Regenerative Medicine as an Approach to Treat Alzheimer's Disease
The authors of this open access paper consider the potential for regenerative medicine to treat Alzheimer's disease, such as by increasing production of new neurons, or delivering neurons via transplantation. While there has been something of an exodus from the amyloid hypothesis of late, given the litany of failure in clinical trials aiming to reduce amyloid in the brain, it still seems clear that protein aggregates (amyloid and tau) occupy a central position in the progression of neurodegeneration. Spurring greater brain tissue maintenance via generation of neurons is a beneficial goal in and of itself, but as a compensatory treatment, it can't be enough on its own to turn back neurodegeneration primarily caused by factors such as metabolic waste and chronic inflammation.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline. Tremendous efforts have been made to develop novel therapeutics to potentially reverse disease progression. Substantial neuronal loss is observed even in mild AD patients. Intuitively, increasing the number of neurons or replacing lost neurons are potential therapeutic strategies for AD. Stem cells are capable of renewing themselves continuously and differentiating into specialized cells, including neurons.
The process of generating new fate-specified, functional neurons from neural progenitor cells, which are functionally incorporated into a neural circuit, is defined as neurogenesis. Across different species, neural regeneration mainly takes place at the dentate gyrus of the hippocampus and the subventricular zone along the lateral ventricle. Notably, the dentate gyrus, which plays a crucial role in memory formation processes, is related to early memory loss in AD. Neurogenesis decline accompanies normal aging. For AD, accumulating evidence suggests that impaired neurogenesis plays a role in its pathogenesis. Multiple molecules involved in AD pathogenesis, such as ApoE, PS1, and APP were recognized to take part in neurogenesis modulation. Therefore, understanding the mechanism of neurogenesis dysfunction and intervening with neurogenesis represents an alternative AD therapeutic strategy.
Generally, neurogenesis can be modulated by multiple factors that are related to lifestyle, including learning, exercise, social interaction, caloric restriction, blood oxygen level, and even microbial colonization. In this regard, advocating a healthy lifestyle exerts at least a mild effect on preventing or controlling AD in the long run. Apart from lifestyle modification, which exerts mild effects, several pioneering studies identified key molecules or drugs that rescue or reverse NSC dysfunction in elderly animal models, such as via plasma exchange.
Transplanting stem cells to substitute for lost neurons is another intuitively feasible strategy. However, studies have confirmed that the main benefit of stem cell transplantation is a neurosecretory effect. Various neurotrophic factors involved in modulating multiple cellular functions that promote the amelioration of pathological features and cognition in animal models have been recognized. There has been increasing commercial interest to transform current advances in transplantation into clinical practice on human patients.
There has not been a single FDA approval for an Alzheimer's drug in the last 14 years
There have been over 400 clincial trial failures in that time frame across all target types
To throw out any single approach is counter productive
Transplanting young neurons might work. And in case it really works, at what point do we preserve the same person and when the treated brain becomes a different person.
It might bring some interesting moral issues. Let's say you have an inmate serving a live sentence, who get's his brain so severely damaged by Alzheimer's that he doesn't remember much any more. And the treatment does miracles and he recovers the brain function but with clear memories. Can we still keep him in jail ?
"There have been over 400 clincial trial failures in that time frame across all target types"
The problem is no combination of targets has been tried ever, AFAIK. And it's not a problem of the FDA but of the companies, that don't want to try. There was an article recently in Alzforum about that, but I can't find it with this computer (damned HTML5...).
@cuberat That's not how brains work.
@Antonio "And it's not a problem of the FDA but of the companies, that don't want to try"
They don't want to try because it would cost them too much. Which brings back the ball to the FDA which is unwilling to make a proper framework for medical trials for post 90s medicine.
@Anonymoose: Nope, please, don't pose your prejudices as facts. The companies say they don't want to try because they consider it more risky than single-target trials. Academia and the FDA encourage the companies to try, but they refuse.
https://www.alzforum.org/news/conference-coverage/combination-trial-debate-energizes-keystone-symposium
Yes, stop making up nonsense Anonymoose. For example, the FDA has been proactive recently with the new RMAT framework which is designed to facilitate cutting-edge medicine like gene therapy. See our commentary and our official comments submitted to the FDA.
https://www.leafscience.org/fda-rmat/
It's a cyclical dynamic
FDA may "encourage" via novel guidances, etc.
But that holds no sway over how individual therapeutic teams may review your product
Hence that scares off companies from even trying simple combinations
@Antonio
????
As always you don't read the articles you post. Or maybe your reading comprehension is just that bad.
If FDA wants them to try they should make a special framework with low risk - which means fast trials with low costs - or heck they should consider government funded trials if they actually WANT them to happen.
The situation has dramatically changed since 2012 when they were talking about combination drug trials for AD seriously for the first time. Multiple companies had potential candidate drugs at the time - all of those failed. Any enthusiasm those companies would've had at the time has vanished. A completely different situation from trials for HIV where companies had successful trials for mono-therapies first.
The article states that 50% of AD cases are Familial AD, and that a major player in the development of the disease is the APP gene. APP is produced by the blood vessel platelets, and can contribute to blood vessel plaque and also be carried to the brain where its is broken down by two enzymatic reactions to Amyloid beta particles that become AD plaque in the brain. My point here is that people differ vary quite dramatically in the platelet count they have. My platelet count is on the low end at about 105K, whereas most people have platelet counts of 200 to over 400K. Why do most people need all those platelets, and why haven't research scientist looked into these high platelet counts as a prime source of future AD.
PS: Another problem addressed by the article is that old blood from elderly patients has progressively more pro-aging chemokines CCL11, Beta2-M, and TGF-beta. These chemokines in the blood vessels of the elderly are aging promoting factors that contribute to decreased neurogenesis, and learning and memory problems associated with AD. It seems more research should be done to see what causes the rise in these chemokines, and how can they be reduced to youthful levels. Is it because the kidneys or liver of elderly are declining in removing toxins, or is there some other cause like cell senescence somewhere in the body. If we could rejuvenate the kidney and liver, perhaps there would be reduced levels of these chemokines.
"Case presentation
We report the case of a 77-year-old Caucasian man with severe dementia and behavioral disturbance secondary to Alzheimer's disease treated with memantine who began adjunct treatment with deoxyribonuclease I. Prior to initiation of deoxyribonuclease I treatment, our patient appeared to be in a stuporous state, with a Mini-Mental State Examination score of 3 and a Functional Assessment Staging Test score of 7. After obtaining informed consent from family members, we started administration of 120 mg of deoxyribonuclease I per day (1500 KU/mg) for treatment of severe cognitive impairment.
Conclusion
Our patient began to demonstrate rapid, considerable improvement in cognitive function 2 days following initiation of deoxyribonuclease I treatment. After 2 months of continued treatment, Mini-Mental State Examination and Functional Assessment Staging Test scores were 18 and 4, respectively."
https://link.springer.com/article/10.1186/s13256-016-0931-6
@Anonymoose:
Huh??? Where does it say that multi-target trials are riskier than single-target trials due to the FDA rules??? That only says that companies, and only companies, consider them riskier. There are no different rules for multi-target trials nor the FDA dislikes them, on the contrary, favours them.
And I read it completely the first time. Again, don't project your prejudices over the parts you don't know.
@Antonio
FDA guidance, while exists, is far from a position of "favour"
https://www.fda.gov/downloads/drugs/guidances/ucm236669.pdf
The big issues of toxicokinetics, pharmacokinetics, pharmacodynamics etc. with complex interventions are always a hurdle, and why many in pharma are afraid of the approach versus monotherapy
Exactly because they don't have different rules is it riskier.
You are mixing drugs. You don't know the drug interactions. Most of these are failed drugs with multiple serious side effects - inflammation, brain swelling, fluid build up in the cranial cavity, etc, etc, etc. Which sane company would take the risk of starting this trial if they are held accountable to the same level they would be in the normal trials? So obviously they would expend more money to try to make the trials at least as safe as the typical ones.
Secondly the economic risk is beyond the money you invest in the drug development and the trials themselves. Companies lose share market value over significantly less damning things than dangerous trials, and to top it off this looks like an insanely desperate move for any company willing to take part in such a trial. I'm obviously talking about economic risk if you haven't realized it yet. That's why I said more expensive. It costs more. The return probability stays the same, or maybe even less if you consider things rationally.
If the FDA doesn't incentivize them to take the risk they won't.
Even then I'm not sure they would do it because the chance they will get a return on their investment seems too low.
Also you should probably learn what the word prejudice means before you use it.
Most AD drugs that reach phase III don't fail due to side-effects but due to lack of efficacy in addressing cognitive symptoms. They clean Abeta, tau or whatever they target, but mental functions still worsen like in the control group.
Indeed, the FDA/NIH has recently changed the AD definition (last month, IIRC), and now it's only defined by the accumulation of Abeta and ptau, not by cognitive or other symptoms, so companies only need to remove them to pass the trial.
As I said the question is, what is the return on investment - when we're talking about drugs which took hundreds of millions of dollars to develop (except for methylene blue but that garbage won't do anything even in a combo trial) and move through the administration , and the proposition being - "instead of one expensive drugs we'll sell 2 or 3 expensive drugs together" - and that's in the case they actually work by the by - because they could still fail or prove to be too dangerous to use together - then the patient base capable of paying for this drops significantly.
So not only is the FDA asking them to throw more money in the air, there is an almost guarantee they won't make their money back. And as I said already they'll even look bad in front of their investors... yeah... guess why they're not going to start a trial like that.
What is so hard for you to understand about this?
The government needs to incentivize them in some massive way. That's the only option left now. That or way for the next round of AD drugs to come in about 20ish years.
@cuberat: "It might bring some interesting moral issues. Let's say you have an inmate serving a live sentence, who get's his brain so severely damaged by Alzheimer's that he doesn't remember much any more..."
Actually this kind of question matters for life-extension treatments in general. How much can and should you give to those sentenced to life without parole? Is it 'cruel and unusual' to keep someone alive, healthy, but destined to be in prison indefinitely? Is it 'cruel and unusual' not to? (and does it mean the same to hand out what are 'might as well be life sentences' either measured in centuries, or mere decades, but for an already-old convict? Both become potentially serveable.)
But your particular scenario also touches on identity issues. After any large-scale brain reconstruction and rejuvenation (from whatever cause), how much is still 'you?' For now (because I know I don't have the answer, either), I will only refer those interested to the 'Consciousness and Identity' video in the Isaac Arthur series.