CRISPR Gene Editing: From Sickle Cell Disease to Alzheimer's Treatment

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CRISPR Gene Editing: From Sickle Cell Disease to Alzheimer’s Treatment

CRISPR Gene Editing: From Sickle Cell Disease to Alzheimer’s Treatment

CRISPR Gene Editing Therapy Takes Root in the UK, US, and Europe, Now Aims to Tackle Alzheimer’s Disease.

“I believe that one day we will be able to change disease-causing genes with the precision of a surgical procedure.” On November 16, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom announced conditional approval for the CRISPR/Cas9 gene editing therapy Casgevy (exa-cel) for treating sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT).

On December 8, the U.S. Food and Drug Administration (FDA) approved its use for treating SCD. On December 15, the European Medicines Agency (EMA) also granted approval for its use in treating SCD and TDT.

Now, researchers are exploring the use of CRISPR/Cas9 gene editing therapy for Alzheimer’s disease (AD).

CRISPR Gene Editing: From Sickle Cell Disease to Alzheimer's Treatment

On December 11, an article titled “How CRISPR gene editing could help treat Alzheimer’s” was published in the journal Nature, attempting to explore the potential of using CRISPR therapy to treat Alzheimer’s disease.

“CRISPR therapy may be a one-time treatment, unmatched by other drugs.” Subhojit Roy, a neuroscientist at the University of California, San Diego, stated, “There is still a long way to go before these therapies can be used to treat such complex diseases. Using current technology to cut and paste genes in the brain is very challenging.”

Changing APOE4 or PSEN1

According to the article, over 550,000 people worldwide are currently affected by dementia, with this number expected to double by 2050. Alzheimer’s disease is the most common form of dementia and also a complex condition.

“We do not fully understand how the brain works, making the understanding and treatment of Alzheimer’s disease and other brain disorders a significant challenge,” said Tara Spires-Jones, a researcher studying neurodegenerative diseases at the University of Edinburgh.

The article points out that most research on Alzheimer’s disease is driven by the amyloid hypothesis, which suggests that the accumulation of beta-amyloid protein in the brain is a major factor in the disease, eventually forming plaques. Amyloid plaques trigger another protein called “tau” to aggregate and spread within neurons. Typically, during this process, symptoms such as memory loss begin to appear. The more tau protein, the more severe the symptoms.

Antibody drugs Aducanumab and Lecanemab for treating Alzheimer’s target beta-amyloid, and clinical trials show they can slow cognitive decline in some individuals. While both drugs have received FDA approval, concerns about their safety and effectiveness persist.

CRISPR gene editing could offer an alternative treatment. Gene editing is an emerging gene engineering technology that allows precise modification of specific target genes in an organism.

One gene associated with late-onset Alzheimer’s disease is apolipoprotein E (APOE), which encodes a lipid transport protein in the brain that may affect neuronal uptake of tau protein. Individuals with the APOE4 gene mutation have the highest risk of developing Alzheimer’s disease, while those with APOE2 and APOE3 gene mutations have moderate and low risks, respectively. Having one copy of the APOE4 gene increases the risk of Alzheimer’s disease by three times, and having two copies increases the risk by 12 times.

In a 2019 paper published in Nature Medicine, researchers discovered a rare APOE variant named Christchurch in a woman who had a genetic predisposition but showed no symptoms before her seventies. Using the CRISPR system, scientists at the Gladstone Institutes in San Francisco transformed the Christchurch gene mutation into mice carrying the human APOE4, producing engineered offspring with one or two copies.

In a study published on November 13 in Nature Neuroscience, the research team found that mice with one copy of the APOE4-Christchurch variant had partial protection against Alzheimer’s disease, while those with two copies did not show the expected signs.

“Our research suggests that by mimicking the beneficial effects of the Christchurch mutation, potential therapeutic interventions can be made for APOE4-related Alzheimer’s disease,” said Yado Huang, a neuropathologist at the Gladstone Institutes.

The article in Nature mentions another potential target for gene editing, a protein called presenilin-1 (PS1), which is crucial for the production of an enzyme involved in beta-amyloid production called gamma-secretase. Mutations in PSEN1 (the gene encoding PS1) increase the production of toxic beta-amyloid 42 in the brain and are associated with early-onset Alzheimer’s disease.

In a conceptual validation study published in Molecular Therapy Nucleic Acids in 2022, scientists used the CRISPR system to cut and disrupt the mutated version of the PSEN1 gene in human cells. The team was able to disrupt half of the mutated PSEN1 genes in cultured cells, resulting in an overall reduction in the quantity of PS1 and beta-amyloid 42.

“This method is well-suited for reducing the levels of toxic proteins because the gene mutations involved participate in the production of toxic proteins,” said Martin Ingelsson, a co-author of the article and a researcher studying the mechanisms of neurotoxicity at the University of Toronto.

The team is now attempting to use a super-precise gene editing technology called prime editing, which can replace individual DNA base pairs. “I believe that one day we will be able to change disease-causing genes with the precision of a surgical procedure,” said Ingelsson.

Challenges of Safety and High Costs

While these strategies show promise in early studies, CRISPR gene editing therapy still has a long way to go. Like any new therapy, safety concerns must be addressed. “Gene editing is not always perfect. There may be off-target effects, including mutations in healthy genes or damage to entire chromosomes,” said Jones.

Roy concurs with this assessment. He stated that experimenting with the CRISPR system on cells and animal models is one thing, but bringing Alzheimer’s disease gene editing strategies to the clinic is another. “There are currently no clinical trials using any CRISPR technology in the brain. It’s essential to establish a research foundation before applying these techniques to such complex diseases.”

Roy and his colleagues are working to continue their research. Following the success of animal studies editing the APP gene related to Alzheimer’s disease using the CRISPR system, the researchers have received funding from the National Institutes of Health (NIH) to advance their research to the preclinical stage, including determining which gene editing system is best suited for use in the human brain.

“I hope that one day, neuroscientists studying Alzheimer’s disease will administer a one-time CRISPR injection, perhaps in combination with other antibody-based therapies,” said Roy.

Additionally, like other gene therapies, the high cost of treatment may pose further challenges. Gerold Schmitt-Ulms, a researcher at the University of Toronto studying Alzheimer’s disease protein function, said, “Given the current pace of innovation in this field, the emergence of transformative treatments may only take a few years. At that point, the biggest challenge will be providing these personalized and expensive treatment methods to the public.”

Reference: Nature Article