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CogniXense – A high-throughput cognitive screen for modeling disorders on-the-fly

Highly scalable biological model platform using tadpoles can analyze human genetic diseases and facilitate drug screening

A magnified and stained image of an embryonic Xenopus tadpole that can be used to model Rett’s syndrome behaviors. Credit: Wyss Institute at Harvard University

There are more than 6,000 known single-gene disorders, in which a disruption to one gene out of the 20,000 in the human genome is enough to cause significant health effects. In order to study these disorders and develop treatments, a given genetic mutation must first be induced in a large number of animal models (usually mice), which are then given candidate drugs to see if they help treat the disease. However, mice take about ten weeks to develop and only give birth to five to ten pups per litter, so it usually takes years of testing before a candidate drug is confirmed to work and ready to be tested in humans.

CogniXense aims to solve this problem by using a different animal model with a much more rapid generation time that still expresses human-like neurological and behavioral responses to genetic mutations: Xenopus frog tadpoles. Xenopus females can produce many hundreds of eggs at a time, and embryos mature into tadpoles within a matter of days. The tadpoles’ behavior and cognition can be analyzed in a highly multiplexed fashion, allowing the generation of large amounts of data in a short time period.

The CogniXense approach allows us to develop an animal model of human genetic disease in a matter of days. We take advantage of gene editing to produce populations of tadpoles that resemble the diversity of patient symptoms, potentially giving us a better idea of how effective a potential treatment would be.

Richard Novak

The first disease to which CogniXense is being applied is Rett syndrome, a rare genetic disorder that almost exclusively affects girls and causes slowed growth, development problems, impaired motor function, seizures, and intellectual disability starting between the ages of six and eighteen months, when the developing brain is being wired. The majority of Rett syndrome cases are linked to mutations or disruptions in one of two primary genes called MECP2 and CDKL5, which are thought to normally function as “brakes” that regulate a number of cognitive and physical processes. So far, no drugs have been identified that can effectively treat Rett syndrome, and women who are affected have shortened lifespans.

A tadpole swims through a maze specially built to test their ability to learn and remember a “correct” sequence of turns. Credit: Wyss Institute at Harvard University

Scientists at the Wyss Institute are creating a tadpole model of Rett syndrome to study how those genetic mutations impact motor function and cognitive abilities. Tadpoles are placed in mazes to evaluate their learning and responses to stimuli, and in circular dishes to observe their swimming patterns. Normal tadpoles generally swim around the outer edge of the dish at a steady pace moving in coordination with their neighbors, but tadpoles with the mutations swim erratically blind to their neighbors, exhibit repetitive twirling motions, or lack movement completely. The team is also developing a high-throughput version of this cognitive screen that allows analysis of hundreds of tadpoles simultaneously, as well as a linked computational discovery pipeline to identify existing therapeutics that could potentially be repurposed to treat Rett syndrome in human patients. Wyss scientists will use these mutants and the CogniXense testbed to screen for potential therapeutics that restore motor function and cognitive ability.

This technology is currently being de-risked at the Wyss Institute.

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