Gene Editing Reverses Huntington’s in Mouse Study – Bioscience Technology

While still early, a new study reports that the disease process and motor symptoms of Huntingtons disease were reversed using CRISPR/Cas9 gene editing methods in mouse models.

The new findings spark hope for future treatments in humans, though much more work to test long-term effects and safety are needed.

Huntingtons is a progressive inherited disease that occurs when a mutant copy of the huntingtin (HTT) gene is inherited from one parent. This leads the production of a toxic protein (mutant huntingtin or mHTT) that that causes brain cells to die and triggers a degenerative process. As time goes on people experience symptoms such as uncontrolled movements, slurred speech, cognitive decline and mood swings.

Researchers led by Su Yang, Ph.D. of Emory University and Renbao Chang, Ph.D., of the Institute of Genetics and Developmental Biology at the Chinese Academy of Sciences, showed in previous work that stopping production of healthy or mutated HTT protein doesnt cause neurological problems or hurt cells in mice older than four months, so they hypothesized that shutting off both copies of the gene could be safe and potentially reverse early signs of the disease.

In the mouse model used, the animals had one human mutant huntingtin gene in place of one of the mouse huntingtin genes and motor problems as well as aggregated mutant huntingtin could be observed by the age of 9 months.

For the study, the team used a gene therapy method based on AAV (adeno-associated virus) to deliver CRISPR/Cas9-guided enzymes into brain cells. They injected millions of viral vectors into the striatum region of the mouse brains, which is the area that controls motor skills. Neurons received either a short guide RNA sequence to mark for the removal of the HTT genes repeats or a Cas9 enzyme to snip out the repeats, effectively knocking out both healthy and abnormal copies of the HTT gene, and stopping the production of HTT protein.

Three weeks later, the team observed a dramatic decrease in aggregated mutant huntingtin in the striatum. The findings indicate that brain cells have the ability to heal themselves if the genetic source of the toxic proteins is removed, the scientists said.

CRISPR/Cas9 injections were repeated in a dozen 9-month old mice and similar protein-clearing results were observed.

Mice that received the CRISPR/Cas9 injections significantly improved on tests of balance, muscle coordination, and grip strength compared to control Huntingtons mice. However they did not improve to the level of healthy control mice.

Interestingly, how well motor skills improved related to the level of toxic protein that was cleared from the striatum.

One issue with CRISPR/Cas9 that has been reported is unintended mutations resulting from off-target editing. However, the NIH-funded team reported that the gene editing occurred primarily around their target sequences and there was not significant genomic edits in other potential off-target genes.

While this early study is promising, the long-term effects and safety of injecting AAV in the brain to express CRISPR/Cas9 still needs to be thoroughly tested before translating this method to patients, senior author Xiao-Jiang Li, M.D., Ph.D., distinguished professor of human genetics at Emory, said.

The findings were published in The Journal of Clinical Investigation.

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Gene Editing Reverses Huntington's in Mouse Study - Bioscience Technology