CRISPR/Cas9 is a new gene editing technique that could potentially treat Huntington’s disease. The approach is currently in preclinical testing, but early results are promising.
How the CRISPR/Cas9 system works in Huntington’s disease
Huntington’s disease is caused by mutations, which introduce long repeating CAG nucleotide sequences in the huntingtin (HTT) gene. When the gene is transcribed, a messenger RNA molecule is made, which serves as the template for cells to make HTT protein.
Because of the CAG repeat expansion, a faulty protein is made, which is then degraded by cells. This leads to the formation of toxic protein fragments, which stick together and accumulate inside cells, leading to neurodegeneration. The length of the CAG repeat region seems to correlate with the severity and age of onset of Huntington’s disease.
CRISPR/Cas9 is a revolutionary gene editing technology, which could permit the “silencing” of the mutated HTT gene and prevent the formation of faulty protein.
Cas9 is an enzyme that cuts DNA very precisely and accurately by using a guide RNA complementary to a specific gene sequence — in this case, the mutated region of the HTT gene. The guide RNAs are designed to target either side of the CAG repeat region in the HTT gene.
Once cut, the DNA strands should be reconnected by the DNA repair machinery of the cell, without the CAG repeats, permanently removing the mutation from the genome of every cell that is edited. The name “CRISPR” comes from the bacterial system in which Cas9 was first identified and characterized.
CRISPR/Cas9 research in Huntington’s disease
In a recent study published in Frontiers in Neuroscience, researchers successfully edited out the faulty region of the HTT gene in cells derived from patient samples using the CRISPR/Cas9 system. Even in samples from patients with differing lengths of CAG repeat regions in their genome, the CRISPR/Cas9 system was able to greatly reduce the amount of faulty HTT protein produced.
This technique could be tested in clinical trials by pharmaceutical companies, both in Huntington’s disease and other neurodegenerative disorders.
Although very promising, the CRISPR/Cas9 system is still a new technology. It is not clear what the potential side effects of the approach will be, and a major concern is the potential, however slight, of Cas9 to edit the genome in unpredictable ways.
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