Interview with Doug Ethel, Head of Leucadia Therapeutics

Leucadia Therapeutics is a company that specializes in Alzheimer's disease and is one of the few who have abandoned traditional approaches to immunotherapy in order to remove amyloid and tau protein aggregations. Leucadia employees are working to create a faster and cheaper effective treatment for Alzheimer's disease, affecting nevertheless the deeper causes of this disease.

In the Alzheimer's study, deviating from the mainstream is probably more difficult than anywhere else. For many years, the National Institute on Aging has been primarily engaged in Alzheimer's disease, and major pharmaceutical companies have also made major investments in this area. As a result, the accumulated institutional inertia pushes for the continuation of the development of large and costly strategies for the removal of amyloids, making only small improvements, although these approaches have failed in the past by dozens. Public promotion of any other path can negatively affect career prospects in such a large and well-structured system. However, for two decades, these efforts have led to nothing, no practical therapy to replace the billions spent, and Alzheimer's heretics are starting to become more organized and influential.

There is no doubt that the role of amyloid and tau protein aggregates in Alzheimer's disease is essential, and if they are safely and efficiently removed, this will benefit patients. But these forms of metabolic debris are not the whole story. Why do they accumulate only in the aging brain? Is, for example, some combination of decreased immune function and persistent microbial infection the root cause of protein aggregation? The evidence for this hypothesis is very convincing . And referring to the work of Leucadia, is there an accumulation of aggregates in the old brain due to the failure of the drainage system ? It is believed that the cerebrospinal fluid transports these aggregates for subsequent processing to other places in the body , but the metabolic pathways used for this are disturbed. Thus, the slow gradual accumulation of amyloids and tau proteins with age can be viewed more as a gradual failure of the mechanisms of purification of these wastes, a problem in the circulation of cerebrospinal fluid, rather than a problem of their overproduction within the cell.
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This hypothesis is also attractive because its testing should be relatively inexpensive and quick compared to the huge costs of current approaches to the removal of amyloids. Leucadia was formed to promote this initiative, and now the research and accumulated data have reached a level that allows for a breakthrough. Methuselah Fund and a number of other private venture investors and organizations, among them Fight Aging! invested in Leucadia Therapeutics. At the end of the current round of funding, I had the opportunity to speak with Leagadia founder Dag Ethel and ask questions about the company and its approach to Alzheimer's.

Interview

Risen : How did Leucadia originate? What led you to such interesting research and development?

Doug Ethel : I have been researching Alzheimer's disease as a professor in medical school for over a decade and spoke at the Rejuvenation Biotechnology Conference in 2015. It was attended by David Gobel , head of the Methuselah Foundation , and later that day during the poster session we talked. David said his foundation would like to fund my Alzheimer's research if I want to start a company. A few months later, I founded Leucadias Therapeutics, and the Methuselah Foundation entered into the company's share.

Risen : Could you briefly describe Leucadia’s approach to Alzheimer's disease and tell what it is based on?

Doug Ethel : Our approach to Alzheimer's disease is to backtrack a bit from molecular interactions and assess where we are. “The specific disease of the cerebral cortex, ” described by Alois Alzheimer more than a hundred years ago, is remarkable in that a significant part of the pathology is formed between cells in the so-called intercellular space . In the brain, these spaces are filled with cerebrospinal fluid (CSF), which washes away metabolites and various debris that does not pass through the walls of blood vessels. We are interested in how CSF cleans the areas of the brain where Alzheimer's disease begins, and our idea is that these pathways are being destroyed.

Imagine a brook in the forest. Above it hang the crowns of oaks, and from time to time the leaves fall down and the water carries them away. At the end of summer, before the foliage falls, the trickle begins to dry. The leaves are carried away more and more slowly, and upon reaching a certain threshold, the fallen leaves form a mat and the water is no longer carried away. Alzheimer's disease plaques are such an amyloid mat. As it turns out, the pathology of Alzheimer's disease appears first in the older parts of the cerebral cortex, called allocortex , where CSF is treated quite differently than in the neocortex . Allokortex is closely connected with the olfactory system , and the CSF, which clears the intercellular space of the allocortex, flows from the brain into the nasal cavity through a porous bone called the cribriform plate .

With age, the holes in the cribrim plate become clogged, and such life events as head injuries and broken noses can speed it up. The end result of the blockage is age-dependent slowing of CSF outflow, and, as a result, less effective cleansing of allo-cortex. These leaves (amyloids) begin to accumulate and stick together, leading to an accumulation of factors that cause the pathology of Alzheimer's disease. In Leucadia Therapeutics, we are developing a way to restore the filtration of CSF in these areas using a product that we call Arethusta . This name is taken from Greek mythology; the river nymph Arethusu was pursued by the god of the river, Alphaeus . Artemis helped her escape, turning her into an underground stream hidden from her eyes. Arethusta creates such a hidden stream so that people can avoid Alzheimer's disease.

Risen : You just completed your first round. What are you planning to achieve with this funding?

Doug Ethel : The money raised gives a powerful impetus, it will allow us to attract more people, expand our intellectual property, solve technical and operational issues and improve our management strategy. Our goal is to begin clinical trials in 2019, so there is a lot of work. And money gives considerable acceleration.

Risen : In recent years, as I recall, independent studies have been carried out by other groups that also support the idea of ​​the problem of CSF filtration as the main cause of protein accumulation in the brain. Which of these results, in your opinion, gives the greatest weight to your work?

Doug Ethel : This work is about the absorption of CSF from the surface of the neocortex using structures called glymphs . Very interesting material, but slightly different from the system of allocortex and the cribriform plate, on which we are focused. I published a description of my hypothesis about the connection between the cleansing of CSF and Alzheimer's disease in a 2014 article in the Journal of Alzheimer's Disease after 2 years of editorial review. I first argued this mechanism in 2010. And the first article about glymphs appeared only in 2013.

Risen : People now put forward many theories about the causes and development of Alzheimer's disease. Many dispute the amyloid hypothesis. Did you find anything convincing?

Doug Ethel : Amyloid deposits (plaques) are a defining feature of the pathology of Alzheimer's disease, therefore, of course, it is not without them. The question is, are they causes or effect? The amyloid hypothesis claims that the accumulation of amyloids causes Alzheimer's disease, but my point of view is that plaques are nothing more than manifestations, if you will, of the underlying condition that allows them to form. Ten billions were spent on many failed clinical trials that focused on the amyloid hypothesis, and some of them are still ongoing, but none of them considered the main cause of amyloid accumulation. Even if they manage to clear some plaques, they will go back. Leucadia's approach is to treat the underlying cause and allow the brain to independently take care of the purification.

Risen : The prolonged lack of tangible progress in the treatment of Alzheimer's has caused people to fix themselves on small improvements, not on the goal of a cure. But how realistic is the success in fighting Alzheimer's over the next decade?

Doug Ethel : I spent more than ten years studying the effects of amyloids on neuronal death and neuroimmune interactions . During this period, it became increasingly depressing to watch a continuous series of unsuccessful clinical trials, played in close-up in slow motion. The ball moved the field a few yards at a time. It did not lead anywhere ... and so for 25 years. The concerted efforts of funding agencies made everyone look at Alzheimer's research in the same way. Nietzsche correctly wrote that the prevailing interpretation is a matter of power, not truth. What Alzheimer's research is desperately in need of and still needs is the voices of dissenters who say: “Here we are missing something. Something important. ” I am one of these voices, and let me say, when you rock a boat, defying dogma, people with connections whose livelihoods are based on this dogma take it to heart, even if their wrongness is confirmed again and again. With regard to progress over the next decade, breakthroughs will occur not in small portions, but in violent flashes. At Leucadia, we are developing very significant progress that moves the industry in a completely different direction.

Risen : If everything works, and Leucadia therapy will really give the desired result on patients, what's next?

Doug Ethel : We are fully focused on slowing the steady development of Alzheimer's disease. This is a very difficult task, and when we cope with it, then we will set new goals.

Translated by Nick Sestrin , SENS Volunteers Group