Over 30,000 people in the United States alone suffer from Huntington’s Disease (HD), a degenerative neurological disorder with no known cure and few available treatments. This disease is an irreversible death sentence. But what if there was a way to relieve patients of the devastating symptoms? A way to alleviate some of their suffering? Researchers at Emory University1 have produced results that appear to do just that. By using genome editing techniques, they have effectively reversed HD in a mouse model.
HD is a genetic disorder and affects the striatal neurons of the basal ganglia, the region of the brain responsible for coordinating movement. An abnormal amount of CAG nucleotide repeats on the Huntingtin (HTT) gene causes the production of a toxic protein: mutant huntingtin (mHTT). The presence of mHTT causes cell death in neurons. The characteristic symptom of Huntington’s Disease is chorea, a movement abnormality of the extremities, which severely reduces an individual’s ability to live a normal life and complete activities required for daily living.
Through the use of CRISPR/Cas9 methods on mHTT expressing mice (HD-140Q-Knock In), researchers have successfully edited the genomes of these mice so that the mutant gene is no longer expressed. The silencing of the gene led to the reduction of levels of mHTT.
CRISPR/Cas9 is a gene editing technology that allows researchers to remove, add, or change DNA sequences. This method relies on two factors that induce change in the DNA strand: Cas9 and guide RNA (gRNA). Cas9 is an enzyme that acts like a pair of scissors, cutting the DNA strands at a specific point in the genome. The gRNA is a pre-designed RNA sequence which binds to the part of DNA that Cas9 needs to cut, which flags the target for Cas9 to cut out of the genome.
In the study, CRISPR/Cas9 was injected into the striatum of the HD carrier mice. Four gRNAs were designed to target the DNA regions with abnormal CAG repeats expression. By removing the defective gene from the mice’s genome, cellular levels of mHTT were reduced. Three weeks after injection, the mice showed significant improvements in motor functions.1
In addition, the researchers concluded that CRISPR/Cas9 mediated inactivation did not prove to be lethal to the mice. This is a breakthrough in and of itself considering that the loss of HTT in utero is known to lead to embryonic lethality. Previously, the same team of researchers showed that the huntingtin gene is not necessary in mice older than four months. This could be good news for people with HD, because the treatment would not have to be specifically tailored to their genome.
Currently there is no treatment available to delay or reverse the symptoms of HD. There are only two FDA approved medications available for treatment of HD. Both minimize chorea but do nothing to combat the symptoms of cognitive decline. CRISPR/Cas9 looks to be a very promising method to revolutionize the way researchers can develop treatments for the disease. Moving forward, the researchers at Emory University are planning to move quickly towards human trials. This research could revolutionize the way neurodegenerative disease treatments are developed. No clinical trials are currently using the CRISPR/Cas9 method to treat this type of disease, so this could be a stepping stone towards a great future in neurodegenerative disease research.