Gene-editing technology may help scientists create new treatments for Alzheimer’s. Olga Sibirskaya/Stocksy
  • Two innovative CRISPR-based therapeutic approaches for Alzheimer’s disease were unveiled during the Alzheimer’s Association International Conference (AAIC) 2023 in Amsterdam.
  • One method targets the APOE-e4 gene, a significant genetic risk factor for Alzheimer’s, aiming to mitigate its effects.
  • The other method focuses on reducing the production of beta-amyloid, a harmful protein associated with the disease.
  • These developments hold promise for advancing treatment options and provide hope for those affected by Alzheimer’s.

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), a gene editing system, is a method scientists use to edit genes.

CRISPR is like a pair of tiny molecular scissors that make a targeted cut in a specific location of a DNA sequence.

Once the DNA is cut, scientists can replace faulty genes with a healthy one, remove problematic genes or even introduce new genes altogether.

CRISPR has the potential to help us understand genetic diseases better and develop new treatments or help expedite the identification of drug targets, ultimately accelerating the drug discovery process.

Recently, scientists unveiled two new CRISPR-based therapeutic approaches to treat and prevent Alzheimer’s at the Alzheimer’s Association International Conference (AAIC) 2023, held in Amsterdam.

As part of the first study, researchers at the University of California San Diego developed a gene-editing technique using CRISPR that specifically targets the amyloid precursor protein (APP), which plays a critical role in Alzheimer’s disease.

The APP gene produces different products, some of which are protective (sAPPa), while others, like beta-amyloid, are associated with pathology.

This approach aims to decrease the production of beta-amyloid while promoting neuroprotective actions. To test their strategy, the researchers conducted experiments on mice with Alzheimer’s disease.

They found that CRISPR treatment resulted in a reduction in beta-amyloid plaques, a decrease in brain inflammation markers, an increase in neuroprotective APP products, and improvements in behavioral and nervous system function.

Importantly, CRISPR editing did not cause any undesirable side effects in healthy mice.

Dr. Brent Aulston, lead author and postdoctoral scholar at the Altman Clinical and Translational Research Institute at UC San Diego, told Medical News Today that “the idea of our therapeutic is to utilize CRISPR to introduce a change in the patient’s genome that is protective against Alzheimer’s disease.”

“So far, we have tested this approach in mice that have the same disease characteristics as human Alzheimer’s patients and found that our therapy decreases markers of disease. Moreover, no unwanted side effects have been observed,” he said.

“Our CRISPR therapeutic was designed so that it can be applied to all forms of Alzheimer’s disease (i.e. familial and sporadic types). We are currently working on translating this approach from the lab to the clinic with the goal of our CRISPR-based gene therapy being a treatment option for the disease someday.”
— Dr. Brent Aulston

In another study, a team of researchers from Duke University developed a potential therapeutic approach using CRISPR to target a genetic risk factor for Alzheimer’s disease called APOE-e4.

Inheriting this gene increases the likelihood of developing Alzheimer’s, with one copy of APOE-e4 increasing the risk by two- to three-fold and two copies further amplifying the risk by approximately eight- to twelve-fold.

The researchers utilized an epigenome therapy platform based on CRISPR/dCas9-editing strategy to lower the levels of APOE-e4.

Their lead candidate demonstrated significant success in reducing APOE-e4 levels in human-induced pluripotent stem cell-derived miniature brains from an Alzheimer’s patient, as well as in humanized mouse models.

Importantly, this approach did not affect the levels of other APOE variants believed to have a neutral or protective effect.

Dr. Ornit Chiba-Falek, professor at the Alzheimer’s Disease Research Center and Center for Genomic and Computational Biology, Duke University Medical Center, a senior co-author of the study, said they had developed this novel therapeutic platform for Alzheimer’s based on gene editing technology.

“The platform reduces the expression of APOE, the strongest genetic risk factor for Alzheimer’s disease, by closing the genomic region surrounding the gene making it less accessible for the transcriptional machinery,” said Dr. Chiba-Falek.

“This study provides proof-of-concept for our therapeutic strategy in both human-based cellular and rodent models, demonstrating the efficacy and beneficial effects related to Alzheimer’s pathology,” she added.

“APOE is a new emerging therapeutic target for Alzheimer’s disease. The outcomes of this study set the stage for gene therapy in Alzheimer’s disease and provide the foundation to advance this APOE-targeted epigenome therapy towards clinical studies and ultimately precision medicine in Alzheimer’s.”
— Dr. Ornit Chiba-Falek

Raymond J. Tesi, MDm CEO and Chief Medical Officer at INmune Bio, told MNT that “this technology is fascinating and promising.”

“However, Alzheimer’s disease may not be the best place to apply CRISPR at this time,” Dr, Tesi said.

“Treating [Alzheimer’s] patients with CRISPR to prevent the formation of additional amyloid is a confusing strategy. As I understand it, CRISPR therapy will stop amyloid production but will not remove amyloid for patients with [Alzheimer’s]. Isn’t the role of amyloid-targeted therapy to remove amyloid from the brain? Does stopping amyloid production have the same benefit as removing amyloid from the brain? I don’t know,” he said.

“Is this result good enough to perform a clinical trial? I believe it is naïve to assume preventing more amyloid production will have the same therapeutic benefits as removing amyloid from the brain. I either need more information, or this therapeutic strategy needs more research.

— Dr. Raymond J. Tesi

When considering the second approach, Dr. Tesi said, “60 percent of [Alzheimer’s] patients express ApoE4. Unfortunately, we don’t know which patients with ApoE4 will develop [the disease].”

“Furthermore, we don’t understand what ApoE4 does. That is, is ApoE4 associated with a pathology that causes [Alzheimer’s] or is ApoE4 the cause of cognitive decline? In my opinion, additional research must be done to better understand if the impact of ‘silencing’ ApoE4 before we apply it to humans,” he said.

“I believe it is time to expand our efforts beyond the therapeutic strategies of targeting amyloid – we know how well that works. ApoE4 is an interesting target that deserves more study.”
— Dr. Raymond J. Tesi

“There are many other targets worth thinking about. We like neuroinflammation and have data to support that therapeutic strategy,” Dr. Tesi added.

Dr. Tesi also pointed out how cost is an important factor to consider in gene therapies. Currently, all available gene therapies are priced in the millions of dollars.

The Alzheimer’s community finds the cost of lecanemab (Leqembi) at $26,500 per year, already burdensome. It is expected that an anti-amyloid CRISPR therapy will be even more expensive than antibody-based treatments.

This practical issue affects patients, payers, and governments, as the cost of therapies, especially preventive ones, should be lower than treatment costs.

It will be important to balance the allure of new technology with its practical application.

Ultimately, these therapeutic strategies are at the proof-of-concept stage, and further research is needed.

Not only to continue to study appropriate therapeutic targets but also to consider the practical and financial challenges of delivering these types of therapy in practice.