In search of a cure for Alzheimer's in a chicken's eye

Many medical advances whose benefits anyone can understand begin with scientists asking questions that are difficult for most people to understand. The story of Tetraneuron, a company that now aims to develop a new treatment for Alzheimer's, begins with the curiosity of a researcher at the Cajal Institute of the CSIC (Spanish National Research Council) in Madrid. José María Frade had spent years studying how the nervous system develops in embryos. While working on the chick retina during his postdoctoral research in Germany, he observed how neurons died when they tried to reactivate their cell cycle, a process that normally only occurs when cells divide and is abnormal and lethal for adult neurons. Upon his return to Madrid, Frade tried to understand this strange mechanism and discovered the central role of the transcription factor E2F4.

Under normal conditions, E2F4 regulates the cell cycle, helping to prevent cells from dividing unintentionally. In adults, the neuronal cell cycle should remain off, but that changes in stressful situations. E2F4 then receives a chemical tag (phosphorylation) and, like a wet circuit breaker box, begins sending abnormal signals, restarting the proliferation cycle of adult neurons. In this uncontrolled environment, the Alzheimer's disease cascade begins, with the formation of beta-amyloid protein plaques in the brain, chronic inflammation, and the degeneration that leads to dementia .

Just over a decade ago, encouraged by the CSIC, Frade says he decided to file a patent based on these ideas emerging from his research: a modified version of E2F4 (called E2F4-DN) designed to resist phosphorylation and thus block cell cycle reactivation and neuron destruction. “We proposed the use of this molecule to prevent diseases of the nervous system and other systems in which problems arose due to cell cycle reactivation and somatic proliferation,” Frade explains. Tetraneuron then emerged through a kind of serendipity , the kind that makes fascinating discoveries possible through unexpected connections. “It was completely by chance, when some entrepreneurs contacted me about another topic. I told them I had that patent, and that's when I met the company's founding partners, with whom we began this journey in 2012,” he recalls.

Until now, Alzheimer's treatments have focused on attacking the beta-amyloid plaques and tau tangles that accumulate in the brain until they become toxic. The latest approved drugs, such as aducanumab and lecanemab , are monoclonal antibodies designed to bind to specific proteins in the body. In the case of Alzheimer's, they bind to the proteins that form beta-amyloid plaques and help the immune system identify and eliminate them. Although these drugs have been able to reduce beta-amyloid levels by up to 20% or 30%, their ability to slow cognitive decline is very limited.

Tetraneuron offers an alternative approach to traditional Alzheimer's therapies. Its proposal is to restore neuronal function through gene therapy, with the potential not only to slow the disease but also to reverse existing damage. Like other gene therapies , it involves introducing a therapeutic gene into the body using a modified, harmless virus as a vehicle. In this case, the gene is a special version of E2F4 (E2F4-DN), designed to resist the action of enzymes that disrupt its function of controlling neuronal balance. Administration is via injection into the cisterna magna, a cavity at the base of the skull that allows the treatment to reach the brain directly. Once inside, the therapeutic gene remains permanently active, without the need for repeated doses. The results in mice have been positive.

To advance the difficult path from basic science to the application of a treatment that improves patients' lives, Tetraneuron brought on Álvaro Pascual Leone, professor of Neurology at Harvard Medical School, who was attracted by the originality of Frade's idea. "We know that neurodegenerative diseases develop at a certain point in life, but they are not caused by aging per se, nor are they obligatory consequences of being 65, 75, or 85," he states. Pascual Leone, who was recently appointed medical director of the company, proposes that aging and what happens to us in life cause changes in the body that activate genes that can trigger disease. Some of these changes affect transcription factors like E2F4, and that is where Tetraneuron's proposal comes in. "By acting on these factors, you can reverse the pathological changes that have occurred, and that is radically revolutionary," he asserts. "Now the challenge is how to demonstrate this in humans without compromising patient safety," he concludes.

For Frade, the most important finding from the animal experiments is the recovery of brain synapse plasticity, which is key to memory formation. "That leads us to believe we'll be able to reverse the disease," he says. "If you restore that capacity, you restore the brain's ability to recreate memories, and since the circuits aren't completely destroyed but are functionally disconnected, in principle, we're talking about recovering the person," Pascual Leone adds.

Ángel Lucio, the company's CEO, is aware of the challenge that remains in reaching patients once the basic research phases and animal experiments are completed. "Gene therapy will be very expensive, and it will be a challenge to see how these types of therapies can be applied to prevalent diseases like Alzheimer's," he indicates. Currently, gene therapies are typically used for rare diseases, which may only affect a few dozen people. For now, Tetraneuron plans to target patients with moderate to severe Alzheimer's, who are more severely impaired than those who can receive existing therapies, which seek to slow the disease in its early stages. "And also, they should be patients who are in an age range that allows them to not suffer such deteriorated health," Lucio emphasizes.

The CEO also mentions another major challenge: producing the therapy on a sufficient scale for its viable use. “Even if the theory works, we'll have to see if we're able to target a sufficient number of neurons in a human brain, which weighs 1.3 kilos, as we have managed to do in a mouse, which has a brain of 0.42 grams. Although we have achieved a good level of expression of the therapy in monkeys, which have brains 140 times larger than those of a mouse, the leap to humans remains a significant technical challenge,” explains Frade.

According to Lucio, the company plans to administer its treatment to humans in the third quarter of 2026, following the regulatory phase and the completion of ongoing primate trials. Fourteen years after the company's formation and more than two decades after Frade's initial findings, Tetraneuron will be able to see if its therapy is effective against a disease against which science can only claim very meager victories.