A novel drug to combat Alzheimer’s disease has shown good safety in a study involving more than 30 patients. The experimental medicine aims to reduce the production of so-called tau proteins in the brain which are relevant to the disease. Experts from DZNE in Bonn and Ulm were involved in this international study. The results have been published in the scientific journal “Nature Medicine”. A follow-up study has already been started to investigate whether the drug can actually contain Alzheimer’s disease and its symptoms.
In the healthy brain, tau proteins stabilize the scaffolding of neurons. However, in the course of Alzheimer’s disease, they detach from the cell skeleton and cluster into tiny aggregates inside neurons. “These clots are associated with the death of neurons. We then find more of the tau proteins in the cerebrospinal fluid,” explains Prof. Anja Schneider, a research group leader at DZNE and director of the Department of Neurodegenerative Diseases and Geriatric Psychiatry at Bonn University Hospital. “How exactly these proteins contribute to cell death is not yet fully understood. However, it is clear that they play a crucial role in Alzheimer’s, along with amyloid beta proteins, which also aggregate, but outside cells. Thus, curbing the production of tau proteins in the brain has been under consideration for some time. Studies in mice suggest that this can reduce neuronal damage and mitigate cognitive impairment.”
Administration via the Spinal Canal
This is precisely the aim of the drug now being tested, which was developed by the company “Ionis Pharmaceuticals”. However, clinical assessment is still in its beginnings: In the current investigation, a so-called 1b study, essentially only the drug’s tolerability was tested. To this end, it was injected with a needle into an interspace in the area of the lumbar spine. The substance was then able to reach the brain via the spinal canal, which runs along the spinal column and contains cerebrospinal fluid. A total of 46 women and men with mild symptoms of Alzheimer’s took part in the study: 34 volunteers received the experimental compound, 12 a placebo. Treatment was given at regular intervals over a period of 13 weeks, involving 12 study centers in Europe and Canada which included the DZNE sites in Bonn and Ulm. After treatment, subjects were followed for several more weeks. “The drug was found to be well tolerated. The most common side effect was headache,” said Anja Schneider, who helped conduct the study. “At the same time, it was possible to reduce the concentration of tau proteins in the cerebrospinal fluid. The clinical testing thus enters the next phase. Now it must be determined whether the drug actually works against Alzheimer’s. A study to this end is already underway. However, results are not expected for several years.”
“Gene Silencing”
The drug now being tested is an antisense oligonucleotide: It reduces the production of tau proteins in the brain by virtually quietening down the responsible gene. In technical jargon, this is known as “gene silencing”. This is achieved by the compound attaching itself to mRNA, the messenger molecule that conveys the blueprint for tau proteins from the genome to the protein factories in neurons. The novel agent interrupts this transmission. “The antisense technique is a very recent approach. Corresponding drugs have only been approved for the treatment of SMA in the last few years. This is a rare muscle disease. For Alzheimer’s, antisense technology is still uncharted territory. This was the first time such a drug was tested in patients,” said Prof. Albert Ludolph, a neuroscientist at DZNE’s Ulm site and medical director of the Department of Neurology at Ulm University, who also contributed to the current study. “The hope is to interfere with the fundamental mechanisms of Alzheimer’s via the tau protein and thus slow down, ideally even stop the disease.”
A Potential Complement to Anti-Amyloid Therapy
The Ulm researcher sees this approach as a potential complement to medicines directed against the aforementioned amyloid proteins. “Lecanemab", a drug of this type, has recently been launched on the US market. Approval for Europe is currently being reviewed by the responsible EU authority. “It would be desirable if Alzheimer’s could be addressed from different angles. Whether the antisense technique can play a role in this must be determined in future research. In any case, the current study has laid the groundwork for this,” said Ludolph.
Original publication:
Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial, Catherine J. Mummery et al., Nature Medicine (2023), DOI: 10.1038/s41591-023-02326-3
April 2023