always a primary concern in biomedical research,” Drapeau’s team wrote. “Biological differences between species may lead to findings that are not necessarily relevant to disease pathology in humans. We have minimized this issue by combining the use of several model systems and capitalized on the strength of each organism to screen large chemical libraries in the search for potential therapeutic drugs for ALS.”

“Our strategy for drug discovery for ALS is now to first start a high-throughput chemical screen in C. elegans and Zebrafish models and validated the ability to hits to reverse or ameliorate the disease phenotype in human motor neurons.

“Such an approach should accelerate development of therapies for ALS.”

In fact, some therapies have already entered clinical trials, thanks in large part to animal modeling with Zebrafish and C. elegans.

Drapeau and Parker screened libraries of more than 3,800 compounds in C. elegans and validated any hits in Zebrafish. They then tested molecules in mice and a limited clinical trial. A group of neuroleptics was found to restore mobility in worms and Zebrafish—of those, the most potent restorer of function was pimozide, a chemical approved previously to treat Tourette’s syndrome. A small trial with ALS patients showed motility was stabilized and drug-target engagement occurred at the neuromuscular junction, a likely therapeutic target.

“Simple animal models can be valuable in the preclinical pipeline to bridge the gap between in vitro assays and most costly screens in mammals,” the researchers wrote. “Not only are simple animal models useful in identifying compounds that hold promise for the treatment of ALS, they may be accurate predictors of clinical trial outcomes.”

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About The Author

InVivo Biosystems

InVivo Biosystems provides essential services to help pharmaceutical, nutraceutical, biotechnology companies and academic research institutions around the globe accelerate their research and drug development efforts. An expert in CRISPR genome editing, InVivo Biosystems creates custom genome edited C. elegans and zebrafish models to enable aging and other disease studies. In addition, InVivo Biosystems provides in-vivo analytical services to produce data and insights for companies that need to make go/no-go decisions quickly in early-stage development of new compounds.

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