Apologies for the horrible formatting. I used the old Hotcopper and it's stuffed up. I'll get the previous one removed but here's another go:
Warning for a long essay below. I’ve been doing a lot of thinking in lock down. Apologies if some of this has been covered. I try to read all the posts but there have been so many recently I’ve lost the plot a bit. Feel free to make any corrections because my intention is as much to learn.
My style is to come at it from all angles: journal papers, listening to doctors, listening to patients on social media and relating to my own experience and observations. There are two sides to the equation; the other side is the body itself, what it’s capable of, particularly where children are concerned. I have experience with three cases of severe acute inflammation of gut and skin in my immediate family that didn’t respond to conventional therapy (the too hard basket)
Presentations on ARDS by Dr Caroline Calfee and Dr Michael Matthay
I posted the youtube link for the presentation below (Nov 2017) as well as other refs. I instantly liked how these two doctors/researchers came across. Their presentation was clear and simple for a non-scientist like me and I was fascinated by the histology and pathology slides, the clear before and after with MSCs compared with zero effect in the control group. Dr Matthay is lead investigator in a clinical trial going ahead in ARDS ( IV delivery). ClinicalTrials.gov Identifier: NCT02097641
Dr Calfee’s presentation.
ARDS can result from a variety of causes:
Pneumonia (which can be caused by any flu)
Aspiration of gastric contents
Near drowning
Sepsis
Severe trauma
Blood transfusions
Drug overdose
Pancreatitis
According to Dr Calfee, ARDS is a common syndrome, around 200 000 cases per year in the US alone. Mortality remains high at 30-40%; (however, Covid-19, said to be highly aggressive, mortality is likely higher). The ARDS Foundation cites the same incidence as Dr Calfee but mortality as 100 000. They also have a lot of information on survivors who've suffered permanent cognitive impairment. I noted in MSB’s recent presentation the emphasis on long-term effects such as fibrosis. It’s not just surviving, it's how you survive, which is highly relevant to GvHD.
Dr Calfee gives an overview of pharmacologic treatments used over the past 25 years which have failed to show benefit (I was interested to see what was top of the list and also prostaglandin discussed below.)
Corticosteroids
Surfactant
Prostaglandin E1
Anti-endotoxins
Anti-cytokines
Procysteine
Nitric Oxide
Ibruprofen
Ketoconazole
Lisofylline
Soluble neutrophil -
elastase inhibitor
SPLA2 inhibitor
Activated Protein C
Albuterol
Omega-3 Fatty Acids
Statins
Dr Matthay's presentation:
I was impressed by how thorough and logical the testing was: mouse model, human lung not suitable for transplant and sheep; mouse MSCs, human MSCs, study and clinical grade MSCs; intra-tracheal and IV delivery. Dr Matthay didn't mention, so perhaps this wasn't statistically significant, but comparing the slides, IV MSCs looked to me a much better result in clearing edema than Intra-tracheal, although both results were good.
One rationale for the study was that MSCs restore endothelial and epithelial barrier integrity. In the human lung model, 'treatment with MSCs or the conditioned media of MSCs returned permeability to normal'.From the histology and pathology slides you can clearly see edema has been cleared from the air spaces. Edema was resolved and rendered normal after four hours. In the sheep model both lower dose and higher dose MSCs had marked improvement on hypoxemia over 24h but the higher dose had more efficacy on pulmonary edema, returning levels to normal after 24h.
A huge part of Dr Matthay's presentation was the antibacterial effect of MSCs: Researchers tested with endotoxins, live bacteria and a model of sepsis. MSCs had a beneficial effect on bacteria both directly and indirectly by secreting antimicrobial peptides and clearing bacteria and infection by enhancing monocytes' ability to phagosize (eat) bacteria.
Dr Matthay gave an overview of factors secreted by MSCs including the release of prostaglandins, which could be highly relevant to Covid-19 ARDS.
Some Thoughts on Dr Matthay's Presention and its Relevance to our Other Candidates
In IV delivery, MSCs migrate to lungs and remain there for hours before being dispersed. Am I right in thinking MSCs are precursors to endothelial cells so probably have some marker on surface that sticks to endothelial cells?
@stokdog mentioned Remestemcel-L secretes PGE2 and provided a link to an interesting article that I re-posted below. With respect to Covid-19, Smeitink et al (April 2020) say this could be the missing link. Authors conclude that “epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions”.
Restoring epithelial and endothelial integrity is also relevant to the gut because of the gut-lung axis. I’ve been banging on for years that evidence is pointing to ‘leaky gut’ being the mother of autoimmune diseases, likely other diseases too, including CHF. Odenwald et al (2018) say that restoring the intestinal epithelial barrier is a “tempting therapeutic goal”.
It was encouraging to see so much emphasis on antibacterial action of MSCs because of ARDS overlap with sepsis and secondary infections. I posted a ref to the study by Krasnodembskaya et al (2010) a couple of years ago but lost confidence in this avenue. It's pleasing to see, however, how highly cited it's become. Furthermore, Alcayaga-Miranda et al (2017) say, "the antimicrobial potential of MSCs-derived EVs can also be heightened through cell conditioning and/or drug loading". These authors ask the question: “Are extracellular vesicles the next big thing for infectious diseases?”
I note MSB has patents for pay-loading technology and in Drug Discovery Today (May 2020) Dr Lorraine O’Driscoll writes with respect to Covid-19,”There is also the possibility to pay-load useful MSC-EVs with other therapeutic molecules, such as antiviral drugs, that could be considered beneficial to have delivered to the site of required intervention”.
Fibrosis wasn't mentioned in the thorough and detailed presentation by Dr Matthay. That makes me wonder if it's difficult to detect, if it takes time to show up? If this is the case, it fits with what I learned from social media with respect to chronic lung GvHD. Dr Matthay received MSCs from the NIH repository directed by Dr Darwin Prockop. Dr Darwin Prockop's work on lung injury and MSCs is highly cited. An unusual surname. Dr Susan Prockop is one of our lead investigators. I was very impressed by Dr Susan Prockop when I listened to her presentation.
In acute GvHD gut, liver and skin are mentioned but I never hear about lungs. Given the gut-lung axis it makes sense that it's there in some form in the acute stage. Better treatment in the acute stage can prevent chronic disease. I didn't get much I didn't know already from the 3 articles on Ryoncil in GvHD except from the trial in 54 children: "Chronic GVHD was reported in 8 patients during the follow-up study; 6 cases were mild, 1 was moderate, and 1 was severe". Chronic lung and skin GvHD are huge problems and steroids and ECP (which is expensive as it's done in hospital) are still the mainstay treatments.
The body is a system with its own natural balance. If you try to control too heavily it can overshoot. You need both sides for balance, which calls for the duality of MSCs with regard to inflammation. The body also likes to heal in a certain order. with small wounds from the outer edges in but too large an injury and (activin?) will throw a tarpaulin over it and you get bad scarring. Folistatin is miraculous (protein?) in itself and I was looking into this years before I knew about stem cells. Am I right in thinking MSCs secrete folistatin which regulates activin?
You have to consider the size of the market before Covid-19, the time it takes to develop a vaccine, its efficacy, whether people will opt for it. There's so much going on in ARDS it's clear that drugs that tackle a single pathway don’t have a chance and there are side effects too, which is also relevant to anti viral drugs. ARDS and cellular medicine are a perfect match and if Athersys succeeds, good on them! The market is big enough for more than one player and competition in the marketplace is good for business as we can see from the biologics Infliximab and Humira.
Roncil, Two Birds in the Hand?
Ryoncil could be used off label for refractory IBD.
Pittsburg Children's Hospital has been seeing an increasing incidence of aggressive IBD in young children including primary sclerosing cholangitis..PSC is associated with IBD and can cause scarring and fibrosis of the bile ducts in the liver and can result in liver transplant. Seattle CH must also be seeing aggressive cases of IBD as they're running a clinical trial comparing GI GvHD and IBD.
Unless I missed it, there was no mention of our trial in Crohn's Disease in the recent CC, which I find frustrating. This trial is in adults with chronic refractory disease, different I would think from the acute fire storm in GvHD pediatrics; I'm therefore optimistic for positive results in p3 CD, but don't view it as a given. I was holding my breath to see how Remestemcel-L would do in chronic GvHD and, while it was only 3 patients, I was encouraged by the results of the study led by Dr Kurtzberg after only 2 infusions.
I've provided a ref to a large study by Kin et al that found the biologics haven't reduced colectomy rates. Based also on my brief exchange with a colorectal surgeon, my opinion is that they haven't prevented surgery but delayed it. I sure see value in that because they can buy you time or the patient goes into surgery in better shape. The biologics in IBD are used as a bridge to the thiopurines (6MP and Imuran) and in RA are paired with anchor drug Methotrexate, the chemo drugs, so how potent are they really? And in the era of the biologics the term 'steroid-dependent' should have disappeared from the lexicon but it hasn't.
No one is saying the biologics have prevented surgery in fistulising CD ( fCD is a subset of CD; there's also inflammatory and stricture causing) because practice in fCD is to combine surgery with drugs. The problem I have with drugs like Infliximab here is the same as with steroids: the too fast, superficial, top-down healing job that can seal in infection. Before giving Infliximab an abscess must be fully cleaned out but it's really hard to get all of it. I know this from experience and also from what Beslenghi et al (2019) say regarding the high response in the placebo group in the Alofisel trial: "A significant volume of undrained sepsis might still have been present and yet described as remission". Such a situation calls for MSCs antibacterial effect.
Mucosal healing is considered the holy grail in IBD. Thorough mucosal healing leads to long-term remission. Exclusive enteral nutrition (EEN) is recommended first-line in pediatric Crohn's Disease in Europe. It gets best results in children if given early after diagnosis (Perhaps the not giving of the steroids might also be a factor here) EEN is a difficult therapy to do because the child has to temporarily give up eating and relapse rate is very high once ended. Dr Robert Canani MD concluded that exclusive nutritional therapy in children with active Crohn's Disease was 'markedly more effective than steroids in producing healing of mucosal inflammation'
I'm not recommending dietary therapy on its own or without the approval of the treating physician, especially as compliance can be poor. It does give us an idea of what is possible, however, when all else fails and the kind of results that can be achieved by a gentle therapy, likely because the gut heals in the way it wants to. It also shows how differently children respond, who are designed to get better.
The Beginning of the End for Steroids?
TWST March 23 2020 SI is quoted:
"but when the attack involves the gut and the liver — otherwise known as stage C/D or grade 3/4 disease— unfortunately the mortality rates approach 90%. And so for those patients with this devastating complication, steroids are usually ineffective".
I think that once approved, it's quite possible Ryoncil will go into clinical practice ahead of steroids:
Chen et al (2014) investigated the interaction between steroids and MSCs and found that steroids abrogated the effect of MSCs. Authors say, "We demonstrated that MSCs indeed could effectively reverse liver fibrosis. However, when Dex was co-administered with mouse bone marrow-derived MSCs, this therapeutic effect was completely abolished"
Chen et al also comment on MSCs in GvHD:.
"Indeed, in a recent clinical trial using combined therapy with Prochymal, the first approved MSC drug in Canada and New Zealand, along with steroids in GvHD patients, there was no significant clinical improvement.20 Thus, it is highly possible that MSCs and immunosuppressants counteract each other".
Patients who are steroid-refractory who receive MSCs second-line will still be tapering off steroids. My question for the medical experts on this forum:
Even among those patients who are steroid-refractory, do we know that inflammation hasn't been dampened to some extent albeit not enough to induce remission? Therefore, if that is the case, is it highly possible the efficacy of MSCs could be reduced? Putting it another way, is it highly possible MSCs given first line would get even better results?
I've long been suspicious that steroids are turning acute cases into chronic ones. I'm not sure how and I'd appreciate any insights, particularly with reference to the major battle in my family with red skin syndrome caused by addiction to topical steroids. Dr Rappaport, a highly respected mainstream dermatologist and the leading authority in this area, writes on his website:
"In my 4000 patient experience there is no such thing as ‘bad, prolonged, chronic eczema.’ The on-going skin problem was all driven by steroids."
Below is a quote from Australian Family Physician. Australian GPs were handing out literature on RSS while dermatologist were still denying it existed and, according to Dr Rappaport, RSS is still not widely known in the US:
"The widespread red skin seen in this condition is thought to be the result of prolonged fixed vasodilatation. TCSs have a suppressive effect on nitric oxide in the endothelium and the release of accumulated endothelial nitric oxide stores results in hyperdilation of vessels".
Cyr et al (2020) report on nitric oxide and endothelial dysfunction:
"Nitric oxide is a strong vasodilatory and anti-inflammatory signaling molecule that plays diverse roles in maintaining vascular homeostasis. Nitric oxide produced by endothelial cells is a critical regulator of this balance, such that endothelial dysfunction is defined as a reduced capacity for nitric oxide production and decreased nitric oxide sensitivity. This ultimately results in an imbalance in vascular homeostasis leading to a prothrombotic, proinflammatory, and less compliant blood vessel wall."
Kolios et al (2004) discuss the duality of nitric oxide in IBD. Authors say "In recent years, nitric oxide (NO), a gas previously considered to be a potentially toxic chemical, has been established as a diffusible universal messenger that mediates cell–cell communication throughout the body. Constitutive and inducible NO production regulate numerous essential functions of the gastrointestinal mucosa, such as maintenance of adequate perfusion, regulation of microvascular and epithelial permeability, and regulation of the immune response. Up‐regulation of the production of NO via expression of inducible nitric oxide synthase (iNOS) represents part of a prompt intestinal antibacterial response; however, NO has also been associated with the initiation and maintenance of inflammation in human inflammatory bowel disease (IBD)"
Linehan et al (2004) say, "The role of NO production in intestinal inflammation remains controversial (18). It seems that excess production of NO after induction of iNOS from microbial products and/or cytokines is harmful for the colonic mucosa (38). In contrast, constitutive NO production is considered to be essential in gut homeostasis and to have a protective role during intestinal inflammation".
"NO is produced at many different sites in the gastrointestinal tract and has been associated with both physiological and pathological events depending on the quantity and timing of NO production (13). Studies in both animal models and humans indicate that NO is involved in gastrointestinal inflammation and has an important role in the pathogenesis of inflammatory bowel diseases (IBD) (12, 36, 45). We have shown that the main cellular source of NO during intestinal inflammation is the colonic epithelial cells
"There is evidence to suggest that corticosteroids might regulate human iNOS (NO synthase) expression and subsequent NO production".
Radomski et al (1990) report on corticosteroids' effect in that they suppress inducible nitric oxide synthase.
I'm still not sure about the role of NO and steroids. I learned about endothelial dysfunction on this forum and read that it's considered the hallmark of all disease and I can really see that now. MSB has evidence their cells improve ED and that's truly amazing. I don't know why it never occurred to me ED was connected to the autoimmune illness in my extended family; the endothelial dysfunction was noticed and treated in two cases but in three others is mild, just occasional lack of blood to extremities (Coid-19 patients can present with a severe form of this), and in my own case the diagnosis is 'not true Reynaud's'. The vascular problems came later in life but I know for a fact gut issues in all cases pre-dated them. Endothelial dysfunction begins in the gut. Fight the battle in the gut. Fight the battle in childhood. It's a no brainer.
Regardless of the organ affected for grades C/D aGvHD, give Ryoncil first line ahead of steroids. Our cells win hands down on healing the gut. Suggest at the same time start with EEN then kick into the Specific Carbohydrate Diet used by Dr Suskind for IBD patients at Seattle CH, as I suggested in a post a couple of years ago (and emailed the company about). I note a paper accepted for publication by Dr Zheng from Seattle CH on two cases studies in steroid-refactory GvHD. The children received MPC infusions then EEN and kicking into the SCD. More diverse flora is linked to greater survival and the diet is heavy on probiotic food, which is most potent anyway. This diet is also heavy on natural sources of vitamins A (the great protector) and D (the house keeper) which are partners and should be high normal. It's important where possible to avoid TPN which goes in a vein in the neck and can damage the liver and if you have any kind of bowel function at all it's best to use it.
Ryoncil approval imo is a certainty and GvHD alonea multi million dollar market.
All IMO. GLTAH
https://www.youtube.com/watch?v=SpqFFpmrtmY&t=548s
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554468/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554158/
https://hotcopper.com.au/threads/ann-msb-draws-us-15-million-from-existing-facility.4602853/page-2
https://www.nature.com/articles/cddis2013537
https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2567.2004.01984.x
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55311/pdf/pnas01049-0545.pdf
https://www.atsjournals.org/doi/pdf/10.1165/ajrcmb.23.2.f195
https://onlinelibrary.wiley.com/doi/full/10.1111/exd.12141
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513194/
https://www.criticalcare.theclinics.com/article/S0749-0704(19)30104-6/fulltext
https://www.frontiersin.org/articles/10.3389/fimmu.2017.00339/full
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293245/
https://journals.physiology.org/doi/full/10.1152/ajpgi.00336.2004
https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.8.2.7509761
https://www.racgp.org.au/afp/2016/june/topical-corticosteroid-addiction-and-withdrawal-%E2%80%93-an-overview-for-gps/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202814/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202814/
https://www.frontiersin.org/articles/10.3389/fbioe.2020.00043/full
https://www.mesoblast.com/images/pdf/MSB_2019_Annual_Report_AR_ASX.pdf
https://www.sciencedirect.com/science/article/pii/S2542454819300013
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371613
https://cyberleninka.org/article/n/474406/viewer
(20min delay)