The first study used CRISPR technology to cut off a small portion of the end of the APP gene in mice with Alzheimer's disease, found a decrease in the number of β-amyloid plaques and associated inflammatory markers, also saw an increase in neuroprotective APP, and most importantly, corrected behavioral and neurological deficits in the mice.
The second study used the CRISPR/dCas9 editing strategy to attempt to reduce APOE ε4, and the primary drug candidate has robustly reduced APOE ε4 levels in human-induced pluripotent stem cell-derived mini-brains in Alzheimer's disease patients as well as in humanized mouse models.
The gene-editing tool CRISPR is taking drug discovery by storm, and scientists are applying "gene scissors" to Alzheimer's disease.
On July 16, local time, at the 2023 Alzheimer's Association International Conference (AAIC) held in Amsterdam, the Netherlands, two independent studies looked at how genes increase the risk of neurodegenerative diseases and how gene editing can reduce risk or protect the brain from amyloid protein accumulation.
"[Conquering disease] always requires a variety of approaches, and CRISPR is another possible technology, and we're just scratching the surface." Maria Carrillo, chief scientific officer of the Alzheimer's Association, said there are also a number of research teams exploring the use of CRISPR to treat Alzheimer's disease and neurodegenerative diseases.
Two studies "pruned" different genes
The first study came from Subhojit Roy's lab at the University of California, San Diego (UCSD), where the team focused not on β-amyloid itself, but on amyloid precursor protein (APP), which causes an overproduction of β-amyloid in the brain, which leads to plaque buildup. It is considered a hallmark of Alzheimer's disease.
Dr. Brent Aulston, a member of Subhojit Roy's lab, called apps "central and indisputable" in Alzheimer's disease.
Researchers have studied different methods of cutting apps, creating protective or pathological products. Alston hopes to reduce amyloid production while increasing neuroprotectiveness. Using CRISPR technology, they cut off a small portion of the end of the APP gene in Alzheimer's mice and found a decrease in the number of β-amyloid plaques and associated inflammatory markers. They also saw an increase in neuroprotective apps and, most importantly, corrected behavioral and neurological deficits in the mice, and they did not observe any adverse side effects in normal mice.
"We believe this shows that in mice, our potential therapeutic strategy is both safe and effective." THESE RESULTS JUSTIFY FUTURE STUDIES AIMED AT APPLYING APP CRISPR EDITS TO HUMAN TESTING. Alston said the team has now received funding to improve the technology and hopes to one day test it on humans, but the process could take years. They are planning to explore which CRISPR enzymes and guide RNA fragments (the technological components that deliver CRISPR to the right places in the genome and cut genes) are most effective, and how to come up with a version that could be deployed in human brain cells.
Another study, proposed by Dr. Boris Kantor and Ornit Chiba-Falek of Duke University in the United States, looked at genes that contribute to Alzheimer's disease risk, specifically APOE ε4. Among the 3 alleles of APOE, APOEε4 is recognized as the strongest risk gene for Alzheimer's disease. The presence of APOE ε4 does not guarantee that a person will develop the disease, it only increases the risk of developing it. People with one copy of the gene have a 2-3-fold increased risk, while people with two copies of the gene have an 8-12-fold increased risk.
Boris Kanter and Onit Chiba-Farek have been working on an epigenomic therapy platform that uses CRISPR/dCas9 editing strategies to try to reduce APOE ε4, and the primary drug candidate has robustly reduced APOE ε4 levels in human-induced pluripotent stem cell-derived mini-brains in Alzheimer's disease patients as well as humanized mouse models without altering other neutral or protective APOE variants.
"These findings are incredibly exciting." "They provide proof-of-concept evidence supporting our approach as a high-potential new strategy to treat and possibly prevent Alzheimer's disease, which is currently incurable," Kanter said. ”
"This study aims to advance the field of Alzheimer's disease towards precision medicine like oncology, and the results so far support further preclinical research that could be used to obtain investigational new drug authorization from the U.S. Food and Drug Administration (FDA), which would allow for human trials," said Ornit Chiba-Farek.
Still at a very early stage
Alzheimer's disease is one of the most difficult areas of medical research. In early July, Leqembi (generic name: Lecanemab), jointly developed by Eisai and Biogen in the United States, received full FDA approval, but it has dozens of failed clinical trials behind it. On July 17, local time, the multinational pharmaceutical company Eli Lilly (LLY.US) announced the complete phase 3 clinical trial data of its new Alzheimer's disease drug Donanemab, and said that it had submitted a marketing application to the FDA, and the FDA is expected to make a regulatory decision within this year.
While the new treatment offers a glimmer of hope for patients and their families, the monoclonal antibody category to which Leqembi and Donanemab belong is not without risk, and the side effects of brain swelling and bleeding have been documented in clinical trials of both therapies.
"This means that innovative ideas like CRISPR are gaining popularity in the Alzheimer's community." Carrillo said that with Leqembi's successful listing, the Alzheimer's community may welcome a lot of cool science.
Resources:
1.https://www.fiercebiotech.com/research/scientists-turn-crispr-scissors-genes-involved-alzheimers
2.https://www.statnews.com/2023/07/16/alzheimers-disease-crispr-treatments/