Comments on: Is science on the verge of curing retinal degenerative disease?

By: daedalus2u

daedalus2u — Fri, 22 Jun 2012 13:53:38 +0000

They are not looking at NO. NO is considered to be too complicated and involved in too many things to be feasible to do research on. There are no ways of increasing NO levels, other than my bacteria pretty much, but I haven’t been able to get enough attention and funding to get the data to “prove” that my bacteria are important.

The problem is that people who are studying other things want/need their stuff to be “the most important thing ever”, to get funding and kudos. They have to (at least unconsciously) denigrate that which they are not working on and which they don’t understand.

It is very much like the anti-sceptics who don’t know the field, but argue against it anyway based on non-fact-based arguments.

By: Greg Laden

Greg Laden — Fri, 22 Jun 2012 02:55:34 +0000

Interesting.

Sorry for the moderation, it’s the links. I just increased that to 4 before moderation. Spam does not use that many links these days.

I wonder if the people researching this are looking at NO.

By: daedalus2u

daedalus2u — Fri, 22 Jun 2012 02:49:56 +0000

Not knowing what Bruch’s membrane is, I looked it up, and I would say yes, via several mechanisms. Low NO lowers the ATP level which turns down autophagy allowing bad stuff to accumulate. This is a “feature”, you don’t want to waste ATP on getting rid of garbage while you are running from a bear, so the low NO of the fight-or-flight state turn those things down and eventually off.

I have written up a lot of the details of how NO regulates vascular stuff.

http://daedalus2u.blogspot.com/2008/10/role-of-low-basal-no-in-capillary-and.html

In looking at pubmed, there are specific markers for low NO in Bruch’s membrane.

http://www.ncbi.nlm.nih.gov/pubmed/20153746

Nitrated proteins are a sign of insufficient NO. Nitrotyrosine comes from peroxynitrite, peroxynitrite forms from superoxide and NO, they react at diffusion limited kinetics. Peroxynitrite damage only occurs when there are near equimolar production of NO and superoxide. If either one is in excess (by 2x or so), there is no production of nitrated proteins.

There are pathways by which CNVs lower the NO level. I think that is the major mechanism by which CNVs cause various disorders. Genes that raise NO levels cause autism when they are deleted, genes that lower NO levels cause autism when they are duplicated.

I have sent you a poster I presented at the Autism Consortium on this.

By: Greg Laden

Greg Laden — Thu, 21 Jun 2012 17:38:59 +0000

It would be interesting to link a faulty genetic product to low NO levels in the blood; wouldn’t there be other outcomes of low NO such as cardiovascular diseases in such cases? Age-relaeted macular degneration is linked to cardiovascular disease. Can NO explain the formatio of Bruch’s membrane in dry AMD? The possible link to wet AMD might really be there, the disease looks a lot like what you describe.

btw a suspect gene is CFH (complement factor H)

By: daedalus2u

daedalus2u — Thu, 21 Jun 2012 16:49:08 +0000

I am pretty sure that macular degeneration is secondary to low nitric oxide levels. The characteristic vascular changes (tortuous vessels and nicking) can be explained through a low NO mechanism. Hemoglobin is the sink for NO, and low NO also causes vessel regression via low NO induced apoptosis. This is how the vascular geometry becomes coupled to the flow, as in a stream meander. Red blood cells are denser than plasma, so in curved flow, the red blood cells are accelerated to the outside of the curve where they are closer to the vessel wall and so that side of the vessel sees a lower NO level so it regresses producing the characteristic tortuous vessels.

I suspect that low NO is a final common pathway in many of these retinal disorders. There may be a genetic “cause”, but the retinopathy is mediated through a low NO mechanism (which is a common stress response) which is why they all look the same (tortuous vessels and nicking).

If you did fix the genetic “cause” in the stem cells you grew the replacement from, it might fix the genetic based retinal disorders, and yes, that won’t be done in the US if Republicans stay in control.

By: Greg Laden

Greg Laden — Thu, 21 Jun 2012 15:57:29 +0000

In reference to that, yes. I was thinking of the less common but very diverse retinal degenerative diseases such as retinitis pigmentosa, macular degeneration, Usher syndrome, Stargardt disease, Best disease, choroideremia, retinoschisis, Leber congenital amaurosis, Bardet-Biedl syndrome, cone and/or rod dystrophies, achromatopsia, and Refsum disease, some of which have been treated successfully with so far fairly half baked implant and stem cell treatments. None of those derive from systemic disease, I think.

I’ve altered the title of the post to make it reflect that distinction.

Having said that, if this method of grown eye-parts is very easy and the surgury is reasonably easy perhaps it would work for systemic disease with the idea of replacing the things every five years or so. Or is the process of damage quicker than that?

By: daedalus2u

daedalus2u — Thu, 21 Jun 2012 13:25:42 +0000

I would say no, at least not based on this research.

The most common retinal problem is diabetic retinopathy. It, and virtually all of the other retinal disorders are secondary to systemic metabolic disorders and are characterized by vascular remodeling which leads to retinal damage and failure.

https://en.wikipedia.org/wiki/List_of_systemic_diseases_with_ocular_manifestations

Putting a brand-new perfect eye in an organism with a systemic metabolic disorder, will lead to vascular remodeling and retina failure.

What causes the vascular remodeling that results in neuropathy is disruptions in nitric oxide signaling. Unless the nitric oxide signaling is fixed, replacing damaged eyes with new eyes grown from stem cells will not be a long term solution.