The Potential of CRISPR Gene Editing for Alzheimer’s Treatment

The recent approval of a gene therapy utilizing the CRISPR–Cas9 gene-editing tool for blood conditions has spurred researchers to explore similar strategies for treating certain forms of Alzheimer’s disease rooted in genetic mutations. While there are existing treatments that can slow the progression of Alzheimer’s, they may not be effective for individuals in later stages or those with specific genetic mutations associated with an increased risk of the disease.

Subhojit Roy, a neuroscientist at the University of California, San Diego, expresses optimism about the potential of CRISPR therapies to serve as a comprehensive and singular cure for Alzheimer’s disease. However, he acknowledges that there is a substantial distance to cover before these therapies can be effectively applied to such a complex condition. The challenges lie in the intricacies of performing gene cutting and pasting within the brain using current technology.

A tool with great potential

Alzheimer’s, the most prevalent form of dementia globally, affects over 55 million people, and projections indicate this number could nearly triple by 2050. Tara Spires-Jones, a neurodegeneration researcher at the University of Edinburgh, highlights the formidable challenge of understanding and treating brain diseases like Alzheimer’s due to our incomplete understanding of how the brain functions.

Much of Alzheimer’s research revolves around the amyloid hypothesis, suggesting that the accumulation of amyloid-β proteins in the brain, forming plaques, is a primary cause of the disease. These amyloid plaques trigger the clumping of another brain protein, tau, which then spreads inside neurons. Symptoms, such as memory loss, typically manifest well into this process. The severity of symptoms tends to correlate with the presence of tau. Antibody drugs like aducanumab and lecanemab target amyloid and have demonstrated in clinical trials their ability to slow cognitive decline in some individuals. However, concerns persist regarding their safety and efficacy.

CRISPR gene editing presents a potential avenue for alternative treatments, particularly in cases linked to specific genetic variants. One such gene associated with late-onset Alzheimer’s is apolipoprotein E (APOE), coding for a lipid transport protein in the brain affecting tau protein uptake by neurons. APOE4 variant carriers face the highest Alzheimer’s risk, while APOE3 and APOE2 variants pose medium and low risks, respectively. Engineering the rare APOE variant called Christchurch into mice carrying human APOE4, Yadong Huang and his team at Gladstone Institutes used CRISPR to explore the impact. This variant, discovered in a woman genetically predisposed to Alzheimer’s, exhibited no symptoms until her seventies.

In a study reported on November 13 in Nature Neuroscience, researchers discovered that mice carrying one copy of the APOE4-Christchurch variant exhibited partial protection against Alzheimer’s, while those with two copies showed no signs of the disease. Yadong Huang, who led the study, suggests that their findings indicate potential therapeutic interventions for APOE4-related Alzheimer’s by replicating the beneficial effects of the Christchurch mutation.

Another target for gene-editing interventions is the presenilin-1 (PS1) protein, essential for producing an enzyme involved in amyloid-β production known as γ-secretase. Mutations in the PSEN1 gene, coding for PS1, have been linked to early-onset Alzheimer’s by increasing the production of a toxic form of amyloid-β called amyloid-β 42.

In a proof-of-concept study published last year in Molecular Therapy Nucleic Acids, scientists utilized CRISPR to disrupt the mutant version of the PSEN1 gene in human cells. This approach successfully disrupted half of all mutant PSEN1 genes in cultured cells, resulting in a reduction in both PS1 and amyloid-β 42. According to Martin Ingelsson, a co-author of the study, this method is particularly effective for reducing levels of toxic proteins when a mutant form of a gene is involved in their production.

The researchers are now employing the super-precise gene-editing technique known as prime editing, which allows the replacement of a single DNA base pair. Ingelsson expresses confidence that this approach will eventually enable the precise alteration of disease-causing genes.

The journey to the clinic is far from short

While CRISPR-based gene therapies show promise in early studies, there is still a considerable distance to cover, according to Tara Spires-Jones. Safety concerns must be addressed, as gene editing is not flawless, potentially leading to off-target effects such as mutations in healthy genes or damage to entire chromosomes.

Subhojit Roy emphasizes the need for caution in transitioning from experiments with CRISPR systems in cells and animal models to clinical applications for Alzheimer’s gene-editing strategies. He highlights the absence of clinical trials utilizing any form of CRISPR technology in the brain, emphasizing the necessity of laying the groundwork first.

Roy and his team are actively pursuing this groundwork, having received funding from the US National Institutes of Health for preclinical research after successful animal studies using a CRISPR system to edit the Alzheimer’s-linked gene APP. The next steps involve determining the most suitable gene-editing system for use in the human brain.

Roy envisions a future where neurologists might prescribe a one-time CRISPR injection, possibly in combination with other antibody-based therapies, for Alzheimer’s patients. However, Gerold Schmitt-Ulms cautions that high treatment costs could pose a challenge down the line. He believes that transformative treatments are only a few years away, but the primary hurdle will be making these personalized and costly treatments accessible to a broader population.

Resources

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4. ^JOURNAL Konstantinidis, E., Molisak, A., Perrin, F., Streubel-Gallasch, L., Fayad, S. M., Kim, D. Y., Petri, K., Aryee, M. J., Aguilar, X., György, B., Giedraitis, V., Joung, J. K., Pattanayak, V., Essand, M., Erlandsson, A., Berezovska, O., & Ingelsson, M. (2022). CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer’s disease PSEN1 M146L mutation. Molecular Therapy – Nucleic Acids, 28, 450–461. [Molecular Therapy – Nucleic Acids]
5. ^JOURNAL Sun, J., Carlson-Stevermer, J., Das, U., Shen, M., Delenclos, M., Snead, A. M., Koo, S. Y., Wang, L., Qiao, D., Loi, J., Petersen, A. J., Stockton, M. E., Bhattacharyya, A., Jones, M. V., Zhao, X., McLean, P. J., Sproul, A. A., Saha, K., & Roy, S. (2019). CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nature Communications, 10(1). [Nature Communications]

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