Researchers have developed a new method that enables high-throughput
screening of Huntington’s disease organoids.
Researchers from Rockefeller University, US, have designed a novel
generic phenotypic screening method at the organoid level. Through this new
method, the team discovered modulators of phenotypes of Huntington’s disease,
which could potentially be used therapeutically. The study was recently
published in Cell Reports Methods.
While organoids are promising tools for modelling complex disease
phenotypes, they often lack reproducibility and scalability in their use of high-throughput
screening assays. The researchers therefore aimed to develop a method of
using reproducible and scalable micropatterned neural organoids for drug
screening and to identify targets that could rescue developmental phenotypes in
organoids derived from stem cells that carry mutations for Huntington’s
disease.
In their report, the scientists explain that although Huntington’s is a
degenerative disease, it has recently been shown to alter human
neurodevelopment in human foetal samples. This therefore suggests that early
human organoid models that reproduce aberrant signalling and morphogenesis in
Huntington’s establish a promising approach for discovering new mechanisms that
are also relevant at later stages of the disease. To create organoids mimicking
the ectodermal compartment during human neurulation, the researchers leveraged
neuruloids that use micropattern-based differentiation, with the possibility
for easy upscaling while retaining excellent reproducibility.
The team then performed a drug
discovery screen aimed at reversing a complex phenotype previously reported for
Huntington’s in the neuruloids, using a previously characterised isogenic
series of human embryonic stem cell lines with graded increases in CAG lengths,
which is a known cause of the neurodegenerative disease.
Finally, the team developed a
deep-learning computational pipeline to analyse the screening results and to
quantify, for each compound, its efficacy at reversing the disease phenotype
back to normal as well as its adverse effects. According to the report, this
combination of tools allowed the researchers to find that those specific
bromodomain inhibitors can efficiently revert Huntington’s phenotypes to wild
type and alleviate neuronal susceptibility to apoptosis in human Huntington’s
neurons in vitro, highlighting a potential new druggable target the condition
that should be further evaluated.
“This study lays the groundwork for
combining deep neural network and bioengineered human microtissues to carry out
drug screens on neural organoids. This is achieved by the combination of a
highly reproducible, scalable organoid platform allowing the easy generation of
large image databanks required for leveraging the power of data analysis
schemes based on deep neural networks,” the researchers conclude in their
paper.
World Journal of Case Reports and Clinical Images (ISSN 2835-1568)
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