Reducing Levels of All Pathological Protein Aggregates Should be a Primary Strategy for Treating Neurodegeneration

The reasons why restoration of cerebrospinal fluid drainage is a very promising strategy for the treatment of Alzheimer's disease go beyond the compelling direct evidence, into matters of research and development strategy. Numerous proteins that become misfolded or altered in ways that cause them to form solid deposits in the aging brain, surrounded by a halo of harmful secondary biochemistry. To date, serious development efforts that have advanced to clinical trials have focused on clearing only one of these aggregates. That may well never be enough: neurodegeneration appears to be a combination of the effects of many mechanisms of similar weight and consequence.

Thus more researchers are beginning to call for broader efforts that target multiple problem proteins. In this context, the importance of improved cerebrospinal fluid drainage is that it can can reduce the levels of all molecular waste and resulting consequences in the brain, both the well understand and the less well understood alike. It all flows out through the same channels, provided that those channels are working well enough. Unfortunately they decline with age, and that is a comparatively simple, mechanical and structural potential point of intervention. I am looking forward to the data produced by Leucadia Therapeutics as their metholodology for drainage restoration progresses over the years ahead: they should be able to fairly quickly definitively confirm the utility of this strategy.

Nearly all major neurodegenerative diseases - from Alzheimer's to Parkinson's - are defined and diagnosed by the presence of one of four proteins that have gone rogue: tau, amyloid-beta (Aβ), alpha-synuclein (α-syn), or TDP-43. As such, investigational drugs and studies aimed at preventing or slowing the disease often hone in on just one of these respective proteins. However, targeting multiple proteins at once may be the real key, according to a recent study. These so-called "proteinopathies" - misfolded proteins that accumulate and destroy neurons - co-exist in varying degrees across all of the different neurodegenerative disorders and may instigate each other to drive disease severity in many aging patients. The prevalence of these co-pathologies suggests that each disease may ultimately require combination therapy targeting multiple disease proteins, and not just a single therapy, in patients with both early and later-stage disease.

"Historically, the focus of most clinical trials has been on targeting the primary pathological proteins of a given neurodegenerative disease such as deposits of tau and Aβ for Alzheimer's disease, but we see now that many of these disease-related aggregated proteins affect most older patients across a full spectrum of clinical and neuropathological presentations. This gives us additional leverage to find ways to detect patients' specific proteinopathies with increasingly sophisticated biomarker and imaging technologies. This will allow us, and other researchers, to better match participants with specific targeted therapies in clinical trials."

The study analyzed 766 autopsied brains and revealed that patients with more severe forms of their diseases had more co-pathologies. Co-pathologies were common but varied among the disease groups, ranging from 27 to 81 percent of patients having co-pathologies. For example, 52 percent of patients with corticobasal degeneration (CBD), in which tau as the primary protein, had multiple other neurodegenerative disease protein deposits present. Tau was nearly universal, with 92 to 100 percent of all patients having at least one form. Aβ was next, with 20 to 57 percent of patients having at least one type of protein deposit, while α-syn pathology, typically seen in Parkinson's disease, was less common, with 4 to 16 percent. TDP-43 deposits, which are characteristic pathological signatures of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, were the rarest, with 0 to 16 percent of patients having these deposits.

The findings not only show a high prevalence of co-pathologies, but also suggest a patient's primary pathological protein may influence co-pathology prevalence and severity, as shown in patients with Alzheimer's and Lewy body disease patients. These findings support the "proteopathic seeding" hypothesis that has been previously established in model systems of neurodegenerative diseases. Misfolded proteins may directly "cross-seed" other normal, vulnerable proteins to accumulate and clump via a cell-to-cell transfer of toxic proteins.

Link: https://www.pennmedicine.org/news/news-releases/2018/july/rethinking-neurodegenerative-disease-treatment-target-multiple-pathological-proteins

Comments

I wonder if the Leucadia therapeutics approach will work for already accumulated deposits. I read this morning that Biogen has seen some success at the 18 month mark; so perhaps both approaches together will ultimately prove the closest to a cure for already progressed Alzheimer disease that we can get.

Posted by: bmack500 at July 6th, 2018 7:31 AM

@Reason see also Proclara (formerly Neuropage) for a promising multi-amyloid candidate.

Posted by: Steve Hill at July 6th, 2018 8:18 AM

Anavex (AVXL) was just approved earlier this week by FDA to conduct a Phase 2b/3 for early stage AD with their drug Anavex 2-73. The stock went up 45% on Tues. The drug reduces Tau and Amyloid beta in the brain, and is being studied for Parkinson Disease and Rhett Syndrome as well.

Posted by: Biotechy Marcks at July 6th, 2018 1:14 PM

PS: The above clinical trial was approved by the Australian Health Agency similar to FDA, not by our Agency as listed above.

Posted by: Biotechy Marcks at July 6th, 2018 1:24 PM

Biogen was up strongly (56 points) today or 18.6% on encouraging Phase 2 results on AD that reduces amyloid beta in the brain. So, we are getting some real action in a couple of stocks that are trying different ways to reduce (not cure) the disease at present.

Posted by: Biotechy Marcks at July 6th, 2018 1:47 PM

PS: Biogen ended yesterday up over 58 points and up over 19%. This is a 12 billion dollar rise in market cap, a quite astonishing movement of investment money in one day for what seems to be a fairly small step in finding a cure for AD. In fact, this drug is not even their leading candidate for helping to cure the disease by reducing amyloid beta alone, which both of their drugs are targeted for. What would SENS be able to do with 12 billion dollars of investment??

Posted by: Biotechy Marcks at July 7th, 2018 5:50 AM

Just today, Anavex has announced that they have mow been approved in Spain to start a Phase 2 trial of Parkinson's Disease Dementia with their drug 2-73. This and the above mentioned Phase 2B/3 clinical trial on Alzheimer's Disease in Australia targeting both amyloid beta and tau are worth watching!

Posted by: Biotechy Marcks at July 9th, 2018 7:43 AM

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