while ago I wrote an article titled The Good, The Bad and The Ugly. It was a reference to an interleukin protein known as IL_6.
Tonight's post is not all that dissimilar but instead of IL-6, we cover a different protein, one that I know a few of you have heard before. Yes it gets a tad sciency, no it won't be boring, stick with it, I'll make it as simple as I can so as to not lose you! Remember, it's about the science yes, but it's the driving factor of the investment that we are all finally here for.
ADAM WHO?
Yeah we are going to need some definitions here and they will be cascading ones. By that I mean I will give you a definition and then we will have to break down those terms, in turn.
It's kinda like Boy meets Girl. But then Boy also has to meet family. Boy has to get to know her and what she likes and what she doesnt like and who to be careful of in her family and yeah the list kinda goes on...Human relationships are complex, but the complexity isn't just surface level, it goes way under the surface!
Relationship dynamics can be quite complex.1
Ok let's go, let's explore underneath.
Before we start this rabbit hole, my intention isn't to bombard you or to lose you, it's actually to give you a small little taste of how complex this stuff can quickly escalate. I kid you not when whole lives can be dedicated to the study of all this stuff. I'm happy to stop at certain high levels without getting too bogged down in it...it could be a rabbit hole I go into and never come out! Someone, thrown me a lifeline if I'm not back in 12 hours !
So bare with me, no prob if you get a bit lost, but after the definition section below, I'll resurface and I'll get to the point of this post, I promise.
DEFINITIONS
ADAMTS-5 is a type of Aggrecanase.2
What is that? Well Aggrecanases are Proteolytic enzymes that belong to the ADAMs (a disintegrin and metalloprotease) family of proteases.
Hmm that one sentence above can be sub broken into a few parts:
A) Proteolytic enzymes is a fancy way of saying a substance produced by a living organisms that assists in breaking down proteins.3
B) Disintegrin are proteins that assist in modulating cell adhesion processes along with interactions within the cellular matrix (The pool between cells that can act as a nutrient repository in which cells can draw upon).4
C) Ahh the ol' metalloproteases, these can be thought of as enzymes that break down collagen for example. They have the word 'metal' in them as they utilise metals such as zinc or calcium to carry out this function.5
By the way, Proteases are enzymes that simply break down proteins into their basic building blocks (known as Amino Acids).
Right, crickey, my mind is spinning and I don't want to look up any more definitions for fear of this never ending, let's get on with this post!
So The Good The Bad and the Ugly:
Less this:
More this: 6
THE GOOD
We all need Adamts-5. It's responsible for a number of processes in human biology.
Some examples Mr Mozz?
Sure:
There was a study performed on mice where they were deficient in ADAMTS5. It was found that there was an increase in trabecular separation.
Trabecular is bone that comprises both hard and soft spongy like material, a picture is going to help here: 8
mm = millimetres µm = micrometres nm = nanometres
Check out some fast measurement facts to give you some idea of scale here: 8.5
One inch equals 25.4 million nanometers.
A sheet of paper is about 100,000 nanometers thick.
A human hair measures roughly 50,000 to 100,000 nanometers in diameter.
Your fingernails grow one nanometer every second.
So we can see the scale above 10 Um is micrometers, nm is really small, it's nanometers. It gives you a nice idea of why iPPS is so important, because at this most basic level, it is looking after, it is promoting your collagen....it's literally assisting cells known as chondrocytes to produce better quality material at the nano level. Remember, it is the chondrocyte cells that literally are responsible for both cartilage production and cartilage repair. To build a bridge, you gotta start with the most excellent 'defect free' nuts and bolts, it's the same with our bones.
One study observed the following:8.7
"Overall, these results indicate that PPS exerts protective effects on the chondrocyte phenotype and may represent a potential therapeutic target for OA treatment. Increasing the molecular weight of PPS could enhance these anabolic effects".
Let's get back to that mice study:
Look at the stats for this research:n = 27 (number of mice observed)But what was the P value?
P < 0.0001
That was in regards to the observed increase in trabecular separation
Again a pic to illustrate: 9
It's literally the boney nodes separating....this is not good.
The conclusion was pretty clear:
"This is the first report of a novel and critical role for Adamts5 in bone formation within the mandibular condyle of the temporomandibular joint. These data indicate Adamts5 may be required in the transdifferentiation of hypertrophic chondrocytes to osteoblasts during trabecular bone formation in development of the mandibular condyle".9
So the above conclusion in the mice study shows us that we need ADAMTS-5. Block it totally and you are going to have problems that subsist. Blocking ADAMTS 5 totally is never going to work.
THE BAD
So what's the problem then? ADAMTS5 is a good thing yeah?
No. Not quite. Too much of it is bad. In fact it was a focused target for quite some time. Its only more recently that scientists are understanding more about it's role.
The bad occurs in OA when too much is produced and it becomes counter productive. ADAMTS5 acts as an enzyme and when there is too much of it and it is out of control, it breaks down cartilage! This then has the knock on effect of making your joints more vulnerable to damage. This then triggers further pro-inflammatory cytokines and we find ourselves in a vicious loop.
A vicious cycle of OA destruction.
Explaining this more scientifically:
"ADAMTS5 is a crucial proteinase for osteoarthritis development.Results: NF-κB family member RelA/p65 was identified as a potent transactivator of ADAMTS5 and regulated the expression and aggrecanolysis.Conclusion: RelA/p65 is a potent transcriptional activator of ADAMTS5 in chondrocytes during osteoarthritis development.Significance: The molecular network related to the RelA/p65-ADAMTS5 axis may represent a therapeutic target for osteoarthritis".10
Jeannie (Operations at the time, 8 min mark - see Appendix A below) also explains (see Points 1, 2 and 3 below) that others have tried single targeting to block IL_6, NGF and ADAMTS5 respectively and ALL have failed.
Paradigmers, let me repeat that. These three massive companies, Roche, Pfizer and Galapagos) have tried and have failed. Our data to date has been stellar. It is pivotal, we are about to garner a revised P3 from the FDA (subject to approval). We do not block anything. We down regulate, we allow mean reversion, the body can start genuinely repairing again as the alarm bells of inflammation are turned not off, but down.
Dr Ravi Krishnan (30 min mark) explained it to PAR investors in PAR's inaugural R and D Day. He put up a slide and proceeded to talk about the concept of NF-KB. It is at this nucleus level of a cell where iPPS starts to induce a chain of events leading to the downregulation of such enzymes as ADAMTS-5 thus in turn having consequences on OA progression. iPPS as a molecule itself binds and downregulates this transcription factor to directly downregulate the production of inflammatory markers. He explains the important and pivotal role iPPS plays here.11
THE UGLY
The ugly really involves single targeting drugs whose only aim is to reduce this one proteinase. This is not the solution. This results in unwanted side effects:
"Since the targeting of zinc-dependent metalloproteinases such as ADAMTS5 continues to be of great therapeutic interest, the accumulation of knowledge surrounding such specific drug targets will assist greatly in assessing efficacy and the potential side-effects of those targeting strategies".12
THE SOLUTION
What we want is a balance. Too much salt in your food is not only bad but it wont be a nice taste. Too little salt and things are bland. It is the same for Pentosan's therapeutic action on the levels of ADAMTS5, you need to get it balanced. We need some of it, but in a highly inflamed state, we don't want too much of it. But single targeting blocking of ADAMTS5 isn't the solution, as we do need some of it, Enter iPPS - rather than block it, iPPS DOWNREGULATES these levels to a more normalised state.
But we know iPPS is certainly NOT single targeting. It acts in many ways and in fact a disease that's as broad as OA needs a broad acting solution. I really do believe this will be our key to success, the fact that we don't JUST relieve some pain.The fact that we also play a hand in repair, but not only that, we allow, we facilitate, we encourage growth as well.
Whether it be by the restoration of the balance, or be it via an indirect method like allowing more vascularisation of the capillary plexus for example.13.
But the above graphic simply does not do it justice, at the time of this post I couldn't find the image I have in my Mozz brain about how thin these capillaries can get.
So I will have to rely on giving you a representation with words:
Capillaries near to the bone can be so thin, they are only 8 to 1 micrometres in diameter. I know there are a few engineers in the house that read these posts and will understand what that exactly means but it a micrometre is just 0.001 of a millimetre! That is SO thin that red blood cells have to pass through them in single file!!!! 14
In the PAR MOA video this graphic representation can be seen. New to us and have never seen it? Please ensure you view this, it's posted in Appendix A, It's only a short video but you will see it at the 3:32 min mark
Speaking of examples let's go back to our ADAMTS5 for sec.
How about this one, there is another protein called TiMP-3. TIMP-3 is short for tissue inhibitor of metalloproteinases. It takes these two and forms a strong bond, it's known as a trimolecular bond. Not only that but its a strong bond. Heparin also forms this bond but it is much weaker and often gets delinked. iPPS increases this affinity particularly when the chains of PPS are long, longer in this example is greater than 11 chains of the saccharide units. This increases the affinity by a factor of not just twice or thrice....
It increases it by a factor of 100. 15
This is the sheer power and indeed the sheer magic of our molecule.
I wait patiently for the sanctioning of our Phase III by the FDA.
DYOR
APPENDIX A
R & D video.
APPENDIX B
Great Mechanism of Action Video, quite short so it's not a time consuming watch, highly recommend if you are new and haven't seen this video. Watch out for 3:32 min mark to see graphic representation of how thin the capillaries can get as demonstrated by the red blood cells flowing through one at a time!
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while ago I wrote an article titled The Good, The Bad and The Ugly. It was a reference to an interleukin protein known as IL_6.
(20min delay)