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More Things to Do With mRNA

After yesterday’s post on mRNA vaccines and RNA mechanisms, I wanted to highlight a completely non-coronavirus application that has recently appeared in the literature. It’s from BioNTech, the German company who’s been working with Pfizer on one of the two mRNA coronavirus vaccines, of course, but they have other therapeutic interests as well.

This latest paper is on an interesting approach to autoimmune disease. As it stands, the great majority of therapies available for such conditions are things that lower the immune response in general. And while that works (up to a point, and certainly not in everyone affected), it also has obvious problems, because you are increasing a person’s vulnerability to infection as well. There’s a long list of diseases that involve inappropriate inflammation of the body’s own tissues (multiple sclerosis, arthritis, type I diabetes, and lupus – just to take some big ones right off the top) and for many years now people have been trying to find a way to turn down those inflammatory pathways without turning down the whole immune response. Autoimmune disorders are generally a mixture of a person’s genetic background, the life history of their own particular immune systems and what it’s responded to over the years, and various environmental factors. The phrase “ill-defined” shows up a lot when you try to talk about the details of how those interact, though – it’s clear that all three of them are important to different degrees in different people, but it’s generally impossible to say exactly what’s going on, who in particular is at greater risk, and what in particular they might be able be able to do about it.

One goal has been to try to selectively affect autoreactive T cells, but that’s a lot easier said than done. The regulatory T cells and regulatory B cells are key players in immune tolerance, the “friend or foe” recognition system that keeps our own immune systems from attacking everything in sight. If you could present some of the antigens involved to those cells in a way that they accepted them as normal human proteins rather than as an external threat, you could presumably turn down their response. A lot of work over the years has gone into trying to do that – Figure 1 of that paper will show you over a dozen different approaches that people have tried. Among them are DNA vaccines, infusion of various blood cell types expressing or carrying these autoantigens, treatment with various polymers and nanoparticles carrying the autoantigens, and more. The autoantigen peptides themselves have been processed and modified in a number of ways for these different delivery systems as well. It’s fair to say that while some of these have shown some of the desired effects on immune cell populations, none of them have had dramatic effects on the clinical course of the autoimmune diseases themselves, Those have generally been MS or type 1 diabetes, not least because rodent models of both of them are available (not perfect models, to be sure, but definitely better than in many other therapeutic areas, and ones that have been used to validate other therapies in those diseases in the past).

This latest work looks at the mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). BioNTech and others have been trying to target the population of lymphoid antigen-presenting cells, known to be very important in immune tolerance mechanisms, but without setting off any of the general inflammation pathways. They have a liposomal formulation (see yesterday’s post) that when injected into the muscle tissue seems to end up almost entirely in the lymphatic system, and they’ve been doing all sorts of modifications to the RNA payload (such as replacement of uridine with methylpseudouridine) to make it as non-immunogenic by itself as possible. The liposome lipids themselves are also chosen to be as non-immunogenic as possible, too – the coronavirus mRNA vaccines actually get an adjuvant boost from such properties, but you don’t want that in this case.

The payload in this case codes for a known epitope of myelin oligodendrocyte glycoprotein (MOG), amino acids 35 to 55. Treating the mice with the modified RNA had a much different effect than with native uridine-containing RNA, as they had hoped. They also did not see signs of inflammatory cytokine signaling with the modified payload, but the treated mice were able to mount a normal inflammatory response afterwards, so it’s not that the treatment impaired their immune systems in general.

How about therapeutic effects on the disease? The modified MOG-epitope mRNA treatment “was capable of blocking all clinical signs of EAE in mice”, the paper says. At all points in the EAE progression in mice, treatment stopped the deterioration and restored various degrees of motor function. These effects lined up with a long list of blood and cellular markers, and were confirmed in a separate form of the EAE model.

A very important effect was the induction of “bystander tolerance”. All these antigen-presenting ideas have a shot at working if you know which antigens are causing trouble. But often we don’t, or there’s an obviously incomplete list of them. If one could generate regulatory T cells (Tregs)with the right activity, though, those cells could damp down the autoimmune response in general, without having to know what antigens were setting it off. The team saw strong evidence for such bystander effects in several models.

The mRNA platform presents some very interesting clinical opportunities. For example, there are antigens (such as MOG 35-55) that are thought to be important in many patients, but there are surely others that are peculiar to smaller subsets (or indeed, even to particular patients). If these can be identified, there’s a real possibility for individualized therapy, similar to what’s being doing with chimeric antigen receptor T-cells in cancer. The paper raises this possibility at the end, and it appears that BioNTech is thinking about making a serious run at this in the clinic.

I’m really interested in seeing how that works out. Effective immune therapy is probably going to have to end up rather targeted to individuals, given how different everyone’s immune system is, so a platform that allows such specificity is very welcome indeed. This also has application to the lesser-known autoimmune diseases (there are dozens and dozens of them), for which there are often very poor treatment options. This work looks like a real advance, and I hope to see it in human trials as soon as feasible.

22 comments on “More Things to Do With mRNA”

  1. Mister B. says:

    Side question on a topic I have literally no knowledge.

    Following the same approach, could allergies also be treated like that ?
    The little I know of allergies is that they are strong immune response.

  2. David says:

    That is a fascinating paper. My one internal twinge is that we’ve cured EAE many times, with treatments that end up effective, but only partly so, when applied to human MS.

  3. Kevin says:

    I was really glad to find a post on In The Pipeline on this exciting topic. It wasn’t immediately clear to me how vaccines for autoimmune diseases would work: usually we think of a vaccine as telling the immune system to target something, not telling it not to target something.

    Your explanation went a fair way toward improving my understanding, and perhaps it’s just a lack of biological and medical grounding, but there’s still something I don’t quite get. How exactly does introducing a modified myelin protein into the lymph nodes diminish the autoimmune response to that protein?

    1. Ilya says:

      T- and B-cells in the lymph nodes can be educated in an inflammatory context, this is when they attack the antigen. They can also be educated in a tolerizing context, which makes them regulatory. In this case, they dampen the immune response to their antigens.

  4. luysii says:

    “All these antigen-presenting ideas have a shot at working if you know which antigens are causing trouble. ”

    You can say that in spades for MS. We have known for half a century that MS spinal fluid contains oligoclonal bands of immunoglobulin G. In fact, in the preMRI era this was how we diagnosed MS (although there are many other causes of IgG elevation in the CSF). You’d think we’d know what the IgG is reacting to after all this time, but we don’t.

    If we did, we could attack the cells reaction to the antigen(s) specifically. MOG as the antigen reacted to has been looked at already with minimal result even though you can induce EAE with it. Perhaps it is time to look again

    1. FormerLabRat says:

      Actually the work of VanNoort showing alpha,B-crystallin as the autoantigen in MS and its link to Epstein Barr virus is where I would put my money. Expression of alpha,B-crystallin in myelin is unique to MS patients and hence brings the epidemiological link of EBV (which releases the autoantigen in infected cells during replication) and the putative autoantigen in full agreement. So, I would agree, targeting MBP, MOG or MAG is a waste of time in MS, regardless of a brilliant the new approach.

      With that said, why don’t they start with myasthenia gravis, at least in humans? They know what the autoantigen is for that autoimmune disease: the nicotinic acetylcholine receptors. Otherwise, this brilliant new approach will never work if you pick the wrong autoantigen.

      1. luysii says:

        Former LabRat: Showing how complicated untangling things are in autoimmune disease: AlphaB crystallin is massively upregulated in early active MS lesions and in EAE. However, the severity of EAE is greater in mice lacking alphaB crystallin, and IV injection of recombinant alphaB crystallin reduces the severity of EAE in mice [ Nature vol. 448 pp. 421 – 422, 474 – 479 ’07 ]. Perhaps you are aware of more recent work contradicting this, but I’m not.

        1. FormerLabRat says:

          Luysii: this is not the place to debate the merits and pitfalls of the rather flawed EAE model of MS, nor the various approaches to ascertain the target of those oligoclonal bands in the CSF of MS patients, nor the body of work surrounding the plethora of putative autoantigens in MS. My point was more that if the world wants to see whether this new approach will work, it would seem that one would do it with a disease where you actually know the autoantigen as opposed to one where you have to guess. If you really want to win the lottery, you rig the odds in your favor. IMO, using this technology with MOG in a contrived animal model of MS is perfectly fine as a proof of concept of the technology. I get all that. However, if I were to use it in people, I would target MG patients. My two cents which also may be all its worth.

          1. luysii says:

            I meant that I agree with you, not that your response was worth 2 cents. Apologies

  5. peter waldo says:

    Regarding Derek’s excellent piece, ‘RNA Vaccines And Their Lipids’. The article’s content and the rich discussions and mRNA questions & issues broken down in the comments section are, to be frank, concerning. Potential cytotoxic effects and a lack of understanding about the vaccine platform’s predictability in vivo are just a few. Has the ’normalcy bias’ lulled us into irrational confidence about how mRNA will actually act in the real world? If vaccine AE’s and anecdotal yet potentially significant occurrences are underplayed and not reported by the media it could make matters far worse. Instead of promoting a vaccination rollout “frenzy”, isn’t there a ethical obligation to the people given the facts here; a compelling case to limit/scale back the mRNA rollout to better identify, track and understand safety signals and issues to ensure no harm is done on a mass scale? And, dedicate time and resources toward accelerating the other vectored/attenuated virus vaccine candidates’ clinical trials since we are more familiar with their side effect and safety profiles should they offer good efficacy?
    “Remember, if you’re heading in the wrong direction, God allows U-Turns” (A. Bottke)
    “The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge” (D.Boorstin).

      1. Charles H. says:

        How many people have been vaccinated?
        How frequent is the disease?

        I don’t know the answer to either, but my first take would be that this is an coincidental happening. It’s seriously worth investigating, but unless there has been an increase in the rate of … thrombocytopenia … it shouldn’t be taken as *that* likely to be related.

        P.S.: Fill in the disease of your choice. When you vaccinate a large enough number of people, it *will* show up.

    1. Peter S. Shenkin says:

      Peter Waldo: And as Will Rogers put it, “It’s not what we don’t know that hurts. It’s what we know that ain’t so.”

  6. Stacey says:


    I was diagnosed with multiple sclerosis 1 month after I turned 50. My grandma is 96 and had it since she was in her 20s. I have been on WORLDHERBSCLINIC MS HERBAL FORMULA, the first TWO MONTHS was daily and now I am on 3 times a week. It has made a tremendous difference for me. The fatigue never gets to me again. When I do too much, I don’t feel weak anymore..

    1. colintd says:

      Despite having two close friends with MS, rather than recommending your panacea, I think I’ll wait for the double blind randomized controlled trial to differentiate your statements from anecdote or snake oil..

      1. colintd says:

        Having looked a little further into “WorldHerbsClinic” (in an idle moment) we find the following biography of their lead “clinician”, recommending Chinese Medicine and acupuncture for stroke treatment….

        “Dr ZIZA FRED (M.B.M.Med) Doctor of Chinese Medicine and Acupuncture.
        DR ZIZA FRED is a registered Chinese Medicine and Acupuncture (CMA/TCM) practitioner both in South Africa and China. He also registers as a Chinese Medicine pharmacist in China. He holds a master’s degree in Traditional Chinese Medicine. In 2015, he was invited to lecture at University of Western Cape. In 2016, he was appointed by University of Johannesburg as a curriculum developer. From 2017 to 2018, he was appointed by the Department of Health Republic of South Africa as an evaluator for an expert committee of The Medicines Control Council. From 2018 to 2019, he was again appointed by Department of Health RSA as an evaluator for an advisory committee of complementary medicine committee. From 1st of September, 2019, he is appointed as a permanent lecturer at University of Johannesburg. He is the FIRST doctor in South Africa who applies acupuncture treatment on stroke rehabilitation. He is the executive committee member of South African Association of Chinese Medicine and Acupuncture. He has been practicing Chinese Medicine and Acupuncture in Fujian Provincial Hospital, P.R.China, for 3 years during the year of 2009 to 2012. He has seen more than 20,000 patients since then. He has published several academic articles. He is majored in Chinese herbal medicine and acupuncture for stroke, stroke rehabilitation, internal medicine, gynecological problems and pediatric diseases.

    2. Anon says:

      When I saw the MUST READ disclaimer, I had a certain expectation of what was to come.

      It did.

      1. Ken says:

        If only medical diagnositic symptoms were all as easy to read.

  7. Dave says:

    I am also interested if this will have any hope of reducing the allergy explosion we seem to be experiencing. As I understand it, the immune system that causes allergies is different from the one that causes auto-immune diseases, so I don’t have much hope.

  8. William OConnor says:

    Could this same idea be used to suppress the immune response for transplanted organs?

  9. Naz says:

    Do you think this mRNA vaccine could be effective in mouse models of EAN (Guillain-Barre Syndrome model)?

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