QuÉbec Researchers Successfully Insert Icelandic Mutation In Vitro

Researchers in Québec have successfully inserted a gene that protects against Alzheimer’s disease into the genome of human cells in vitro, the first step toward studies in mice expressing the disease and eventual human trials.

The rare mutation was first identified in 2012 in the Icelandic population and has no known disadvantage for those who carry it, says lead author Professor Jacques-P. Tremblay with the Research Center of CHU de Quebec-Université Laval, Department of Molecular Medicine.  The Icelandic mutation makes it harder for the beta-secretase enzyme to cleave amyloid precursor protein, a process that results in the formation of amyloid plaques and, consequently, neuron death.   “Using an improved version of the CRISPR gene editing tool, we have been able to edit the genome of human cells to insert this mutation,” Tremblay says.

In theory, introducing the Icelandic mutation into the genome of people at risk of developing Alzheimer’s could prevent or slow the progression of the disease. “Unfortunately, we can’t go back and repair the damage that caused neurons to die,” Tremblay says. “The treatment would therefore be particularly suitable for people from families affected by the hereditary form of the disease, which manifests itself in memory problems from the age of 35 to 40. If successful, it could also potentially be used to treat people with the most common form of Alzheimer’s, which occurs after age 65, at the earliest signs of the disease.”

The challenge now is to find a way to edit the genome of millions of brain cells, Tremblay says. “We are looking at different possibilities, including the use of non-infectious viruses, to deliver the editing complex inside neurons. Now that the proof of concept has been established in human cells in vitro, we will test this approach in mice that express Alzheimer’s disease. If the findings are conclusive, we hope to be able to conduct a small-scale study in people with mutations that cause the onset of Alzheimer’s at age 35 to 40.”

The work, entitled Insertion of the Icelandic Mutation (A673T) by Prime Editing: A Potential Preventive Treatment for Familial and Sporadic Alzheimer's Disease, was recently published in The CRISPR Journal.