How CRISPR gene editing could help treat Alzheimer’s

Last month confirmed the first approval of a specific treatment using the CRISPR-Cas9 gene-editing tool, a treatment for sickle-cell disease and β-thalassemia that works through the correct cutting of a wrong fat in human cells. .

Meanwhile, researchers who are studying new treatments for Alzheimer’s disease are hoping to combine the same strategies against types of disease caused by genetic mutations.

Although there are currently some treatments to slow the progression of Alzheimer’s, they often fail to benefit people who are in the final stages or who have mutations that increase the risk of the disease. sick.

“CRISPR therapy can be a one-and-done solution, which no other medicine can match,” said Subhojit Roy, a neuroscientist at the University of California, San Diego. But he added that there is a long way to go before these treatments can be given against such a complex condition. “Cutting and pasting a gene is much more difficult to do in the brain using current technology.”

Promising equipment

Alzheimer’s is the most common form of dementia, a health issue of worldwide concern. More than 55 million people are affected by dementia, and this number is expected to almost triple by 2050. “We don’t fully understand how the brain works, which is difficult. there is a lot of challenge in understanding and treating brain diseases like Alzheimer’s,” said Tara. Spiers-Jones, who studies neurodegeneration at the University of Edinburgh, UK.

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Much of Alzheimer’s research is driven by the amyloid hypothesis, the idea that amyloid-β proteins build up in the brain, which eventually leads to plaque formation. These are called plaques, which are the main cause of the disease. Amyloid plaques cause another brain protein, called tau, to stick together and spread between neurons. It is usually during this process that symptoms such as loss of consciousness begin to appear. Generally, the more weather there is, the more severe the symptoms.

The drugs aducanumab and lecanemab target amyloid, and have been shown in clinical studies to slow cognitive decline in some people. Both drugs have been approved by the US Food and Drug Administration, but concerns about safety and efficacy remain.

CRISPR gene editing could open the door to other treatments in cases where the disease is linked to various diseases. One of the genes associated with late-onset Alzheimer’s apolipoprotein E (WHEN), which codes for a lipid transport protein in the brain that appears to affect tau protein uptake by neurons. People with genetic differences are called AFTER 4 There is a greater risk of developing Alzheimer’s, but those who have the APOE3 and APOE2 Different ones are in medium and low risk, respectively. One copy of AFTER 4 increasing human disease threefold. Having two copies increases it twelvefold.

In what Natural Medicine paper¹ Published in 2019, rare WHEN The mutation known as Christendom was found in a woman who, despite developing Alzheimer’s disease early in her life, did not show any symptoms. until he was seventy years old.

Yadong Huang, a neuropathologist at the Gladstone Institutes in San Francisco, California, and his colleagues used a CRISPR system to engineer the type of Cholesterol model in mice that carry people. AFTER 4. These mice were bred asexually, producing offspring with one or two copies of the genetic mutation.

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In a study published on 13 November i Nature Neuroscience²the team of mice with one copy of the AFTER 4-Christchurch variant partially protected against Alzheimer’s. Mice and two copies showed no expected signs of the disease.

“Our study suggests specific interventions for treatment AFTER 4– targeting Alzheimer’s disease by simulating the positive effects of the Christian mutation,” Huang said.

Another potential target for gene expression is a protein called presenilin-1 (PS1), which is essential for making an enzyme that affects in the production of amyloid-β is called γ-secretase. Mutations in PSEN1the gene that codes for PS1, increases the amount of a toxic type of amyloid-β called amyloid-β 42 that is produced in the brain, and is associated with early Alzheimer’s.

In a proof-of-concept study published last year in Nucleic Acid Molecular Therapy³scientists used a CRISPR system to cut, and disrupt, the mutant version of the PSEN1 gene in human cells.

The team managed to neutralize half of all mutants PSEN1 genes in cultured cells, which led to a complete reduction of PS1 and amyloid-β 42. This method is suitable for reducing the level of toxic proteins that affect a mutant form of a gene in their production, said study author Martin. Ingelsson, who studies neurotoxic mechanisms at the University of Toronto, Canada.

The team is now using the most precise gene-editing technique known as prime editing, which allows a partner to be replaced single DNA base. “I feel confident that one day we will be able to modify disease-causing genes with a precise surgical procedure,” Ingelsson said.

It’s a long way to the hospital

These strategies show promise in early research, but CRISPR-based gene therapies still have a long way to go, Spiers-Jones said. As with any new treatment, safety concerns must be addressed. “Genetic regulation is not always perfect. “There may be unintended consequences including changes in healthy genes or damage to entire chromosomes,” he said.

Roy agrees. It’s one thing to experiment with CRISPR techniques using cells and animal models, he said, but it’s another to take the test. Alzheimer’s disease in the hospital. “There is no clinical trial to use any type of CRISPR technology in the brain – it needs to be established first.”

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Roy and his friends are pursuing this path. Follow up on successful lesion studies using the CRISPR system to correct an Alzheimer’s-related gene called APP⁴, the researchers have received funding from the US National Institutes of Health to continue their research in a first phase. It involves finding out which gene sequence is best used in the human brain.

Roy hopes that “one day the neurologists who treat Alzheimer’s disease will prescribe a single dose using CRISPR, may be combined with other antibody-based therapies”.

As with other disease treatments, high treatment costs can present a challenge down the line, said Gerold Schmitt-Ulms, who studies protein functions in Alzheimer’s at the University of Toronto, Canada. “At the current pace in this area, innovative treatments are only a few years away,” he said. “At that time, the biggest challenge was to make these specialized and affordable treatments available to the masses.”