Deleting only a small portion of a gene in brain cells might slow the progression or delay the development of Alzheimer鈥檚 disease. In mice, the therapy reduces the formation of amyloid plaques, the characteristic clumps of proteins seen in the brains of people with the condition.
Past attempts at using CRISPR gene-editing technology for neurodegenerative diseases often focused on removing DNA sequences implicated in disease pathology, but this can have unintended consequences. Take for example the APP gene, which contains instructions for making a protein called amyloid precursor protein. The protein is concentrated in the brain鈥檚 synapses and found in amyloid plaques. Mice without the APP gene don鈥檛 accumulate amyloid plaques, but they develop neuroinflammation and cognitive impairments and have fewer neurons.
鈥淭urns out APP does a lot of good things. It鈥檚 something we want to keep in the brain,鈥� says at the University of California, San Diego. That is why Aulston and his colleagues took a more conservative approach. 鈥淲e鈥檙e not knocking out an entire gene, we鈥檙e only editing out a small piece of it,鈥� he says.
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The small segment they have identified is located at the tail end of the APP gene, and when expressed by brain cells, it kickstarts a chain reaction that leads to amyloid plaque formation.
The researchers used CRISPR to remove this gene segment from the brain cells of four mice that were 1.5 months old. An equal number of mice serving as controls received a scrambled CRISPR sequence, meaning it didn鈥檛 target and remove any genes. All the mice had been genetically modified to develop characteristics of Alzheimer鈥檚 disease at around 2 months of age.
After two-and-a-half months, the researchers euthanised the mice and examined their brains. They found that mice lacking the gene segment had 44 per cent fewer amyloid plaques, on average, than mice in the control group. Levels of a protein associated with neuroinflammation were also about 40 per cent lower in the gene-edited mice compared with controls.
鈥淚f you applied that to a human, that would probably be pretty exciting,鈥� says Aulston, who presented these findings at a November meeting of the Society for Neuroscience in San Diego, California. The disease characteristics seen in these mice is typically more aggressive than Alzheimer鈥檚 disease in humans. 鈥淚n a less aggressive model [the results] might even be better,鈥� he says.
Aulston says he and his team have conducted subsequent experiments in which the mice were observed for longer, sometimes up to a year, and had similar results. In future experiments, they plan to assess whether the CRISPR therapy also improves cognition. This step will be key 鈥� many drug treatments designed to clear amyloid plaques from the brain have failed in clinical trials because they didn鈥檛 meaningfully improve cognition.
The gene-editing approach didn鈥檛 cause any adverse side effects, including in a separate group of mice that were genetically modified before birth to not have the APP segment in any of their cells. These mice didn鈥檛 differ from their untreated littermates in terms of body weight, brain weight or neuroinflammation, but they did show signs of improved cognition.
However, like all other applications of CRISPR, one major challenge is finding a way to deliver the therapy across the blood-brain barrier and into cells, says at Laval University in Canada. While the blood-brain barrier protects brain cells from harmful chemicals and pathogens, it also keeps out many medicines.
Aulston and his colleagues packaged CRISPR into a non-pathogenic virus called an adeno-associated virus (AAV), which crosses the blood-brain barrier in mice. 鈥淭here鈥檚 lots of ongoing trials with AAVs in humans already, so that鈥檚 why we wanted to use that approach,鈥� he says.
While this technique significantly improves CRISPR鈥檚 ability to cross the blood-brain barrier, it isn鈥檛 perfect. The researchers estimate that they were only able to edit half of the brain cells in the mice, and they are currently working to establish the minimum number they must hit to make the treatment effective.
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