Towards Exosome Therapy for Neurodegenerative Conditions

Many approaches to stem cell therapy might be replaced in the years ahead by delivery of exosomes secreted by those stem cells. Most cell therapies produce benefits via the signals generated by the transplanted cells. Those signals produce beneficial changes in the behavior of native cells, such as suppression of inflammation or greater tissue maintenance activities. Without extensive engineering of supporting structures the transplanted cells survive only for a short time. Thus why not just deliver the signals? A sizable fraction of cell signaling is delivered via extracellular vesicles such as exosomes, membrane-wrapped packages of signal molecules that pass between cells. Harvesting exosomes from cell cultures for use in therapy is logistically easier than building cell therapies, and thus a great many research groups and companies are presently working on regenerative therapies based on delivery of natural or modified exosomes.

Despite the recent advances in the biology of neurodegenerative diseases, these disorders remains incurable, and most of the existing drugs provide only symptomatic relief and do not affect the progression of the disease. For this reason, there is a pressing need to identify alternative therapies to treat these disorders. Therefore, there is an urgent need for new treatments for these diseases, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years.

In this sense, cell therapy, using stem cells, has been recognized as the best candidate for treating incurable diseases, including neurodegenerative disorders. However, in the last decade, accumulating evidence supports the idea that mesenchymal stem cells (MSCs) perform their therapeutic roles in a paracrine manner. For a long time, it was considered that the therapeutic effects of the stem cells were associated with the replacement of dead cells. However, in a model of kidney injury it was verified that transplanted stem cells remain in the injury site up to a few days only, and, subsequently, are not found in the tissue. Similar results were observed in subsequent studies.

Altogether, these data suggest that the therapeutic effects of MSCs are mediated by their "secretome", which is composed of a spectrum of protective bioactive molecules, which are comprised of anti-inflammatory cytokines, growth factors, neuronal factors, and antioxidants. The rediscovery that cells secrete a plethora of factors into nanosized vesicles surrounded by a lipid bilayer membrane (extracellular vesicles) has allowed exploring the therapeutic use of these vesicles in a novel therapeutic modality known as cell-free therapy.

The class of extracellular vesicle known as exosomes emerge as a promising therapeutic approach for neurodegenerative diseases. This is because, due to their nano-sized diameter, the exosomes can cross the blood brain-barrier, acting as carriers of bioactive molecules naturally secreted by their derived cells, or they can be engineered as carriers of drugs. Despite the evidence of the benefits of cell-free therapy for neurodegenerative diseases, efforts are necessary to improve the available exosome isolation methodologies in order to realize scalable vesicles production for clinical purposes. In addition, it is also crucial to provide guidelines for studying these vesicles in order to guarantee acceptance criteria by regulatory agencies.

Link: https://doi.org/10.3390/cells9122663

Comments

This is off-topic but how is the SENS fundraiser going? Can FA! report on this? Their website does not show their progress. It may spur last minute donors if they are behind. The first $600,000 in donations are being matched.

Posted by: Morpheus at December 28th, 2020 8:00 AM

Offtopic: TL DR Happy New Year, a long one for the new year, and a long health/life to all.

Hi there! Happy New Year

''It is quite another thing to make sense of that data, to arrange it into cause and consequence, to identify processes that produce the observed results, to move from observation to proposed therapy. Comparatively little has been accomplished on that latter front, as illustrated by the point that epigenetic (or transcriptomic, or proteomic) clocks that correlate with age and mortality risk are well established, but no-one can yet explain exactly why these epigenetic changes are associated so closely with the process of becoming old.''

I think I have aging a bit more figured, it is subtle like that, it seems that programmed aging or aging caused by 'time passing', is more causal to longevity - than DNA damage. DNA damage itself does not cause the Intrinsic Epigenetic Aging Process to accelerate; in fact, DNA damage does not Cause intrinsic aging, it only exacerbates the Extrinsic Epigenetic Aging, the Intrinsic ones is different and Unrelated to damages. Now it gets confusing because there are 2 Epigenetic aging, Intrinsic and Extrinsic...Intrinsic is a process that happens With or Without any DNA damage, while Extrinsic is accelerated by DNA damage and is more like a proxy for 'health' and survival (immediate), this was shown in African Americans epigenetic studies, where it showed that they have Higher Extrinsic Epigenetic Aging clock but Lower Intrinsic Epigenetic clock....which translates as they are having a Lower Epigenetic Age...but a faster 'life/external factors' 'health aging'...such as obesity, smoking, eating crap, oxidative stress, DNA damage; this means that they may succomb to diseases more with age - but they are Younger by the epiclock.

Which means, that they are afforded a Longer Lifespan - IF - they do not succomb of health problems (extrinsinc epigenitic aging). While Caucasians had a Higher Intrinsic Epigenetic Age..but a Lower Extrinsic Epigenetic Age...so this means, that they 'fared better' on 'health'...by having less extrinsic epiaging...But, their Intrinsic Epigenetic Aging clock was Accelerated..which meant that 'in terms of longevity - they are more limited'

...so it means that Caucasians 'mature faster' than African Americans...it was demonstrated that 'maturing/puberty/reproduction entry' is 100% related to Intrinsic Epigenetic Aging...in other words, reproduction is a Cause of Intrinsic Epigenetic Aging and is a 'maturing process' (in other words 'the program 'continuing its course' by 'maturation').

Well, it so happens that women who have Faster entry in menopause and menarche have Accelerated epigenetic aging (most likely intrinsic one), women that are more fertile and reproducing faster show accelerated epigenetic aging. And this corroborates studies on long lived animals: Naked Mole Rats have protracted puberty (they live 35 years...), like humans who have puberty at 10-13 years old...and even better example is ***greenland sharks that enter puberty - at 100 Years Old***...these sharks live 400+ years. So it means that evolution 'imprinted' epigenetic aging by/as a 'maturing process/reproduction process'...that if reproduction happens the goal is met (for special survival) and thus the individual becomes moot/no use anymore beyond..the 'task' completed/done (having reproduced/made offsprings). Africans can enter menaupose later/enter puberty later - despite that they may show more DNA damage and more external epigenetic aging (like health problems causing diseases). This means that they Age Slower intrinsically (since they postpone puberty) - despite extrinsic clock. This is the same thing in centenarian offsprings - they have Protracted/Post-poned puberty and post-poned maturing processes; and they have a Lower Epigenetic Intrinsic Clock than other regular aging offsprings. It is interesting because Demethylation of specific CpG islands in DNA causes 'maturing' - and this in turn, cause the epigenetic (intrinsic) clock to advance/accelerate.

Such as 5-azacytidine/sodium valproate (valproic acid), ascorbic acid (vitamin c) and
5-hydroxymethylcytosine (unlike 5-methylcytosine - the inverse of it; hydroxylation is what causes that), all of them cause 'cell differentiation' (of the stem cells) and 'maturing/blooming' process (by increasing endocrine/sex hormones needed for sex reproduction) - which is entering into reproduction mode/puberty. So, they cause 'program advancement'; this means Intrinsic Epigenetic 'program' to advance its course - and - That - Is, truly, being Older (intrinsically).

The telomeres also are independent from the epigenetic clock (yet communicate with it Also/on top of this surreptitious/ambiguous connection), the telomeres should be construed as a
'mitotic clock'/'replicative (rounds/bouts)/cell cycles clock' and a 'cancer break pedal' (by inducing replicative senescence as they shorten - to twarth cancer formation/as a counter-mechanism against rogue cell formation), mitotic clock/cell cycling clock because that is how much/many rounds the cells will be able to divide/replicate (by telomere size). A epigenetic Steve Horvath study of 2016 showed that DDR (DNA damage response) - Does Not - cause epigenetic aging (the intrinsic one...albeit the extrinsic one may accelerate though; not the intrinsic one). DSBs/SSBs (Double-Strand Breaks/Single Strand Breaks in DNA) do Not cause epigenetic aging in the intrinsic clock; maybe in the extrinsic though. DNA damage is Unrelated to the the Intrinsic Epigenetic clock. That is to tell you how longevity/aging is much more subtle than we thought. In that study, DNA damage does not cause More epigenetic aging...there is No Difference to the (intrinsic) epiclock after DDR at telomeres...

DNA Damage Response is what happens at telomeres when DNA damages happens - this Would normally make aging progress - but it does not happen, the (intrinsic one) epigenetic clock does not change after the DNA damage. This demonstrates that 'we are out there in the field...with longevity/aging'...as in 'lost'...in total ambiguity.

If telomere are shortened - they cause replicative senescence entry - and this manifests as Physical/visual aging on the body (such as stem cells becoming depleted as their telomeres too short..cause stem cell replicative senescence), this will show as an 'aged body'...but it DIFFERS from the Intrinsic Epigenetic Aging clock (maybe not from the Extrinsic epigentic clock though).
As the stem cells become depleted, there is less tissue renewal so this will mean more and more 'old/used/damage' tissue, thus visually will look older. But -Not- by Intrinsic Epigenetic clock. Let us Remember DNA damage - Does Not - cause Intrinsic Epigenetic Clock to advance/accelerate/change. DNA damage contributes to senescence/telomere DDR (telomere DNA Damage Response) - which activates premature cell cycle exit (G2 phase) or if maximal replication (Hayflick limit) it causes replicative senescnce. While cancer causes oncosenescence ( a different form of senescence than replicative or premature/spontaneous 'damage-caused' 'premature cell cycle exit' senescence).

It means (and shows it is more complex and infinitely more nuanced than we thought), (intrinsic) aging/longevity is driven 'by the program following its course (maturation causing it to 'continue its course')' (in the Intrinsic Epigenetic clock). It is hard to untangle this tangled mess - between DNA damages and epigenetic aging clock; which is correlative and which Causative or not. It is truly being a rat, lab rat - in a rat maze/laboratory lab lab labyrinth..stuck, and lost 'going in circles and repeating self like a parrott' with an infinite amount of 'catch-22s'. So so sooo many 'dead ends' in that lab maze lab/labyrinth. A lab rat lab is what it is. Cul-de-sac after cul-de-sac.
It's a small wonder that this rat has simply not given up already and say 'that's it.....I won't move an inch anymore, I'm dying in this maze (..stuck), anyway'. No way out, no figuring out of aging.

A proof that intrinsic epigenetic aging is related to Longevity/Maximal Longevity is in extremely long lived animals; 100+ years old Centenarians - their offsprings have Reduced Epigenetic aging - compared to other control offsprings...this means that the centenarians offsprings have a lower age and an advantage - they will live longer than the offspring of shorter-lived parents. The centenarian offspring may reach the centenarian age - of (like) their centenarian parents. But this Requires a reduced instrinsic epigenetic age (by DNA methyl clock).

''but no-one can yet explain exactly why these epigenetic changes are associated so closely with the process of becoming old''

They are associated closely to the health/diseases (extrinsic epigenetic aging) and the longevity/maximal specie lifespan potential (intrinsic epigenetic aging), because these epigenetic changes 'regulate' the 'program', as in 'make the program Happen and Follow its Course'...which is tantamout to aging 'following'/'ensuing'/'continuing itself' - 'blooming/maturing' - as a normal linear process/stocastic process. So we could see aging as like 'the program 'maturing'' and 'becoming''...as the programs 'unfolds' it 'becomes' and it makes you age/become older...during that time you may be Limited by Extrinsic factors that weigh on the Extrinsic Epigenetic clock, which will cause arrival of diseases....while the Intrinsic Epigenetic clock records the 'time passing'/keeps tabs of the days/weeks/months/years....if you have Faster Extrinsic Epigenetic aging you will Enter Disease Faster..and die Prematurely..of a disease. And this is the kicker...
if you do not have ANY premature disease of aging...you WILL aging 'normally' by the intrinsic epigenetic clock - as in, your program will follow its course until it is not viable to function anymore (epigenetic drifting happens with time), and the epigenome will become completely demethylated; which means that soon the cell will commit senescence or apoptosis will happen.

Because telomeres shrink during that time and they are mitotic clock - they will Stop the cells from replicating once they are too short. But here is the Double Kicker...if the telomeres are increased, Intrinsic Epigenetic Aging Will Proceed Even So - despite the telomeres length.
In other words, the cell will commit to death - Because it Remembers the 'tabs/how many years passed' in the Intrinsic Epigenetic Clock.

Let us remember the Epigenetic clock is INDEpendent from telomeres (yet, they communicate too, but remain 2 separate entities/clocks that do not measure the same thing at all; one measures the 'programs age' while the other measures 'mitotic age'), anyway that is my understanding so far after being deceived repeatedly about aging and reading new and new studies (by Steve Horvath/Hannum) on epigenetic aging; it's so much more nuanced than simple 'DNA damage = aging'...apparently not (this car analogy of car damage to be repaired is not subtle enough -

-the real analogy is 'car damage happens but it does not mean/equate to the lifespan of the car - the 'time tabs-tabulometer' inside the car is what means the longeivty of the car - irrespective of how much damage it has'. This means therapies that will repair DNA damage - Will Not - reverse physical intrinsic aging, the clock will not simply reverse itself because DNA damage - this means it *Requires* Epigenetic Reprogramming of the epiclock (intrinsic) to Reverse Intrinsic Aging. Only if we Replace the parts we might overcome aging; because of continuous 'new young' parts added to replaced old used parts..but will see if possible in entirety of body.

Just a 2 cents.

Posted by: CANanonymity at December 28th, 2020 10:18 AM

Hi Morpheus (and Reason, maybe you can make his question and this answer more visible?),

Thank you for asking about the SRF fundraiser. Actually the matching situation is even better than "The first $600,000 in donations are being matched": that match (which is already the biggest we'd ever had) was offered by Michael Antonov, and he suggested that we should encourage other major donors to "co-match" some of it so that small donations would be trebled rather than "only" doubled. Michael persuaded one of his Oculus co-founders, Brendan Iribe, to provide $100k, and we steadily brought more of them on board over the next few weeks; as of last week we made it to $500k, so now the entire $600k is being trebled. And it's definitely been working: the total of other donations is already some distance ahead of any previous year. The total shown on the SRF home page is a bit misleading because it includes some of the co-matches as well as the donations that are being matched, and also it's being updated manually (not least because we have to integrate money from several different sources - credit cards, paypal, crypto, checks, stock, European money coming to SRF-EU and TGE...) so I don't have an exact number as of today, but I think we're over $450k in "matchee" money at present - and yes, the challenge is open until the end of Thursday!

If anyone wants to donate but they need more information on how to do so in their preferred way (e.g. an unusual cryptocurrency), please drop us a note using the sens.org contact form or else just email me at aubrey@sens.org. Thank you so much to everyone who has already donated!

Posted by: Aubrey de Grey at December 28th, 2020 1:01 PM

Yes, much remains to be explored regarding potential applications of the MSC secretome

Mesenchymal stem cells secretome, I do believe in its broad application potentials. I think the next step in this field needs a push from the commercial industry.

How would the therapy for neurodegenerative diseases be administered?

please drop us a note to: emailgarvin@gmail.com

Posted by: Garvin Timmann at December 28th, 2020 4:23 PM
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