A world first trial at UCL and UCLH has found a new gene therapy for Alzheimer’s disease that can safely and successfully reduce levels of the harmful tau protein known to cause the disease.
The trial, led by consultant neurologist Dr Catherine Mummery (UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery), represents the first time that a ‘gene silencing’ approach has been taken in dementia and the disease Alzheimer’s.
The approach uses a drug called BIIB080 (/IONIS-MAPTRx), which is an antisense oligonucleotide (used to stop RNA from making a protein), to “silence” the gene that encodes the tau protein, known as the microtubule-associated protein tau (MAPT) gene. This prevents the gene from being translated into protein in a testable and reversible manner. It will also decrease the production of that protein and alter the course of the disease.
Further trials in larger groups of patients will be needed to determine if this leads to clinical benefit, but the phase 1 results published in Natural medicine — with results from 46 patients, they are the first indication that this method has a biological effect.
There are currently no treatments targeting tau. The drugs aducanumab and lecanemab, recently approved for use in some situations by the FDA, target a separate disease mechanism in AD, the accumulation of amyloid plaques*.
The phase 1 trial looked at the safety of BIIB080, what it does in the body, and how well it targets the MAPT gene. It involved the UCL Dementia Research Centre, was supported by the NIHR UCLH Center for Biomedical Research, was supported by the NIHR UCLH Center for Biomedical Research and took place at the Leonard Wolfson Center for Experimental Neurology at NHNN.
Forty-six patients, average age 66, enrolled in the trial, which ran from 2017 to 2020. The trial looked at three doses of the drug, given by intrathecal injection (an injection into the nervous system through the canal spinal cord), compared with placebo.
The results show that the drug was well tolerated, with all patients completing the treatment period and more than 90% completing the post-treatment period.
Patients in both the treatment and placebo groups experienced mild or moderate side effects, the most common being headache after drug injection. However, no serious adverse events were observed in patients receiving the drug.
The research team also observed two forms of the tau protein in the central nervous system (CNS), a reliable indicator of disease, for the duration of the study.
They found a greater than 50% reduction in CNS total tau and phosphorous tau levels after 24 weeks in the two treatment groups receiving the highest dose of the drug.
Dr Mummery said: “We will need more research to understand the extent to which the drug can slow the progression of physical symptoms of the disease and to test the drug in older and larger groups of people and in more diverse populations.
“But the results are an important step forward in showing that we can successfully target tau with a gene-silencing drug to delay, or possibly even reverse, Alzheimer’s disease and other diseases caused by tau accumulation in the future.” “.
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