CRISPR gene therapy: Can it cure Alzheimer’s disease?

CRISPR gene therapy: Can it cure Alzheimer’s disease?

During the Alzheimer’s Association International Conference (AAIC) 2023 in Amsterdam, two cutting-edge CRISPR-based therapy strategies for Alzheimer’s disease were disclosed.

One strategy is to lessen the impact of the APOE-e4 gene, a substantial genetic risk factor for Alzheimer’s. The second strategy is to lessen the amount of beta-amyloid, a damaging protein linked to the illness.

These innovations offer hope to people who are impacted by Alzheimer’s and have the potential to advance treatment options.

Scientists modify genes using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) mechanism. Similar to a pair of tiny molecular scissors, CRISPR makes a precise cut in a particular spot in a DNA sequence.

Once the DNA has been sliced, researchers can eliminate undesirable genes, replace defective genes with healthy ones, or even add new genes entirely.

CRISPR has the potential to advance our understanding of genetic disorders, and aid in the creation of fresh therapies. Also, it hastens the discovery of new therapeutic targets and eventually speed up the drug discovery process.

At the Alzheimer’s Association International Conference (AAIC) 2023, which was recently held in Amsterdam, researchers announced two new CRISPR-based therapeutic strategies to cure and prevent Alzheimer’s.

Decreased synthesis of amyloid beta after CRISPR

As part of the initial investigation, scientists at the University of California, San Diego, created a CRISPR-based gene-editing method. It selectively targets the amyloid precursor protein (APP), a key component of Alzheimer’s disease.

The APP gene generates a variety of byproducts, some of which are pathological (beta-amyloid, sAPPa), while others are protective (sAPPa).

This strategy seeks to increase neuroprotective effects while reducing beta-amyloid formation. The researchers experimented on mice with Alzheimer’s disease to see how well their plan worked.

They discovered that beta-amyloid plaques decreased with CRISPR therapy, as did brain inflammatory indicators, and neuroprotective APP products increased. Also, behavioral and nervous system performance improved.

Importantly, CRISPR editing did not have any unfavourable impacts in mice that were in good health.

According to study, lead author Dr. Brent Aulston, a postdoctoral researcher at the Altman Clinical and Translational Research Institute at UC San Diego, “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 tried this strategy in rats that exhibit the same disease symptoms as do human Alzheimer’s patients, and we have discovered that our medication lowers disease markers. Additionally, no unfavorable side effects have been noticed,” he added.

Our CRISPR therapy was developed to treat both familial and sporadic varieties of Alzheimer’s disease, according to the authors. Dr. Brent Aulston stated, “We are currently working on transferring this strategy from the lab to the clinic with the hope that our CRISPR-based gene therapy will someday be a treatment option for the illness”.

The APOE gene’s expression may be reduced via CRISPR.

In a different study, a group of scientists from Duke University created a potential therapeutic strategy utilizing CRISPR to target APOE-e4, a genetic risk factor for Alzheimer’s disease.

It is more likely to get Alzheimer’s if you inherit this gene; one copy of APOE-e4 enhances the risk by two to three times, and two copies further magnify the risk by about eight to twelve times.

To reduce the levels of APOE-e4, the researchers used an epigenome treatment platform based on the CRISPR/dCas9-editing technique.

In human induced pluripotent stem cell-derived miniature brains from an Alzheimer’s patient as well as in humanized mice models, their lead candidate showed notable efficacy in lowering APOE-e4 levels.

It’s significant that this strategy had no impact on the levels of other APOE variants thought to have a protective or neutral effect.

The most powerful genetic risk factor for Alzheimer’s is APOE.

As a senior co-author of the study and professor at the Duke University Medical Center’s Alzheimer’s Disease Research Centre and Centre for Genomic and Computational Biology, Dr. Ornit Chiba-Falek stated that they have created this innovative 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,” explained 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,” the researcher continued.

A newly discovered therapeutic target for Alzheimer’s disease is APOE. Dr. Ornit Chiba-Falek stated, “The findings of this study pave the way for gene therapy in Alzheimer’s disease and lay the groundwork for the advancement of this APOE-targeted epigenome therapy towards clinical studies and ultimately precision medicine in Alzheimer’s.”

Proof-of-concept, therefore more study is required

The chief medical officer and CEO of INmune Bio, Raymond J. Tesi, MD, told MNT that “this technology is fascinating and promising.” However, Dr. Tesi noted that at this time, Alzheimer’s disease might not be the optimal condition to use CRISPR.

“Using CRISPR to treat [Alzheimer’s patients] and stop the production of new amyloid is a confused approach. According to what I understand, CRISPR therapy will prevent the creation of amyloid but will not eliminate it for people with [Alzheimer’s]. Is not removing amyloid from the brain the goal of amyloid-targeted therapy? Does eliminating amyloid from the brain have the same advantages as preventing its production? I’m not sure,” he replied.

Is this outcome sufficient to conduct a clinical trial? To think that stopping more amyloid synthesis will have the same therapeutic advantages as eliminating amyloid from the brain strikes me as naive. Dr. Raymond J. Tesi remarked, “I either need more information or more research on this therapeutic approach.”

Dr. Tesi stated that while thinking about the second strategy, “60% of Alzheimer’s patients exhibit ApoE4. Unfortunately, we are unsure of which ApoE4 patients may ultimately get [the condition].

“In addition, we don’t know what ApoE4 does. In other words, does ApoE4 contribute to the pathology that results in [Alzheimer’s] or does ApoE4 itself contribute to cognitive decline? Before we apply it to humans, in my opinion, more research needs to be done to better understand the impact of’silencing’ ApoE4,” he said.

I think it’s time to broaden our efforts beyond the amyloid-targeting therapy approaches; we know how effective they are,” Dr. Raymond J. Tesi declared that ApoE4 is an intriguing target that merits more investigation.

There are a lot of other targets worth considering. We favour neuroinflammation and have evidence to back up that therapeutic approach, said Dr. Tesi.

Another aspect to take into account is cost.

Dr. Tesi also emphasised the significance of taking into account cost while planning gene therapies. All currently accessible gene therapies cost millions of dollars.

The lecanemab (Leqembi) community considers its $26,500 annual cost to be prohibitive. Anti-amyloid CRISPR therapies are anticipated to cost significantly more than antibody-based therapies.

Patients, payers, and governments are all impacted by this issue in practice because therapies, especially preventative ones, should be less expensive than treatments.

It will be crucial to strike a balance between the attractiveness of new technology and its actual use.

Ultimately, more research is required because many therapeutic approaches are only at the proof-of-concept stage.

In addition to continuing to research potential treatment targets, it is important to take into account the logistical and financial difficulties involved in actually providing these kinds of therapy.


For Alzheimer’s disease medications that have been suggested by doctors worldwide are available here

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