Bristol Researchers Converted APOE4 to APOE3 in Blood Cells from People with Alzheimer's Disease
Bristol Researchers Converted APOE4 to APOE3 in Blood Cells from People with Alzheimer's Disease
On September 28, a team at the University of Bristol reported an experiment on immune blood cells obtained from people with Alzheimer's disease: the APOE4 gene variant, which carries elevated disease risk, was converted to APOE3 in these cells. According to the university, the editing had little effect on the rest of the cells' DNA.
The APOE gene exists in several variants that differ in their influence on Alzheimer's disease risk. APOE4 is considered the strongest known genetic risk factor, while APOE3 is associated with lower risk. The difference lies in the protein encoded by this gene: it helps the brain clear beta-amyloid, a toxic protein that accumulates in the brain in Alzheimer's disease and forms characteristic plaques. The APOE4 protein clears beta-amyloid less effectively than the protein of the more common APOE3, and it was this conversion, from APOE4 to APOE3, that Associate Professor Kevin Kemp's team performed in these cells.
For future clinical use, the authors are considering delivering the therapy through the bloodstream. Their rationale involves the blood-brain barrier, a layer of cells between the blood and brain tissue: according to the University of Bristol, this barrier prevents some Alzheimer's treatments from reaching all regions of the brain. Another therapy is also attempting to reach the brain through the blood: the gene therapy VY1706 from the American company Voyager, a viral vector that must cross the same barrier to suppress production of tau, another toxic protein that accumulates in the brain in Alzheimer's disease. Kemp's team chose a different approach: rather than using a vector that must breach the barrier from outside, they edit the gene directly in immune blood cells that already circulate in the bloodstream. For now, this is a cell-based experiment.
A separate approach was already tested in the clinical trial LX1001: a viral vector delivered the code for the APOE2 variant into the fluid surrounding the brain and spinal cord. In the international clinical trials registry ClinicalTrials.gov, this phase 1/2 study with 15 participants is listed as completed. The LX1001 approach adds a new copy of the APOE2 gene to the body, whereas Kemp edits the existing APOE4 gene directly in blood cells.
"Our research is still at an early stage, but we are very excited about the results we are seeing. By targeting the high-risk APOE4 gene, we hope to address one of the key risk factors for Alzheimer's disease and ultimately develop a new treatment," Kemp said.