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An Interview with Doug Ethell of Leucadia Therapeutics

Leucadia Therapeutics is a startup company focused on Alzheimer's disease, noteworthy for being one of the few ventures to depart from the orthodoxy of immunotherapy to clear amyloid and tau protein aggregates. The Leucadia staff are working on the establishment of a faster and cheaper path to an effective therapy for Alzheimer's that nonetheless still addresses the deeper causes of the condition.

Leaving the mainstream is perhaps more of a challenge in the Alzheimer's research community than elsewhere; the US National Institute on Aging has for years been primarily an Alzheimer's concern, and the biggest of Big Pharma entities have made equally large investments in the field over that same period of time. As a result there is a great deal of institutional inertia to continue to push forward with large and costly amyloid clearance strategies that are only incremental improvements on those that have failed by the dozen in the past. Publicly advocating any other path can have a negative impact on career prospects when embedded in such a large and structured system. However, going on for two decades in to these efforts, and with no practical therapy yet to show for the billions spent, the Alzheimer's heretics are starting to become more organized and influential.

It is undeniably the case that protein aggregates of amyloid and tau are important in Alzheimer's, and if they were removed safely and efficiently, patients would benefit. But these forms of metabolic waste are not the whole story; how is it that their presence only grows in the aging brain? Is some combination of declining immune function and persistent microbial infection a significant source of protein aggregates, for example? The evidence for that hypothesis is quite compelling. And in the case of Leucadia's work, are protein aggregates observed in the aged brain there due to a failure of drainage systems? The cerebrospinal fluid is thought to carry these aggregates away for disposal elsewhere in the body, but the pathways used fail with age. Thus the slow buildup of amyloid and tau with age might be thought of as a progressive failure of clearance of these waste products, a structural and fluid flow problem, rather than a cellular problem of greater production.

This is an attractive hypothesis, not least because testing it should be a comparatively low-cost, rapid effort - very far removed from the vast expense of current amyloid clearance approaches. Leucadia is the company formed to carry this initiative forward, now that the research and evidence gathered to date has reached the point of making that leap. The Methuselah Fund and a number of other angels and organizations have invested in Leucadia Therapeutics to date, Fight Aging! among them. Since the latest round of funding is now complete, I recently had the chance to talk to founder Doug Ethell and ask some questions about the company and the approach to Alzheimer's disease.

How did Leucadia come about? What led you down this interesting path of research and development?

I'd been undertaking Alzheimer's disease research as a medical school professor for well over a decade and I gave a talk at the Rejuvenation Biotechnology Conference in 2015. David Gobel, director of the Methuselah Foundation, was in the crowd and we got to talking at a poster session later that day. Dave said the foundation would like to fund some of my Alzheimer's research, if I wanted to start a company with that money. I founded Leucadias Therapeutics a few months later and the Methuselah Foundation made an equity investment.

If you could provide an overview for the audience here of the Leucadia approach to Alzheimer's disease and the underlying rationale?

Our approach to Alzheimer's disease has been to take a step back from molecular interactions and see where we are in the forest. The 'Peculiar disease of the cerebral cortex,' that Alois Alzheimer described over a hundred years ago is notable because a significant part of the pathology forms between cells in what is called interstitial spaces. In the brain, those spaces are filled with cerebrospinal fluid, or CSF, that clears away metabolites and debris that won't go blood vessel walls. We are interested in how CSF clears away regions of the brain where Alzheimer's disease starts first, with the idea that those routes are breaking down.

Think of it a small creek in the forest. Oak trees overhand the creek and occasionally a leaf falls in and gets carried away. In late summer, before the leaves change, the creek starts to dry up and leaves are carried away slower and slower, until a threshold is reached where they form a mat and then none of them are carried away. The plaques in Alzheimer's disease are mats of amyloid-beta. As it turns out, Alzheimer's disease pathology appears first in older parts of the cerebral cortex, called allocortex, where CSF is handled very differently than in the neocortex. The allocortex is intimately connected to the olfactory system and CSF that clears interstitial spaces in the allocortex drain from the brain to the nasal cavity thorough a porous bone called the cribriform plate.

With age apertures in the cribriform plate become occluded, and that can be accelerated by life events such as head injuries and broken noses. The net effect of those occlusions is an age-dependent slowing of CSF outflow, resulting is less efficient CSF-mediated clearance of the allocortex. Those leaves (the amyloid) start to accumulate and gum up the works, leading to in the accumulation of factors that cause Alzheimer's disease pathology. At Leucadia Therapeutics, we're developing a way to restore the clearance of CSF from those areas, with a product we call Arethusta. The name is derived from Greek mythology; the water nymph Arethusa was being pursued by the river god, Alpheus. Artemis let her her escape by helping her turn into a hidden underground creek. Arethusta creates a hidden stream so people can escape Alzheimer's disease.

You just raised your first round; what will be achieved with the funding now in hand?

This raise provides a tremendous boost as it allows us to hire more people, expand on our intellectual property, resolve engineering and manufacturing issues, and refine our regulatory strategy. Our goal is to start clinical trials in 2019 so there is plenty to do. The raise adds quite a bit of momentum.

In recent years I recall some independent research from other groups to support drainage issues as a significant cause of protein aggregation in the brain. Which of these results do you think add the most weight to your work?

That work involves CSF uptake from surface of the neocortex by structures that have been called glymphatics. Very interesting stuff, but a bit different than that allocortex and cribriform plate system we focus on. I published a hypothesis paper about the CSF clearance and Alzheimer's disease connection in a 2014 paper in the Journal of Alzheimer's Disease, after 2 years of editorial review. I first reasoned this mechanism in 2010. In comparison, the first glymphatic paper appeared in 2013.

A lot of alternative theorizing on the causes and progression Alzheimer's is taking place these days, people challenging the primacy of the amyloid hypothesis. Have any of these caught your eye as compelling?

Amyloid deposits (plaques) are a definitive feature of Azheimer's disease pathology, so it is certainly involved. The question is, are those deposits cause or effect? The amyloid hypothesis states that amyloid accumulations cause Alzheimer's disease, but my perspective is that plaques are simply effects, manifestations if you will, of an underlying condition that allows them to form. Ten billion has been spent on many failed clinical trials that centered on the amyloid hypothesis, and some are still ongoing, but none of them addressed the underlying cause of amyloid accumulation. Even if they were successful in clearing some plaques, they'll come right back. Leucadia's approach is to treat the underlying cause and let the brain take care of amyloid clearance by itself.

I feel that the long absence of tangible process towards therapies for Alzheimer's disease has led people to fixate on tiny gains rather than the goal of a cure. But what does realistic success look like in the fight against Alzheimer's over the next decade or so?

I spent over a decade looking at amyloid effects on neuronal death and neuroimmune interactions. Over that period, it got to be more and more depressing to watch an unbroken string of failed clinical trials up-close, played out in slow motion. The ball was pushed down the field a few yards at a time. It didn't go anywhere ... not for 25 years. There was a concerted effort by funding agencies to keep everyone viewing Alzheimer's disease research the same way. Neitzsche had it right when he wrote that the prevailing interpretation is a question of power and not truth.

What the Alzheimer's field desperately needed, and still needs, is dissenting voices that say, "There's something we're missing here. Something big." I'm one of those voices and let me tell you, when you rock the boat by challenging dogma, well-connected people whose livelihoods are built on that dogma take great offense, even if they've been proven wrong time and again. As for progress over the next decade, advances won't come in dribs and drabs but in bursts of activity. At Leucadia, we're developing a very significant advance that takes the field in an entirely different direction.

If this all works out well, and the Leucadia therapy does produce the desired outcome in patients, where next?

We are absolutely focused on slowing the relentless progression of Alzheimer's disease pathology. That's a pretty tall order, and once we get there, then we'll see about setting some new goals.

Comments

Much like the whole statins/cholesterol thing where it seems the symptoms are being treated rather than the underlying disease. This applies to that "and let me tell you, when you rock the boat by challenging dogma, well-connected people whose livelihoods are built on that dogma take great offense" as it does to many areas of science. We need the heretics.

Posted by: Neal Asher at December 13th, 2017 3:37 AM

@Neal Asher: Possibly a little more nuanced than a binary of symptoms versus disease process; there are many layers of cause and effect in even the more easily described disease processes, and some are better points of intervention than others. All other things being equal, higher/later layers should be worse points of intervention, because that leaves the lower layer to do other things beyond the one that is being addressed, but the details of each case matter. For example, the developing heretical views of Alzheimer's deprioritize intervention at protein aggregates, but in the case of, say, transthyretin amyloid and cardiac issues, clearing that amyloid may still be the best place to work. For statins, the limited benefits occur by reducing one of the inputs (cholesterol) determining the pace at which atherosclerosis progresses, but one would probably generate better outcomes moving further up the chain of consequences to make macrophages immune to damaged cholesterol, or clear out that damaged cholesterol in plaques every so often.

Posted by: Reason at December 13th, 2017 6:53 AM

But why do these amyloid deposits gather in the interstitial spaces? Are they pushed out of cells? I assume this must be the case, and therefore what is not being dealt with inside the cells to make this export necessary? Also, is this a case of a continuous build up throughout life, due to the inability of even a young cell/body to deal with it, or are these build-ups only occurring late on in life once some youthful clearance process has failed? It seems until we understand these questions we don't understand Alzheimer's at all, and will not be able to cure it.

Posted by: Mark at December 13th, 2017 7:31 AM

@Mark: Levels of unwanted amyloid in the brain are very dynamic, even in young people, but there it is dealt with by some combination of being destroyed in cells by autophagy or similar processes, being dumped outside cells where microglia and the like can consume it, or exported to other parts of the body where it is broken down. All of these things are known to decline with age - cellular maintenance processes that recycle unwanted proteins stop working due to cellular damage, the microglia suffer the same fate as the rest of the immune system, and the drainage breaks down.

That said, there is plenty of evidence for increased production of amyloid in older individuals also, such as via hyperglycemia (the connection to metabolic syndrome and type 2 diabetes, and the consideration of Alzheimer's as a metabolic disorder) or the presence of tau, or microbes such as spirochetes, etc.

I think that determination of which of the potential culprits are the most important will only follow from removing specific contributions - that's the fastest path forward to find answers. So in that sense Leucadia and analogous efforts for other mechanisms are absolutely the right path ahead.

It nonetheless remains the case that if someone succeeds in producing a low-impact method of clearing amyloid from the brain, we'd expect that to be beneficial if repeated at some interval - though it is a question as to what the interval should be.

Posted by: Reason at December 13th, 2017 8:03 AM

Decreased CSF outflow could also be due to reduced CSF production with age:

https://www.fightaging.org/archives/2017/11/more-support-for-impaired-drainage-theories-of-neurodegenerative-disease/

https://www.nature.com/articles/s41467-017-01484-6

"Since under homeostatic conditions, CSF inflow must equal CSF outflow, this decreased outflow in aged mice may be at least in part due to reduced CSF production by the choroid plexus or by sources from within the interstitial tissue such as the blood-brain barrier16,70"

People can get dry eye disease with age, so maybe in some cases Alzheimer's is partially "dry brain disease"?

Posted by: Jim at December 13th, 2017 8:32 AM

Microglia are part of the immune system, which we already know falls over as you get old - so my money is on that for being the #1 contributor to Alzheimer's. Fascinating though that CSF outflow reduces; I am sure the lymphatic system is important too. I guess the reason Alzheimer's is such a difficult disease to cure is because there is such a catalogue of problems to pick between, without any real certainty of causality.

Posted by: Mark at December 13th, 2017 9:54 AM

Recently it has been suggested that beta amyloid derives mainly from blood platelets and is carried to the brain and deposited there, resulting in AD. Reference: Inyushin et al, 2017 Peptide originated from platelets promises new strategy in anti-Alzheirmer's drug development. One strategy that could be used to reduce the production of beta amyloid would be to reduce the number of platelets in the blood stream that produce this disease causing substance. I have Gilbert's Syndrome (a genetic syndrome that results in 2 to 3x bilirubin levels in the blood, and about a 40% reduction in PLATELETS. What do you need all those damn platelets for? I have never had a blood clotting problem, and my platelet count is about 103K, while most people have way higher platelet count. Unfortunately, only about 5% of Caucasians have Gilbert's Syndrome.

Posted by: Biotechy at December 13th, 2017 10:57 AM

On Dec. 6, 2017 ScienceDaily posted an article entitled: Healthy Mitochondria Could Stop Alzheimer's. It is based on a recent article by V. Sorrentino of EPEL where they fed AD affected mice NR for a period of time and then found that amyloid plaque was reduced in the brain of the mice, and cognition improved. The therapy has not been tested in humans yet but could be a major breakthrough for curing AD. Eureka Alert has posted a similar article to the one in ScienceDaily.

Posted by: Biotechy at December 14th, 2017 12:27 PM

I wonder if the brain also loses csf drainage capacity as the result of repeated blows to the head?
For example, boxers, a soldier whom has been near an explosion, etc... and perhaps even some link to PTSD?

Posted by: bmack500 at December 14th, 2017 1:18 PM

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