A world-first experiment at UCL and UCLH has discovered a potential gene therapy for Alzheimer’s disease that can safely and effectively reduce levels of the toxic tau protein believed to trigger the disease.
The trial, led by consultant neurologist Dr. Catherine Mummery (UCL Queen Square Institute of Neurology & the National Hospital for Neurology and Neurosurgery), is the first to use “gene silencing” in dementia and Alzheimer’s disease.
The technique employs BIIB080 (/IONIS-MAPTRx), an antisense oligonucleotide (used to inhibit RNA from generating a protein), to “silence” the tau protein-coding gene, known as the microtubule-associated protein tau (MAPT) gene. This inhibits the gene from being dosed and reversibly translated into protein. It will also reduce the creation of that protein, changing the course of the condition.
More trials in bigger groups of patients will be required to evaluate whether this strategy results in clinical benefit, but the phase 1 results reported in Nature Medicine—results from 46 people—are the first evidence that this method has a biological effect.
There are presently no therapies available that target tau. The medications aducanumab and lecanemab, which were recently approved by the FDA for usage in certain settings, target a different disease mechanism in Alzheimer’s disease, the formation of amyloid plaques.
The phase 1 trial investigated BIIB080’s safety, what it does in the body, and how successfully it targets the MAPT gene. It involved the UCL Dementia Research Center, was funded by the NIHR UCLH Biomedical Research Center, and took place at the Leonard Wolfson Experimental Neurology Center at NHNN.
The experiment, which lasted from 2017 to 2020, involved 46 participants with an average age of 66.
The medication was well tolerated, with all patients finishing the treatment period and more than 90% finishing the post-treatment period.
Patients in both the treatment and placebo groups experienced mild to severe adverse effects, with the most prevalent being a headache following medication injection. However, no major side effects were observed in patients who received the medicine.
Over the course of the study, the researchers also looked at two variants of the tau protein in the central nervous system (CNS), which is a reliable indication of disease.
After 24 weeks, they discovered a more than 50% drop in total tau and phosphor tau concentrations in the CNS in the two treatment groups that got the highest dose of the medication.
Dr. Mummery said, “We will need further research to understand the extent to which the drug can slow the progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations.
“But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow—or possibly even reverse—Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”
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