CRISPR genome editing offers new approaches to treating Alzheimer's

Two potential new treatments for Alzheimer's disease using CRISPR-based genome editing have been reported at the Alzheimer's Association International Conference, in Amsterdam, the Netherlands.

Scientists from the University of California San Diego, have shown that CRISPR genome editing is able to reduce the production of amyloid beta, a toxic protein in the brain that is a known hallmark of Alzheimer's disease. Whereas, scientists from Duke University, Durham, North Carolina, targeted the APOE ε4 allele of the APOE gene, which is well-known to influence Alzheimer's risk.

'Studies such as these two that focus the most advanced technologies... are enthusiastically welcomed, and need to be multiplied many times over,' said Dr Maria Carrillo, chief science officer at the Alzheimer's Association. 'We envision a future where multiple treatments address every aspect of this most complex disease. And that, once proven, the treatments can be combined in ways that complement and enhance each other to reduce risk, treat effectively, stop the progression and eventually cure Alzheimer's disease and all other dementia.'

At the University of California San Diego, Dr Brent Aulston and colleagues developed a genome editing approach to target the amyloid precursor protein (APP). In the brain, APP is cut by enzymes to create smaller fragments, known as peptides, two of which are soluble amyloid precursor protein (sAPP) and amyloid beta (β) peptide. sAPP is neuroprotective, whereas, amyloid beta is pathologic, and is the main component of amyloid plaques found in the brains of people with Alzheimer's disease.

The researchers found that genome editing in an Alzheimer's disease mouse model led to a reduction of beta amyloid plaques and associated brain inflammatory markers, and an increase in sAPP and correction of behavioural and nervous system function deficits. Furthermore, the researchers noted that no undesirable side effects were observed.

Dr Aulston commented: 'We believe this demonstrates that, in mice, our potential treatment strategy is both safe and efficacious… These results justify future studies aimed at getting APP CRISPR editing into human testing.'

At Duke University, Professor Ornit Chiba-Falek, Dr Boris Kantor and colleagues used the CRISPR/dCas9 approach to specifically target the APOE ε4 allele. The dCas9 enzyme binds to its DNA target but does not cut it. The binding alone prevents the cell from initiating transcription, therefore inhibiting gene expression.

There are at least three alleles of the APOE gene, ε2, ε3, and ε4, each associated with different risks of developing Alzheimer's disease. APOE ε3 is the most common, and found in more than half of the general population. It is neutral with respect to Alzheimer's disease. APOE ε2 is thought to provide some protection against the disease, whereas APOE ε4 increases a person's risk of developing the disease and is associated with an earlier age of disease onset in certain populations. But, it is worth noting that not all who carry the high-risk allele will develop the disease.

The researchers discovered that the lead candidate of their epigenome-editing-based gene therapy significantly reduced the levels of the APOE ε4 allele and APOE ε4 protein in both human induced pluripotent stem cell derived miniature brains from an Alzheimer's patient and humanised mouse models. Importantly their approach did not change the levels of the other neutral or protective APOE alleles or associated proteins.

'The findings are incredibly exciting,' Dr Kantor said. 'They provide proof-of-concept evidence supporting our approach as a high potential new strategy to treat and possibly even prevent Alzheimer's disease, which currently has no cure.'