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ALS Worldwide
February 16, 2016

Preclinical Trial Results: MicroNeurotrophins

The main goal of a preclinical trial is to determine whether or not a drug is safe for humans by first conducting in vivo (animal model) and in vitro (cell culture) studies.

After rigorous testing, MicroNeurotrophin show no signs of toxicity or harmful side effects. In addition, these drugs appear to protect and strengthen the nerve cells affected by ALS.

As a result, we are now able to move forward with FDA-required independent studies to reconfirm safety results by using larger animal models that more closely mimic humans.



Drs. Laura Ferraiuolo and Pamela Shaw

The Sheffield Institute for Translational Neuroscience (SITraN) based at the University of Sheffield is a pioneer in the development and use of zebrafish for testing drugs for humans. Like humans, zebrafish have organs, a brain and a spinal cord. As a result, zebrafish have emerged as good models to study human diseases that occur in adulthood, including complex neurological diseases like ALS.

Since stress on nerve cells is a major cause of their deterioration and death in ALS patients, SITraN researchers focused on testing whether or not MicroNeurotrophin drugs can reduce the stress response of nerve cells in zebrafish.

  • MicroNeurotrophin drugs reduced the stress response in a zebrafish model of ALS by 50% without producing any harmful side effects. (Drs. Chris Binney, Tennore Ramesh and Pamela Shaw, Co-PIs, University of Sheffield, Sheffield Institute for Translational Neuroscience, Sheffield, U.K.)
     
  • A significant body of research suggests that astrocytes, cells that are supposed to support a healthy central nervous system, actually secrete chemicals that kill nerve cells in models of ALS. For this reason, SITraN researchers tested MicroNeurotrophins in vitro (cell culture) to determine if the drug could help protect nerve cells from this deadly process.
     
  • MicroNeurotrophin drugs reduced death in nerve cells exposed to astrocytes derived from people with the most common form of ALS by up to 90%.


       
Drs. Laura O’Brien, David Brohawn and James Bennett, Co-PIs

MicroNeurotrophins were developed to mimic the beneficial properties of neurotrophins, proteins essential for the growth, maintenance, and survival of nerve cells.

To confirm this, researchers at Virginia Commonwealth University and Neurodegeneration Therapeutics, Inc., a nonprofit laboratory in Charlottesville, Virginia, used state-of-the-art “next generation gene sequencing” to determine if MicroNeurotrophin drugs act like nerve growth factor, one of the most important members of the neurotrophin family.

  • In vitro (cell culture) studies of human nerve cells made from stem cells show that MicroNeurotrophins produced gene expression changes nearly identical to Nerve Growth Factor. 



Dr. Ghazaleh Sadri-Vakili

Researchers at Harvard University studied the effects of MicroNeurotrophins using an ALS mouse model to determine if the drug protected nerve cells and improved survival rates.

  • The first experiment using smaller numbers of mice found clinical improvement and increased nerve cell survival in MicroNeurotrophin drugs.
     
  • However, these findings could not be replicated in a larger study where the mice were treated with pellets of the drug implanted under the skin instead of injections. The results are not conclusive because the mice in the larger study did not tolerate the large pellet of MicroNeurotrophin drugs.
     
  • Independent experiments conducted by Cyprotex, a highly respected contract research organization, showed that mice metabolize MicroNeurotrophins too rapidly to serve as useful animals for assessing safety or effectiveness of this class of drugs.
     
  • No harmful effects were observed in animals treated with MicroNeurotrophin drugs for many weeks.