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Scientist with Microscope

Drug Repurposing Project


Children's Hospital of Philadelphia (CHOP)

Lead Investigators

Marni Falk, MD

Neal Mathew, PhD


Mechanistic and Therapeutic Modeling in ARS2 Class of Primary Mitochondrial Disease in C. elegans and zebrafish animal models

Project Cost

$320,459 over 3 years

Date Awarded

October 2022

What is Drug Repurposing?

Drug repurposing involves the study of existing drugs and using it for a medical condition different than that for which it was originally developed. This strategy may offer an expedited and cost saving route to developing new clinical treatments in comparison to traditional drug development.  High-throughput screening in the proposed research program will examine several thousand already approved FDA drugs simultaneously to test their effectiveness within an animal model of ARS2-based mitochondrial disease.  

Initial research project goals

Step 1

Create animal models, one with loss of expression of each ARS2 gene, using C. elegans, which are microscopic worms. Each ARS2 gene knockdown model will be studied to understand their level of mitochondrial dysfunction and influence on overall animal health.  Based on these results, stable genetic mutant worm and zebrafish models will be generated and characterized for representative ARS2 genes.

Step 2

High-throughput screening:
Screen 2,560 FDA approved drugs in representative ARS2 genetic mutant worm models to identify lead compounds that rescue animal health and mitochondrial function.  

Step 3

Validate lead drug candidates in additional ARS2 worm and zebrafish models to identify safe and effective doses to evaluate in future clinical trials in ARS2 human subjects.

animal models will be created for
the following ARS Genes

advantages of Zebrafish & C. elegans worms

Zebrafish are a tropical freshwater fish commonly sold in pet stores and named for their horizontal blue stripes.

70% of human genes are found highly conserved in zebrafish. These fish are vertebrate animals that have a brain, spinal cord, intestine, heart, ears, eyes, muscle and other similar characteristics to humans. Many metabolic pathways are highly maintained between zebrafish and humans. Several advantages to using zebrafish are they are small, inexpensive, require less space than a larger mammal (such as a mouse), are readily amenable to genetic manipulation for study of mitochondrial disease, and can breed rapidly (approximately every 10 days adult mating pairs can produce 50-300 eggs).

C. elegans are invertebrae nematodes, or microscopic worms, that are easy to care for, easy to feed and have an average lifespan of only 2 weeks. These animals are transparent, making it easier to observe cells and the aging process, since they enter different phases of the life cycle in a short period of time. Worms are good animal models for understanding neuronal development and these studies can be done quickly due to their short lifespans. C. elegans have been used as a model organism to study human diseases ranging from Parkinson’s disease to mitochondrial diseases, as well as studying the immune system.  They are readily amenable to genetic manipulation for study of mitochondrial diseases, have highly conserved mitochondrial structure and function with humans, and can breed rapidly (after a 3 day developmental period, adult worms are hermaphrodites that each produce ~300 offspring over several days).


Image Credits: Heiti Paves /

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