INTERVIEW WITH DR CHRISTIAN GRUBER – MEDICAL UNIVERSITY OF VIENNA AND UNIVERSITY OF QUEENSLAND

BD: Brett Drummond, MStranslate
CG: Dr. Christian Gruber, Medical University of Vienna & University of Queensland

BD:  So, welcome everyone to our MStranslate interview today. It’s our pleasure to be joined by Dr. Christian Gruber, who is from the University of Vienna and about to transition to the University of Queensland here in Australia. You may be aware of Dr. Gruber’s work from a summary piece that we published last week about plant cyclotides and the effect they may be having as a potential treatment for MS

Christian, thank you for joining us today. I might just get you to give us a bit of an introduction to yourself and tell us how this project came about.

CG: Yes, thanks a lot for giving me the chance to comment on the recent study we published. Now, as you mentioned, I’m at both universities at the moment. My main research place is Queensland, so last year I went on a move to Brisbane on an ARC Future Fellowship but the most part of the study has been done here at Vienna, at the Medical University of Vienna, and we have, as you know, found and identified a circular plant peptide which potentially could help and make its way as a drug for multiple sclerosis.

Now, we and I have been working with those type of peptides already since more than 10 years. We, or they have been initially discovered in the African medicinal plant, Oldenlandia affinis, which is also the source of the peptide now mentioned in that study. And they have been thought of as really pharmacological treasure troves, meaning that the plants make those circular peptides for reasons we don’t fully understand currently but possibly for the plant to give it like as in a way of survival fitness with regards to insect predators for example. Nevertheless, these peptides do show effects in a multitude of different disease models, amongst them being immune cells.

Now, when we started, we took an extract of the plant and we simply tested how immune cells, namely the T-lymphocytes, would be affected in their capacity to proliferate in the presence of those, that plant extract and as you are aware of, a proliferation of immune cells is one of the crucial steps in developing multiple sclerosis, namely if the immune cells are proliferating too much, if they have an over-reactivity, that is one cause, or an initial cause of developing the disease.

So, what we found is those peptides in the plant, we eventually isolated one major active ingredient, one of those circular peptides, and we continued working with the isolated one so as of then we didn’t work with the plant extract but with the isolated peptide and we saw an anti-proliferative/immunosuppressive effect. An immunosuppressive effect then is fairly broad and non-selective, but what we do see is that our, the effects we observed are mediated mainly by the cytokine Interleukin 2.

And I think in that regards our compound distinguishes itself from other current medications which are in place to treat, ameliorate, multiple sclerosis symptoms. Okay, now from that initial discovery we made on a cellular level, we then designed experiments to test its efficacy in an animal model and we chose the rodent model of multiple sclerosis and I think the most exciting results are that a one-off dosing and oral dosing, so that’s the good thing about those peptides, they are very stable and you can give them orally and they don’t get degraded in the stomach or in the gut which is with most peptides, pharmaceuticals, around these days, you know you have to give them intravenously and they only have a very short half-life but those are very stable so you can give them in the form of a tablet if you wish and that is what we did and a one-off treatment of that cyclotide, the T20K, we call it, you call it, the media calls it, was really effective in reducing the symptoms of the typical MS symptoms in those animals to a degree that they did not appear to have any symptomatic episodes any more. OK, so I think that was the most exciting result.

Now, on the other hand, we also tested the sort of, how would you be able to ‘cure’, ‘cure’ is maybe the wrong expression, but how to treat the symptoms once they are already established and I think that’s an interest to most of the people who are affected already now by multiple sclerosis and in the animal model again, we saw that at least that’s what I can say in the animal model the administration of the peptide would halt or stop any further symptoms. OK, so what we think of is we could approach both treatment options, one more as a prophylactic means to sort of give, not before you get diagnosed obviously, but at the moment where you get diagnosed with multiple sclerosis if you would be able to get, receive treatment with the drug it may stop even symptoms at all or the other option would be once you have been getting episodes of multiple sclerosis to at least stop progression of the episodes.

Now, this is probably the most crucial part of my interview today so this is very, very difficult right now to translate these results we’ve been observing in the animal models to humans, OK. Because this is just two different symptoms so what we need to do right now is to test first of all safety and efficacy in an animal model and then move on to clinical trials in humans and we are doing or trying to continue the project at the moment with a company in Sweden called Cyxone and this company will be responsible for all further development and according to the plan we could see this compound, this peptide, derived from the plant in Phase 1 as soon as 2018, given that we have no safety concerns in the animal models.

BD: Yeah and I mean I think interestingly as well in that first study you also compared the efficacy in the animal model anyway against some current MS medications and saw that they actually did better in some cases than what is currently available.

CG: Well, I wouldn’t go as far as claiming that they would do better, OK. I mean this is some criticism we received from clinicians asking us well what can your drug or what could your drug do what others can’t. Now, first of all, as far as I know there’s only three specific MS drugs around which are available orally/which you can take in tablet form so this is an advancement of ours because it can also be so it is one of those few which can be taken by mouth.

We compared in our study the efficacy to Fingolimod, so the Gilenya is the name, the marketing name, and we do see very similar effects. Now we can’t really comment on potential side effects. Now we know Gilenya is not the safest thing if you take it chronically and you often have to take it on a daily basis but I think many patients tolerated quite well and do not have major adverse effects but there is the occasional issue with it.

Let’s just leave it at that, but I can’t really, I’m not a clinician so I can’t comment on Gilenya and its use but what we do see in the animal treatment that we can compare efficacy with Gilenya on a daily basis – whereas Gilenya in a one-off treatment at the higher dose doesn’t show any effect whereas the peptide at the one-off treatment does seem to reduce symptoms.

BD: OK, yeah I mean ….

CG: Now I think , sorry to wrap that up so that I think is the only difference between the two but as I said Gilenya has been gone through the whole of clinical trials so I’d be leaning out the window very far if I make that comparison translating to humans readily OK but let’s just say, in the animal they seem to be as good.

BD: I mean that it’s safe to say, it’s really interesting and exciting work. As you say, it’s important to mention that this is a long process and obviously it’s those of us who have been in research know that it’s a long process and there are many steps along the way where things can change and it’s important that people know that but obviously we’re going to be putting this interview out to a lot people with MS.

Is there anything people with MS can be doing at the moment to help support the work that you’re doing or help support the work you’re doing in the future?

CG: Well, to put it short, no, since we are not at that stage yet, so together with the company as I mentioned if everything goes well in those last trials we’re doing in animals at the moment, then the drug will be going in to Phase 1 in 2018. OK.

So you know, Phase 1 will be on healthy volunteers first. It will take approximately 1 year. It’s not very sure at the moment. but so let’s say if we are optimistic which we are as scientists, we can expect to see T20K in Phase 2 in 2019. But we have to be realistic as well, we have to do the testing first, it’s a very meticulous process, pharmaceutical drug development, but it is also a necessary and important to really monitor the safety profile in animals first and the efficacy before one goes into humans and I understand it will take a long time but at the end it is good for us and for the people who would receive any drug that will be released on the market so don’t want to have any bad, you know, surprises afterwards so that is why I think it’s really necessary to go through the process even though it may not offer, you know, an immediate relief to people suffering from MS symptoms now. I understand it’s very difficult but yes we have to do all those trials first.

BD: It’s crucially important to make sure that when anything actually gets out there that’s it as safe as it can be and as effective as it can be for people with MS.

CG: Absolutely

BD: In the meantime, just for them to stay interested, stay engaged with the work that’s being done and we’ll keep them updated with the progress as it comes to hand.

CG: Yes, so what we intend to do is obviously, any news, any new developments, we will communicate again via our universities, via MS Societies, so that really affected people get the latest news. I mean, maybe the only thing or help I can expect at the moment is that we will get funding for those projects because only with public funding we can, you know, carry out all that research for developing T20K further as well as for studying new projects on related autoimmune diseases etc OK, so that’s important to mention.

BD: Yeah, I think we are seeing more and more that the sort of projects the public gets behind and support just by being enthusiastic and being vocal can have an impact on the level of funding that scientists can receive for them.

CG: Yes.

BD: You know, thank you again for taking to talk to us, it’s really much appreciated not only by myself and Mstranslate, but by all the people that are part of our community. As we’ve sort of discussed, it’s really important that we think that researchers communicate really clearly and really strongly to the people that it’s going to affect so thank you again for your time, and good luck with the project, all the research and the move to Queensland.

CG: Thank you very much.

BD: Thank you.

4 Responses

  1. Nigel Wadham

    Hi Brett,
    great interview as always.
    Brett if the T and B cells are found in the CSF/CNS in PwMS does that mean there has been a breach of the BBB?
    I read elsewhere that T and B cells don’t switch themselves off and that there is other immune cells that are in the blood that switch them off in a timed process as such. If these immune cells enter the CSF/CNS and the breach does not remain ‘open’ then how are the immune cells switched/killed off rather than them being immortal within the CSF/CNS dividing and living happily and doing damage?

    Reply
    • MStranslate

      It’s an excellent question, Nigel, and probably something of which we don’t currently have a great understanding. You are right in saying that certain cells can suppress the immune response, the most common being regulatory T cells. Cells can also secrete chemical messengers, known as cytokines, that can lead to dampening the immune response. My thought is that a breach in the BBB would allow multiple different cell types in, not just the T and B cells, so that may help the explanation. Cells will also have a certain lifespan after which they will die out, depending on the sorts of stimulation that are around.

      However, there is also the question about what signals the cells to travel to that location in the first place. I know there is research being undertaken in this area, and it could be a topic for another interview.

      Reply
  2. Michael Sure

    I have to admit that although I have a reasonable knowledge of peptides technology, I wasn’t aware that they could be used successfully to treat MS.
    Here in Australia we tend to view peptides as products to treat anti-ageing and muscle building, fat loss etc. This however, is an incredible discovery for those poor sufferers.

    Reply
    • MStranslate

      Hi Michael,

      Thanks for your comment. As you say, the term “peptide” is often used in Australia in relation to supplements related to improving sports performance. However, peptides are just small proteins or parts of proteins that play a number of important roles in the body. As you can see with Christian’s work, he has managed to utilise ones found in nature to potentially help people living with multiple sclerosis.

      Peptides are also what is presented to the immune system and it is thought that some of these peptides are what cause the body to attack itself in MS. For this reason, other researchers are looking at whether peptides can be used to create a type of ‘vaccine’ that makes the immune system tolerant to these peptides and so avoid the damage.

      Whilst they may be small, they are being investigated in many ways and hopefully the use of peptides in some way, shape or form will help provide better outcomes for people living with multiple sclerosis.

      Thanks,

      Brett

      Reply

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