612 replies to this topic

[playground]

playground: some good news.

I googled Rita Levi Montalcini and "gocce" (which means drops) and a whole lot of super interesting stuff came up.

 

There are SEVERAL studies going on right now using NGF as a way to cure retinitis pigmentosa AND ocular tumors.

The type of drops used are "rhNGF", aka recombinant human nerve growth factor.

Another study involves rhNGF for ocular tumors.

Another to repair the cornea.

Im going to past the related links here, you can google translate, a whole lot of information is in these articles, at the moment i am about to head out but i will search for more stuff later and translate what i can.

 

http://www.galileone...rare-la-cornea/

 

http://www.galileone...ite-pigmentosa/

 

http://www.galileone...lla-montalcini/

 

http://www.iapb.it/news3.php?id=2044

 

One of the articles is from April 2015, as you can see, so we have very recent stuff and some of the studies mentioned are about to end and the results will be published (one is supposed to end in November 2015).

 

What i found here is just about the eye so far, apparently Rita started taking the drops for some issues with her eyesight and later realized the drops could reach the brain and improve her neuronal capacity (probably butchering the terminology here).

 

I alwo wonder about the difference between rhNGF and NGF... which is not clear to me.

 

Excellent, good work Asor!

 

In which article does it says this:

 

"Rita started taking the drops for some issues with her eyesight"  ?

 

Is it that Rita is quoted as saying that she started the NGF when she had problems with her eyesight ?

Or is it ... that.... some journalist is giving a summary ? 

 

Does the same article (or any article) tell us when when started having problems with her eyesight ?

 

You've said here that she started taking the eye drops, and then subsequently realised that

the NGF could reach her brain.  

 

"Rita started taking the drops for some issues with her eyesight and later realized the drops could reach the brain"

 

So this means that there must be two dates involved:

1) The first date is when she first learned that NGF eye drops could help with failing eyesight.

2) The second date is when she found out that NGF could reach the brain via eye drops.

 

Presumably, you wouldn’t put NGF into your eyes unless there was some

experimental evidence to suggest it would work, right ?

 

So, the first date must have been after the date when research interest in treating retinal

problems with NGF began. 

My search through google suggests that this date is approximately 1989.

(However, a more thorough search might easily find earlier dates)

 

In 1996, her friend and colleague Dr Aloe, performed his own studies into this.

So definitely by 1996, at the latest, Rita knows that NGF can help with failing eyesight.

However, those studies were in vitro,  or via injection.

 

The first NGF eye-drops study looking at repairing retinal nerves was (surprisingly recent) in 1998.

 

In the first published study about the application of
NGF-eyedrops [172], severe corneal ulcers associated
with anesthesia (corneal neurotrophic keratitis) were
treated with purified mNGF.

source: http://www.translati...5876-10-239.pdf

 

What is reference [172] ?  It's this:

 

172: Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L:
Topical treatment with nerve growth factor for corneal neurotrophic ulcers.
N Engl J Med 1998,338:1174–1180

 

This suggests that Rita started on the eye drops sometime after 1998.

 

The second date is when the first studies are published with radioactively labelled NGF.

You put radioactively labelled NGF into the eyes of  mice/rats/rabbits and then

sacrifice them two hours later to see where the NGF went.

 

Metagene's NGF-eye drops patent details experiments of this kind with rabbits.

However, the patent describes the experiment, the results, but doesn't cite any references.  :-|

 

Here's the patent pdf for anyone that fancies trying to track down this study:  (search for the string '[0044]')

https://docs.google....EP1948217B1.pdf

(It might possibly have a date on it earlier than 2005)

 

However, i do have a date for the discovery that NGF eye-drops would pass to brain areas

behind the eye.  It's 2005.

 

Recent studies reported that NGF can be safely delivered into the brain by nasal

(Chen et al., 1998; Koevary et al., 2003; Di Fausto et al., 2007) or

ocular administration (Lambiase et al., 2005; Di Fausto et al., 2007;

Lambiase et al., 2007; Lambiase et al., 2009),

          souce:  http://www.ncbi.nlm....les/PMC4146309/

 

What is this Lambiase et all (2005) reference ?  It's this:

http://www.ncbi.nlm....pubmed/16186366

 

They used radioactively labelled NGF to see if it had entered the optic nerve

behind the retina.  And of-course, it had.

 

So it looks like the second date is 2005 (or slightly later)

Probably the patent study with the rabbits probably came after the finding that NGF

was diffusing into the optic nerve

 

 

The summary is:

 

It looks as if Rita started on the NGF eye-drops in or after 1998 and before 2005.

 

So... Rita must have been 89 years old, or in her early 90's, when she started

on the NGF eye drops.

 

This is long way from my original understanding, which was that she started the

eye-drops 40 years ago, in the mid 1970's.

 

Also note that this 1998 date is after the date when human recombinant NGF (rhNGF)

became available. This (arguably) suggests that she was using human, not mouse NGF,  (mNGF).

 

Let's not forget, that no Pharma company has gone to market with rhNGF eye-drops.

Genentech abandoned stage 3 trials because they encountered "toxicity".

 

Playground.

 

Edited by playground, 06 June 2015 - 04:52 PM.

[Asor]

In which article does it says this:

 

"Rita started taking the drops for some issues with her eyesight"  ?

 

Is it that Rita is quoted as saying that she started the NGF when she had problems with her eyesight ?

Or is it ... that.... some journalist is giving a summary ? 

 

 

http://www.corriere....44f02aabc.shtml
 

Pietro Calissano said it, in occasion of Rita's 100 years birthday.

 

Pietro Calissano, vicepresidente dell'Ebri (European Brain Research Institute), che da 44 anni collabora con la celebre scienziata, ha detto a margine della celebrazione a lei dedicata in Campidoglio che prende tutti i giorni il Ngf (Nerve growth factor) in forma di gocce oculari per problemi alla vista. Si tratta della molecola scoperta dalla stessa Montalcini negli anni '50 e che le è valsa il premio Nobel. Calissano ipotizza che la sostanza raggiunga il cervello, favorendone la naturale plasticità

 

tranlasted in short: Calissano said that she takes NGF every day in form of eye drops for eyesight issues. Calissano hypothesizes that the substance reaches the brain, favoring its natural plasticity.

 

No other infos regarding when she started or anything else.

[resveratrol_guy]

Asor and Playground, thank you both for your thorough research (and correcting that my understanding of "rh"!).

 

So in a way, this sounds even more impressive. If she only started taking NGF in the 1990s, it appears to have had a huge effect very late in life. She never suffered the mental decline that she reasonably should have, at that age, despite her healthy lifestyle.

 

What should we do next? Just proceed with a group buy and guestimate the dosage? Contact Calissano and try to answer the remaining questions? Or something else?

 

And BTW what did Genentech say about the nature of the "toxicity" of NGF? Were they using eye drops or some other form of administration?

Edited by resveratrol_guy, 07 June 2015 - 12:21 AM.

[playground]

Hi RG, Asor, beatstar, metagene, Ark, dz93, positiveeddy, normalizing, keizo,  Hebbeh, et al

 

I think we should continue the pursuit.

 

Rita said that she felt she was mentally clearer 'today' than she was when she was 20.

That's got to be a rare statement from a lady in her late nineties.

 

I don't think it's a good idea to guesstimate the dosages.

I think it's a better idea to find out what dosages have been applied during the previous

trials.  In particular the Genentech trial.  Whatever dosage they used,  use less.

 

I suggest that the focus now should be on finding out more about NGF toxicity.

In particular, i think we should try to find out more about the Genentech stage 3 trial.

My understanding is that they did two things differently between stage 2 and stage 3 trials.

1.  They increased the dosage.

2.  (And this bit puzzles me) They changed the formulation of the rhNGF.

 

Here is a quote from a paper which is evidently talking about the Genentech trials.  It's title is:

Nerve Growth Factor for the treatment of diabetic neuropathy:

What went wrong, what went right and what does the future hold?

 

These early studies, however, revealed that painful side effects were dose limiting for NGF.

A large-scale phase III clinical trail of 1019 patients randomized to receive either rhNGF

or palcebo for 48 weeks failed to confirm the earlier indications of efficacy. Among the

explanations offered for the discrepancy between the two sets of trails was a robust palcebo

effect, inadequate dosage, different study populatioms, and changes to the formulation of

rhNGF for the phase III trail. As a result of the phase III outcome, Genentech has decided

not to proceed with further development of rhNGF.

source:  http://www.ncbi.nlm....pubmed/12198818

 

I would very much like to get my hands on the full paper.

I have only access to the abstract at the moment. 

This paper might details the following important details.

1) What dosages were being applied ?

    (In particular what dosages at stage 2, and what dosages at stage 3)

2) What toxicity effects were reported ? 

    (know these effects sufficiently well that, if they happened to us, we would recognise them as NGF toxicity)

3) What do they mean 'changed the formulation of rhNGF' ?

 

Does anyone have academic library membership that would grant access to the full text of this article ? 

We could all benefit enormously from a PDF or DOC copy of this article.

I would, of-course, be very grateful :-)

 

It's quite interesting because, in stage 2 trials they applied dosage X.

The got a 'robust placebo effect' ... in other words it seemed to work.

They then increased the dosage X + ?  _and_ changed the 'formulation'...  and then got toxicity.

 

What was this changed formulation ?  Was this form of NGF the cause of the toxicity ?

Is it perhaps, that if you exceed dosage X... NGF does bad things,

but if you stay at dosages below X, it does good things ?

 

I think it's important to find out more about what was learned during the NGF trials

before people [we] start self-administering. 

 

 

Playground.

 

 

 

 

 

 

 

Edited by playground, 07 June 2015 - 08:44 PM.

[Metagene]

I use Libgen

https://drive.google...a0tLajI5RDJ1Rjg

[resveratrol_guy]

I think they decreased the dosage: "These early studies, however, revealed that painful side effects were dose limiting for NGF".

 

Anyway, this sounds like a farce of a trial. Let's see:

1. Give NGF to patients suffering from neuropathy from either diabetes or HIV. In other words, try to restore sensation in people in horrible physical shape. This shows dubious ethics, to begin with.

2. Unfortunately, it works. The patients develop terrible pains because the whole inflammatory pain feedback system comes back to life. Rheumatoid arthritis pain thrives on NGF. Likewise, longterm users of lion's mane report itching and tingling in places which were previously numb.

3. The researchers decide that the side effects are too much, so they cut the dosage for phase 3. But given the good phase 2 results, the phase 3 participants are highly optimistic. So the placebo effect strengthens. But at the same time, the real NGF effect diminishes because they cut the dose.

4. They decide that NGF isn't sufficiently better than placebo, so they terminate the trial.

This is almost as idiotic as injecting Alzheimer's patients with NGF and randomly hoping for it to end up in the brain. I think we can do better with eye drops. Rita must be rolling in her grave!
 

Edited by resveratrol_guy, 07 June 2015 - 10:53 PM.

[playground]

I use Libgen

https://drive.google...a0tLajI5RDJ1Rjg

 

He's done it again.  Truely a star !

 

Thank you Metagene.  I appreciate your help.

 

Playground.

 

PS..And thanks for the tip about libgen.

[resveratrol_guy]

Thanks again, Metagene!

 

Now that I can read it, the study only seems to confirm my fears: "Much of the evidence favoring a beneficial effect of NGF in the treatment of neuropathy is derived from animal models (see earlier discussion). The doses of NGF used in those studies ranged from 1 to 10 mg/kg administered from three times a week to seven times a week. In contrast, rhNGF was administered at a dose of 0.1 ug/kg in the clinical trial. This is at minimum a 10,000-fold difference." In other words, they did a phase 1 study in phase 3. What they needed to give up on was their strategy of being conservative to the point of ineffective, not rhNGF as a promising compound.

 

By contrast, we're talking about 10ish ug per eye per day -- 100X that used in this study. And it might be more like 1000X, effectively, because it will be largely trapped in the brain after the fact.

 

It seems that 0.3 ug/kg (injected) is the threshold where we begin to see perceptible effects on sensory neurons. So I would say that I now have more faith that something like 10 ug per eye per day is going to be useful for cognitive enhancement.

 

But it looks like rhNGF now has a bad name for an unfair reason, which may explain the dearth of studies lately.

 

[resveratrol_guy]

BTW I just had a crazy idea that might help the non-billionaires here.

 

So first of all, this study says that lion's mane stimulates NGF, but doesn't actually contain any. (Can you work any magic on this one, Metagene?) That's OK, because in my naive understanding of evolution, mushroom peptides should generally be much shorter than human ones because they're way down there on the genetic totem pole. They also appear to have some pleasant side effects on inflammation and immune function, if I recall. This is all to say that, at worst, it would seem that they have low toxicity not unlike any other mushroom; at best, they do what the anecdotes purport.

 

You can see where I'm going with this: could we drip lion's mane extract into our eyes, and hope that the NGF precursor crosses into the brain? I know this sounds crazy, but precursors have the advantage of controlling the NGF production rate, in case spiking it is dangerous for some reason. So it may well be safer than straight up NGF eye drops. Not to mention 10X or more cheaper.

 

I'm thinking:

 

1. Obtain lion's mane liquid extract from a rock solid source, such as Fungi Perfecti. (No nonsense grown in soils from industrial waste, etc.)

 

2. Boil the extract. Who knows what might be living in it, and we're talking about our eyes here. Hopefully this won't destroy the precursor. If it does, we'll have to resort to other techniques or just "drip and pray". (Beware meningitis!)

 

3. Let it cool to room temperature.

 

4. Put a few drops in each eye.

 

5. Repeat twice a day for a month. See what happens.

 

The thing is, there is a high quality set of anecdotes and even a clinical study or two confirming lion's mane's cognitive benefits. But surely most of it is wasted on the digestive system. If we administered it in this manner, it would become affordable for many more people, and avoid all of the nonsense with importation etc.

 

I'm probably willing to do this myself, if no one volunteers. I'm currently on a 40-day amyloid cleanse with megadose Longvida, but after that, I'm open.

 

But first... is this nuts?

 

Edited by resveratrol_guy, 08 June 2015 - 04:19 AM.

[burnlife]

 Why are there no news on any progress with the group buy? I think we have enough people for it now. 

[ceridwen]

I don't think the growth caused by lions mane lasts.

[Nuke]

Lion's mane extract that was used to increase NGF was an ethanol extract. I don't think Boiling it is necessary. From here - http://examine.com/s.../Yamabushitake/

 

 

[ceridwen]

I read the paper and it seems that NGF would in fact be no good for me but what if not all of my brain is diabetic? Could that be possible? Though actually the Noopept and the Hydergeine were not working as they should. Even C60 was not working to full effect. The energy restoring side has gone though it restored my sense of smell and I don't get drunk any more.
I don't suppose there would be a group buy for rhNGF would there? Rita clearly still believed in it or she would not have been taking it. There is a mystery here though. What did she die of?and why was the cause of death not recorded? Does that have implications for rhNGF?
On a less important note should I take NGF to protect parts of the brain that may still be living on glucose? Or will that just cause a faster die off? Should I try to halt the overall decline instead through dietary or herbal means? The problem is NGF does give very good effects when it works and I think the pine needles are doing something though this might be delusional this is not confirmed by brain games. I've stayed at the same level. There is 1 more possibility I suppose Rita may simply have been addicted to rhNGF and continuing to administer it despite the fact it was killing her? Interesting.

[playground]

I've been considering this 'group buy' thing.

There is a post in the members' forum next door

which paints a bleak picture of group buys

Posted 18 July 2014 - 10:20 PM

Quote
    LongeCity leadership will listen to members about experiences with 'group buy' initiatives and private forums.

If these turn out to be negative, or if it appears that the tools we provide are being used in contravention of our site

rules or to bring LongeCity into disrepute, we will take steps to prevent such activities being associated with LongeCity at all.

It has been suggested that since the statement above was formulated not a single attempted 'group buy' has transpired

without some kind of irregularity, fraud, money lost or mismanagement.  Not a single initiative has been successful.

Should they be tolerated at all?

source:  http://www.longecity...-on-group-buys/

 

This post was made by Caliban, an Admin at longecity.org. 

It was posted in the Members forum. 

I'm not sure if Registered Users get access to the Members forum. 

For some of you, the above 'source' link might not work.  

 

The point is simply that things go wrong with Group Buys.

There's fraud, or incompetence, changed plans, a failure to communicate etc.

 

The Group Buy initiative on this thread appears to have died.

So perhaps it needs new life breathing into it.

 

What would be the idea arrangement for a group buy ?

 

Here are some suggestions:

 

The organiser of the Group Buy :

 

1 =>  should not be anonymous;  known only by his/her username.

     'doofus'  in New York. etc.

      This person should have a public identity.

 

2 =>  should have no interest in consuming / using the chemical

      for him or herself. 

 

3 =>  should be honest and trustworthy

 

4 =>  should be technically competent in this area.  e.g.

      (a) knows about how to handle these things in a sterile manner.

      (b) knows how to divide up, say, 5mg into 20 equal parts.

      © knows about storage media and storage considerations generally.

      (d) know the difference between different types NGF so that the wrong

           thing isn't ordered.

 

 

To be clear, i'm not proposing myself. 

I'm not technically competent.

And i suspect i may join in on the group buy.

 

So if this person has no interesting in using NGF why would they agree

to broker the deal and handle the material ?

We would, i think, need to offer an incentive in terms of some kind of

commission. 

 

The person that brokers a group buy is actually doing a lot of work:

 

=> research to figure out what to buy.

=> research to figure out where to buy from.

=> research to figure out storage and shipping requirements are required.

=> negotiation with suppliers to figure out price and delivery arrangements.

=> agree to using his / her bank account as the 'group buy' bank account.

=> communicate with group buy members

=> receive the goods

=> use appropriate apparatus / tools & techniques to  divide up the goods.

=> store 20 or 30 measures in suitable storage contains.

=> send out 20 to 30 registered mail / signed for packages to group buy members

=> deal with any hassle from group members that back out, complain

or act in disreputable way.

 

This is actually, quite a lot of work and potential hassle.

 

If anyone has any thoughts to add to this,  please share them.

If i've overlooked anything, or made an error.. please let me know.

 

I have someone in mind that might meet the criteria i've proposed above.

I'm not sure this person would willingly take on the work / hassle involved.

But i want to do a little more research and consider it a few days more

before proposing a name on this thread or broaching the subject with them.

 

Playground.

[playground]

BTW I just had a crazy idea that might help the non-billionaires here.

 

So first of all, this study says that lion's mane stimulates NGF, but doesn't actually contain any. (Can you work any magic on this one, Metagene?) That's OK, because in my naive understanding of evolution, mushroom peptides should generally be much shorter than human ones because they're way down there on the genetic totem pole. They also appear to have some pleasant side effects on inflammation and immune function, if I recall. This is all to say that, at worst, it would seem that they have low toxicity not unlike any other mushroom; at best, they do what the anecdotes purport.

 

You can see where I'm going with this: could we drip lion's mane extract into our eyes, and hope that the NGF precursor crosses into the brain? I know this sounds crazy, but precursors have the advantage of controlling the NGF production rate, in case spiking it is dangerous for some reason. So it may well be safer than straight up NGF eye drops. Not to mention 10X or more cheaper.

 

I'm thinking:

 

1. Obtain lion's mane liquid extract from a rock solid source, such as Fungi Perfecti. (No nonsense grown in soils from industrial waste, etc.)

 

2. Boil the extract. Who knows what might be living in it, and we're talking about our eyes here. Hopefully this won't destroy the precursor. If it does, we'll have to resort to other techniques or just "drip and pray". (Beware meningitis!)

 

3. Let it cool to room temperature.

 

4. Put a few drops in each eye.

 

5. Repeat twice a day for a month. See what happens.

 

The thing is, there is a high quality set of anecdotes and even a clinical study or two confirming lion's mane's cognitive benefits. But surely most of it is wasted on the digestive system. If we administered it in this manner, it would become affordable for many more people, and avoid all of the nonsense with importation etc.

 

I'm probably willing to do this myself, if no one volunteers. I'm currently on a 40-day amyloid cleanse with megadose Longvida, but after that, I'm open.

 

But first... is this nuts?

 

Not sure.... potentially, it could be a really good idea.

Have there been any research studies using Lion's Mane eye drops ?

If so, how did they process the lion's Mane ? 

 

I remember from the radioactively labelled mNGF eye drops study with rats that

the NGF was put into a saline solution which was 'isotonically balanced' so as

not to cause irritation of the eye (which presumably would lead to tears and loss of the NGF)

 

Playground.

 

[dz93]

We could always use a viral vector that will attach to our neurons to continuously stimulate NGF production. No need for constant dosing and you'll have a life time supply. Lol. If I remember correctly there is a drug in the works that does this. I'm sure I've posted that information on here in an earlier post.

Genscript does work with CRISPR. Anyone here familiar with genetics? Lol


Edit: Find or make CERE-110. Problem solved :D lol

Edited by dz93, 08 June 2015 - 12:06 PM.

[resveratrol_guy]

First of all, I fully support a group buy. I would hope that the administrators would continue to tolerate these, because everyone recognizes the risks mentioned above, and frankly it's better than no group buy at all. I would direct people to the second dihexa group buy for potentially competent assistance.

Secondly, some of you said that my proposal needs references. I agree. On the one hand, I'm unable to find any precedent in the literature for the use of transocular lion's mane extract (tincture). However, the neurological effects pursuant to other delivery methods have been studied extensively. For example here, here, here, here, and here. Several more references are at the bottom of this page.

And yes, ceridwen is right: the effects last only weeks beyond cessation of dosing. But that's probably because neurons continue to die every day, especially in old diseased brains with few growth factors, and are never replaced in sufficient numbers after around age 20. Only by increasing NGF or injecting neural stem cells, can we hope for a better outcome. So anyone seriously entertaining NGF or NGF precursor dosing should assume that they'll need to do it periodically for the rest of their life. As we all know, that's what Rita did.

Furthermore, I found some very promising links to lion's mane extract, which seems to be about twice as expensive as the powder, but that would be trivial if in fact it would allow us to preferentially target the brain.

Note that some of these products make reference to "nerve growth stimulating factor" (NGSF). As I understand, this is simply a generic term for a substance which promotes endogenous NGF production.

I would advocate boiling because (1) it's impossible to trust that the extracts are sterile and (2) doing so would reduce the amount of ethanol, which is (mildly) neurotoxic.

Extracts are 10-100X cheaper than NGF, drop for drop. So in other words, they're a better deal if they work only 10% as effectively. Sources are here, here, here, here, and here.

 

dz93 is right: The study for endogenous NGF amplification using adeno-associated viruses is CERE-110. But it's in trials in the US, which means it won't be in the clinic for 400 years or so. And you can't simply make it at home because it requires intracranial injection.

 

EDIT: NGF is 26 KDa, as Metagene pointed out; but lion's mane's hericenones B, C, and F (and maybe others) are better than 10X lighter! So I think we have a good case for transocular diffusion into the brain, assuming sufficient solubility.

Edited by resveratrol_guy, 08 June 2015 - 05:09 PM.

[dz93]

No need to wait 400 years lol. NSI-189 has only completed phase 2 yet I have a few grams sitting right next to me.

Now, NSI-189 isn't a viral based drug but I was wondering if we couldn't dig up more information about CERE-110 and maybe go through genscript to make us something that would do the same thing. Of course this is a long shot but I'd like to hear your guys thoughts and opinions. I think it'd be worth looking into because viral based drugs seem like they'll be taking off in the near future. Especially since CRISPR was discovered. BioViva already offers gene therapy using AAV.

I know very little about genetics and viral based drugs so forgive me if I seem like a giant noob because I am lol

[resveratrol_guy]

No need to wait 400 years lol. NSI-189 has only completed phase 2 yet I have a few grams sitting right next to me.

Now, NSI-189 isn't a viral based drug but I was wondering if we couldn't dig up more information about CERE-110 and maybe go through genscript to make us something that would do the same thing. Of course this is a long shot but I'd like to hear your guys thoughts and opinions. I think it'd be worth looking into because viral based drugs seem like they'll be taking off in the near future. Especially since CRISPR was discovered. BioViva already offers gene therapy using AAV.

I know very little about genetics and viral based drugs so forgive me if I seem like a giant noob because I am lol

 

The AAV approach is potentially revolutionary. The problem is that it's not in the form of a pill or simple injection. So I think the chances of seeing AAV therapy for Alzheimer's in a Western country in the next decade is nil. And in this case, I wouldn't look to the third world for any help, on account of the high competency level required to for intracranial injection (prion hazards, not the least of which). So where does that leave us as far as NGF is concerned? At best, we might synthesize it by inserting the right RNA sequence into bacteria. But presumably, the existing vendors are already doing that. Given that $470 per 500 ug is the best price I've found for a vendor that even looks potentially competent, I would say that a group buy is our best hope, if in fact someone here has the skills and equipment required. That said, it's still going to be expensive. Which is why I'm interested in exploring a cheaper solution in between NGF eye drops and lion's mane pills.

 

NSI-189 has its own thread. Based on the poll results, it looks promising. I need to read up on it. While I'm not generally in favor of superficial "receptor tweaks" like SSRIs, this stuff sounds like it operates on a structural and growth level, so thanks for the comment.

 

[dz93]

No need to wait 400 years lol. NSI-189 has only completed phase 2 yet I have a few grams sitting right next to me.

Now, NSI-189 isn't a viral based drug but I was wondering if we couldn't dig up more information about CERE-110 and maybe go through genscript to make us something that would do the same thing. Of course this is a long shot but I'd like to hear your guys thoughts and opinions. I think it'd be worth looking into because viral based drugs seem like they'll be taking off in the near future. Especially since CRISPR was discovered. BioViva already offers gene therapy using AAV.

I know very little about genetics and viral based drugs so forgive me if I seem like a giant noob because I am lol

The AAV approach is potentially revolutionary. The problem is that it's not in the form of a pill or simple injection. So I think the chances of seeing AAV therapy for Alzheimer's in a Western country in the next decade is nil. And in this case, I wouldn't look to the third world for any help, on account of the high competency level required to for intracranial injection (prion hazards, not the least of which). So where does that leave us as far as NGF is concerned? At best, we might synthesize it by inserting the right RNA sequence into bacteria. But presumably, the existing vendors are already doing that. Given that $470 per 500 ug is the best price I've found for a vendor that even looks potentially competent, I would say that a group buy is our best hope, if in fact someone here has the skills and equipment required. That said, it's still going to be expensive. Which is why I'm interested in exploring a cheaper solution in between NGF eye drops and lion's mane pills.

NSI-189 has its own thread. Based on the poll results, it looks promising. I need to read up on it. While I'm not generally in favor of superficial "receptor tweaks" like SSRIs, this stuff sounds like it operates on a structural and growth level, so thanks for the comment.

Yes, Bioviva is an American company but they do their genetherapy over seas, if I remember correctly.

This is off topic but do you think maybe genscript could provide an AAV that would continuously stimulate telomerase production? I ask because Bioviva charges $100k or so for genetherapy. It'd be nice if this stuff wasn't only limited to the rich. Especially since there is a strong desire by the rich to keep technology like this only available to the rich.

And yes, I know genetherapy is still in its infant stage. I'm just pondering the possibilities.

As far as NGF goes, I'd be willing to join the group buy if we can get some concrete evidence that NGF will actually be of benefit to cognition or longevity. Its all speculation at this point. I can't deny lions mane has a beneficial effect on cognition but will NGF by itself?

Which, of course, is why we're seeking out other alternatives. I've been following along with everything you guys have researched and you've done a fantastic job. I've never seen dedication like this anywhere else. Keep up the good work. If there's anything I can do to help please let me know.

[resveratrol_guy]

 

Yes, Bioviva is an American company but they do their genetherapy over seas, if I remember correctly.

This is off topic but do you think maybe genscript could provide an AAV that would continuously stimulate telomerase production? I ask because Bioviva charges $100k or so for genetherapy. It'd be nice if this stuff wasn't only limited to the rich. Especially since there is a strong desire by the rich to keep technology like this only available to the rich.

And yes, I know genetherapy is still in its infant stage. I'm just pondering the possibilities.

As far as NGF goes, I'd be willing to join the group buy if we can get some concrete evidence that NGF will actually be of benefit to cognition or longevity. Its all speculation at this point. I can't deny lions mane has a beneficial effect on cognition but will NGF by itself?

Which, of course, is why we're seeking out other alternatives. I've been following along with everything you guys have researched and you've done a fantastic job. I've never seen dedication like this anywhere else. Keep up the good work. If there's anything I can do to help please let me know.

 

 

I'm certainly no expert on the effects of systemic AAV therapy. Granted, the possibilities that you're referring to are real, but they're impeded by crushing government bureaucracy. Which is why I like this whole eye drop concept: it's very targetted and involves familiar compounds which are already available. I wouldn't replace simplicity with complexity when we haven't yet given ourselves a chance to observe the potential benefits of the former.

[resveratrol_guy]

BioViva actually looks more promising than I first supposed, due to technical competence and an FDA avoidance strategy, so here is a thread relating to them and a good introductory YouTube video. Big thanks to dz93 for the mention!

 

Edited by resveratrol_guy, 08 June 2015 - 09:24 PM.

[dz93]

Maybe we can do a group gene therapy

[Diego55]

I wonder if NGF spray could help me with my long-term struggle with cripling social anxiety, GAD and other issues mostly related to anxiety ?

 

 

[playground]

It was a little disappointing to discover that the Genentech trials were

'injecting' NGF under the skin.

 

We know that high local concentrations of NGF create swelling and pain.

This is what causes the pain of rheumatoid arthritis.

This is why NGF is present in the venom of snakes.

 

They were injecting 1mcg per kilo of body weight in the phase 1 trials

and 0.1 to  0.3 mcg per kilo of body weight in the phase 2 trials.

And then 0.1 mcg  per kilo of body weight in the phase 3 trials.

They progressively reduced the dosage from one trial to the next.

 

I understand that diabetics tend to be overweight...

so... as a guess, the average diabetic (american) woman weighs 70 kilos,

and the average diabetic (american) man 90 kilos

So each injection must have been 7-9mcg to 21-27mcg (depending on the

weight of the patient).

 

Unsurprisingly... patients reported pain, sometimes really severe pain,

at the injection site where the NGF was administered.

I'm sure many patients dreaded those 3 weekly injections.

 

I was a little shocked to read that the phase 3 administrators decided to

'spike' the placebo injections, with hypertonic saline, to make the injections

painful. Why did they do this ?  So the placebo group wouldn't guess they

were receiving dummy injections (containing no NGF). (See page 405

of the article).    Surely that's utterly unethical.  And actually, unnecessary.

 

It seems me that injecting NGF was a bad idea.  You could have

predicted, right from the start, that those injections were going to be painful.

They were essentially administering 'snake bites' to subjects, so of-course they

were going to be painful.

 

The objective is to get a certain volume of NGF into subject's bodies.

We've already learned that NGF has an amazing ability to pass through

tissues of apparently any type, despite it's substantial molecular size.

Why not simply apply it topically as a dermal cream.  Rather than inject a high

concentration, that will sensitize the local nerves and cause pain, why not

apply a low concentration skin cream across a large area of skin... feet, lower legs, etc.

(maybe i should patent that idea ;-))

 

I was left wondering whether the same sensitisation of local nerves could

occur with eye drops... leading to pain and swelling (as per the injections).

Probably, you'd have to be careful with the concentration of the eye-drop solution.

The higher the concentration, the higher the risk of sensitisation.

It was notable, i thought, that they reduced the concentration of NGF

for the phase 3 trials in order to reduce the inject site pain.

 

An interesting detail for me was the argument that NGF was, in theory,

particularly suitable for diabetic neuropathy (DN) since DN is initially

evident due to damage to 'small fiber sensory nerves'.   And NGF is

protective and trophic of these same 'small fiber sensor nerves'.

 

There's a handy little table on page 396 showing which neuron

types are served by which neurotrophin:

 

NGF    ---  Trk-A  ---  small fiber sensory neurons  (Sympathetic nervous system)

BDNF  ---  Trk-B  ---  midsized fiber sensory neurons  (Motor neurons)

NT-3    ---  Trk-C  ---  large fiber sensory neurons  ( Motor & Sympathetic nervous system)

NT-4/5 ---  Trk-B  ---  midsized fiber sensory (Motor)

 

This left me wondering which varieties of neurons were most prevalent in the brain ?

Which varieties are in the Hippocampus ? (which is badly affected in Alzheimer's)

Which varieties are located in the frontal and pre-frontal cortex ?

(associated with working memory & consciousness)

 

 

Playground.

 

 

 

Edited by playground, 09 June 2015 - 02:32 AM.

[dz93]

I'm wondering what the effects of getting NGF, BDNF, NT-3 and NT-4/5 to the brain would be. They're all neurotrophins. Maybe a super nootropic? Lol.

About the NGF cream, wouldn't it still be difficult for it to cross the BBB?

I'm wondering if there's a way to make a carrier of sorts to carry NGF past the BBB. Is NGF simply too large for it to pass at all or is the properties of NGF the reason why it can't pass?

Edit: I remember reading that NGF combined with Lions mane caused the highest increase of NGF than just NGF by itself. That happened in lung cells not in the brain. But the dose of NGF was pretty low. I think it was 10ng/ml combined with 1mcg/ml lions mane extract.

What I'm trying to get at here is we may be able to get away with taking a lower dose of NGF if we supplement with lions mane at the same time to get maximum NGF for the price. Of course we still have to figure out how to get NGF to the brain.

Its late at night so if Im thinking completely wrong right now its because I'm pretty tired lol. I just had the idea so I figured I should mention it. I'll try to find that study I read in case anyone wants to see what I was referring to.

This is it.
http://www.ncbi.nlm....pubmed/24266378

Edited by dz93, 09 June 2015 - 02:35 AM.

[playground]

I'm wondering what the effects of getting NGF, BDNF, NT-3 and NT-4/5 to the brain would be. They're all neurotrophins. Maybe a super nootropic? Lol.

About the NGF cream, wouldn't it still be difficult for it to cross the BBB?

I'm wondering if there's a way to make a carrier of sorts to carry NGF past the BBB. Is NGF simply too large for it to pass at all or is the properties of NGF the reason why it can't pass?

 

Maybe you're right, maybe to be super-effective, for example against dementia, the eye-drops/nasal spray should

contain multiple varieties of neurotrophin.... specifically those for which there are lots of receptors in the affected brain areas.

 

The NGF cream was an idea for treating diabetic neuropathy (as in the genentech trials).

So it wouldn't necessarily need to get to the brain.

If you had a loss of sensation in your feet, for example, you'd put the cream on your feet.

 

My understanding is that NGF travels extremely easily through nervous tissue. 

In rats and rabbits, for example, It passes from the eyes to all areas of the brain within 2 hours.

So.. perhaps it should be able to travel from the peripheral nervous tissue, eg,

from your hands or your feet,   to your brain in the same manner.

 

In fact, i think there's an association between Rheumatoid Arthritis (RA) and protection from Alzheimer's.

(If you have RA you're less likely to suffer from Alzheimer's)

How does that work ?  Presumably it works because the excessive NGF in your hands

somehow travels through nervous tissue to the brain...  where it helps to prevent brain cells from dying.

However, i don't know that's how it works, i'm presuming.

 

Playground.

 

Edited by playground, 09 June 2015 - 02:52 AM.

[dz93]

I was part of a group buy for GHK here and one of the posts on there mention that when taking GHK its basically destroyed in 30 seconds (you would want to inject it for maximum efficiency, SubQ would work). Even though GHK is destroyed so quickly, just its short exposure to cells cause a chain reaction that starts a rejuvenating effect.

I bring this up because I'm wondering if its possible that NGF could be setting off a chain reaction that would cause NGF levels in the brain to elevate. Its just another crazy idea lol

[resveratrol_guy]

In fact, i think there's an association between Rheumatoid Arthritis (RA) and protection from Alzheimer's.

(If you have RA you're less likely to suffer from Alzheimer's)

How does that work ?  Presumably it works because the excessive NGF in your hands

somehow travels through nervous tissue to the brain...  where it helps to prevent brain cells from dying.

However, i don't know that's how it works, i'm presuming.

 

Playground.

 

 

I believe that part of the answer is NGF upregulation due to pain resensitization. It has the incidental effect of supporting CNS health. But GMCSF upregulation is also an important factor, if not the dominant one; it mobilizes microglia to attack amyloid (and probably phosphotau), at least in this mouse study. I provided a lot of details of a related human trial here. (Before you ask, you can get GMCSF (Leukine) powder in Canada for like $150/day. And you only need maybe a month's worth if the mouse studies translate to humans. If anyone actually manages to find a doctor willing to prescribe this for memory enhancement, PM me anytime! There are some theoretical risks, potentially severe, so this is not an adventure for the uneducated.)

 

I don't think we can learn anything about NGF for memory support from the Genentech circus. Or the treatment of diabetic neuropathy with painful injections, for that matter. But it was a brilliant illustration of how bad science can hold back promising therapies for years. Maybe your "resensitizing cream" has a promising future!

Edited by resveratrol_guy, 09 June 2015 - 03:25 AM.

[playground]

I'm wondering what the effects of getting NGF, BDNF, NT-3 and NT-4/5 to the brain would be. They're all neurotrophins. Maybe a super nootropic? Lol.

About the NGF cream, wouldn't it still be difficult for it to cross the BBB?

I'm wondering if there's a way to make a carrier of sorts to carry NGF past the BBB. Is NGF simply too large for it to pass at all or is the properties of NGF the reason why it can't pass?

Edit: I remember reading that NGF combined with Lions mane caused the highest increase of NGF than just NGF by itself. That happened in lung cells not in the brain. But the dose of NGF was pretty low. I think it was 10ng/ml combined with 1mcg/ml lions mane extract.

What I'm trying to get at here is we may be able to get away with taking a lower dose of NGF if we supplement with lions mane at the same time to get maximum NGF for the price. Of course we still have to figure out how to get NGF to the brain.

Its late at night so if Im thinking completely wrong right now its because I'm pretty tired lol. I just had the idea so I figured I should mention it. I'll try to find that study I read in case anyone wants to see what I was referring to.

This is it.
http://www.ncbi.nlm....pubmed/24266378

 

Good post!

 

Yes.. that's an excellent idea. 

Take NGF with something that works synergistically with NGF.

 

I think the two established (non-surgical) routes for getting NGF into the  brain are:

(1) by eye-drops,

(2) by nasal spray.

 

Here's an interesting article:

 

Development of a non-invasive NGF-based therapy for Alzheimer's disease.

See here:  http://www.mycopro.c...2011_heri-5.pdf

 

I haven't read this one yet, only the abstract.  I'll be reading it next.

 

Interestingly,  at the end of the abstract they say:

 

       Finally, we demonstrated that intranasally delivered hNGF-61 is significantly more effective than ocularly applied hNGF-61

 

Don't be distracted by hNGF-61 (it's just their version of NGF)... the point here is that they seem to

be saying that their nasal spray NGF is better than eye-drops NGF.   On this thread we've been

discussing the NGF Eye-Drops patent (that metagene posted).    So we know someone's got a patent

out already for the eye-drops application of NGF.    I wont be surprised to find out that these

people have filled a patent for the nasal spray NGF.    And so... saying the nasal version is 'more effective'

is possibly just advance marketing.... or to put it another way...  a pack of lies.

 

What's interesting about a nasal spray application of NGF, is that Alzheimer's is thought to begin

in the nasal nerves... specifically the nasal nerves on the right hand side.  Why that should be ... isn't clear. 

So applying NGF nasal spray might make it much harder for Alzheimer’s to get started.

 

This stuff might also result in you developing a super-sensitive sense of smell too.

 

 

Playground