Rapid high-throughput in vivo screening method for chemicals that prevent human age-related neurodegenerative diseases

Life Sciences : Research Tools

Available for licensing

Inventors

  • Jonathan Pierce-Shimomura , University of Texas at Austin
  • Ashley Crisp , University of Texas at Austin

Background/unmet need

Alzheimers disease (AD) is now the sixth leading cause of death, according to the CDC. Unfortunately, there are currently no drugs that prevent or delay the progression of AD. Many drug screens for novel therapeutics rely on in vitro cell culture models that are unable to recapitulate the important features of AD, such as neuron-subset specificity, age of onset, and an intact nervous system. To screen for potential therapeutic drugs for AD in vivo, companies routinely use rodent models that are too expensive and slow for high-throughput drug studies, which severely limits the amount of compounds that can be tested.

Invention Description

The Pierce-Shimomura lab at The University of Texas at Austin has developed a rapid, cost-effective method to test potential AD therapeutic compounds in vivo with a C. elegans AD model. These model strains express a single copy of human APP or an extra single copy of the worm gene equivalent (apl-1). They are the first "humanized" C. elegans strains that demonstrate age-related neurodegeneration and APP accumulation related to AD. In addition, these model worms express GFP in a subset of neurons to determine neuronal health as an animal is aging.

To visualize APP accumulation, additional worm strains were generated that knock-in a single copy of mCherry-tagged APP or apl 1. All four model worms recapitulate neurodegeneration demonstrated in human AD. The mCherry tagged worm strains also display an age-related increase in APP accumulation in neurons prior to cell death.

Benefits/Advantages

  • Obtain results on whether a drug prevents age-related neurodegeneration with an in vivo model of AD in a week.
  • Can simultaneously identify whether drugs cause systemic side effects with this model.
  • High throughput: Substantial improvement over drug screening using rodent models, with the ability to test hundreds of drugs in one month, thousands in as little as six months.
  • Much more cost-effective than screening with rodent models.
  • Can be used to determine whether drugs prevent apoptotic death of the same neurons
  • Can be used to determine mechanism of action by measuring death in different mutant backgrounds

Features

  • Two drugs tested in rodent models relevant to human AD displayed similar positive effects in this worm model, demonstrating a strong proof of concept to use this model for drug screening.
  • By using this in vivo model, the efficacy of drugs to prevent neurodegeneration can be tested in one week, with the capacity to test hundreds of drugs per week in parallel.

Market potential/applications

Pharmaceutical and biotechnology companies interested in screening or investigating neurodegeneration targeted drugs

Development Stage

Beta product/commercial prototype