Invent: Life Sciences

TTP - Highlight reel transcript

Stuart: Throughout this series, we have explored how the work of life scientists drives progress in human health, from the way medicines are discovered, to how they are manufactured, and delivered.

Guests we’ve spoken to work in fields as diverse as organoids, mRNA, and
process analytics.

So, Join me Stuart Lowe, as we listen back to the highlights from Season 2 of Invent: Life Sciences, a podcast brought to you by technology and product development company, TTP.

Let's start with a clip from episode 5 where we asked how in vitro models are revolutionising drug development and testing.

I spoke with Sylvia Boj (Boch) - Chief Scientific Officer at Hub Organoids, who’s spent years investigating and promoting organoid technology…

Sylvia: Probably the most unexpected result of developing this model is that indeed, we already have been able to impact patient treatment, and this is in the area of cystic fibrosis.
Stuart: And what has that model allowed you to do with cystic fibrosis patients?
Sylvia: Cystic fibrosis is a monogenetic disease in which one gene is mutated, CFTR, this is an ion channel, and this ion channel is expressed in many tissues, among them, the intestine.
So, actually, with organoids we can evaluate if the CFT channel is functioning by what we call a swelling assay. This assay was developed by the lab of Jeffrey Beekman in the children's hospital here in Utrecht.
As soon as he learned about the developments of the intestinal organoid models in in Hans’ lab, he had this great idea that we could measure indeed that we could develop an assay in which by measuring swelling of the organoids, we could evaluate the activity of CFTR.
And this is the base of an assay that now, is giving access to patients with a rare or ultra-rare mutations in the CFTR gene.
Stuart: And how does the assay help those patients?
Sylvia: So, there is a characteristic of the cystic fibrosis disease, and it's that there are more than 2000 different mutations identified that impact the activity or the functioning of CFTR.
And actually, for some of the mutations, we can go from two patients in the world to maybe groups of 20, 30, 45 patients with the same mutation.
So, if we think about how currently patients get access to a drug, and these are the clinical trials, these trials required a large number of patients in which you do placebo and compound and do a lot of tests, and try to build numbers to show the effect of your compound.
So, for this group of patients, the current process of drug development and drug validation does not allow them to have access to compounds. But then with organoids, we can create patient avatars, we can test it in the lab, and we can see if this is a small group of patients.
So, this specific mutation responds to the available drugs. And actually, this has been the case.
In 2015, a Dutch guy (he was 15, 16 at that time), was the first person in the world getting access to treatment that was working for him thanks to an organoid test. Otherwise, he would have not had access to such a compound because indeed there are only two people in the world with this mutation, himself and his aunt.

Stuart: In episode 3 we asked; Can new classes of drug target reinvigorate drug discovery and provide better medicines to patients? Here’s a clip from Rabia Khan, founder and CEO of Serna Bio…

Stuart: What's the significance of RNA in this story between genetics, disease, and drug discovery?
Rabia: So, DNA makes RNA makes protein, we know this. In fact, 70% of the genome, we believe to date, may not make protein, at least in the classical sense, it only makes RNA. So, there's a large amount of biology that is transcribed into RNA, not translated into protein by the classical sense.
So, if we just think about sheer target space, I believe that targeting RNA opens up a large target base that we haven't been able to modulate. And any company that is either small molecules, ASOs, SI, or any other modality has access to that larger target space.
And from my perspective, 30 years from now, even 20 years from now, I think we're going to have more RNA targeting companies than we have protein targeting companies.
Stuart: Oh, well, yeah. And I suppose if you just take that ratio of transcription RNA to proteins, that would make sense, right?
Rabia: I think so. I think it's a function of probability.
Stuart: So, I can understand if there's a maladapted protein or a mis performing enzyme that you could look to inhibit that or block it somehow. How would the mechanism of actin work with a RNA targeting medicine?
Rabia: I love that question. Let me tell you why. First of all, the first RNA protein targeting drug was approved, risdiplam, it targets splicing. So, there are so many mechanisms that we can go after if we can modulate RNA.
We can interfere with pre mRNA to mRNA processing. In the world of splicing, that opens up all the splicing in oncology as well as splicing disorders. But what I find most beautiful about small molecules targeting RNA, and we see this even at Serna, is you can have a gradation of effects.
So, you can increase translation, maybe 20%, maybe 50%, you can decrease translation. And with complex disorders, ASOs and SI, they can be binary. It's a knockdown, PROTACs is a knockdown.
Whereas with small molecules, you can increase translation, you can decrease translation, you can affect splicing, you can affect RBP binding, RNA binding proteins. And most exciting to me, which I think we're just beginning as an industry to look at, is target the long non-coding RNA and microRNA.

Stuart: Dr James Choi from Imperial College London joined me to un-pick whether innovations in delivery can help us overcome the blood-brain barrier. James leads the Noninvasive Surgery & Biopsy Laboratory and is an expert in the blood-brain barrier… here’s a moment from our conversation...
James: So, the way we've approached this problem is very different than probably your traditional drug modification technologies where you put the drug in a cargo. We use microbubbles and sound. It sounds very strange, but I'll walk you through it.
So, what we're trying to do with the microbubbles and sound is to modify the permeability of the blood-brain barrier. And the way we do this is we inject the microbubbles into the bloodstream. They're about the size of red blood cells. They're already used for ultrasound contrast imaging.
So, they're clinically approved agents, a few macrons in diameter, and they'll freely flow in and out of the blood vessels. These on their own do nothing. So, they do nothing. They will freely flow into your brain capillaries and out. We then apply a focus pulse of ultrasound onto the region where the disease resides.
And so, the bubbles within that acoustic field will then experience an oscillation. So, it'll expand and contract due to the acoustic pressure field, mechanically opening the blood-brain barrier, and then allowing the drugs within the bloodstream to come out.
And so, the really cool thing about this technology is that the focused ultrasound that is being applied is completely noninvasive and localised. So, you don't have to cut open the skin, the skull's completely intact, we can just focus the sound through the skull onto the region you want to target. And only in those regions do the microbubbles open the opening barrier and release the drugs into the brain parenchyma.
Stuart: That sounds really powerful actually.

Stuart: In episode 6 we discussed Women's Health.. asking; how can a focus on the individual improve health outcomes for marginalised groups? Here’s a clip from Shirin Heidari, President of GENDRO, a not-for-profit, advancing sex and gender equity in research…

Shirin: So, at the time when we developed the guidelines, we kind of went for the low hanging fruits. I was an editor in chief by that time, so it felt like I can enforce that in my own journal.
Our focus was at that point, more on the reporting, because we also recognize that many people actually collect the data on sex and gender. It's just that they're not paying attention to it. They don't report it, they don't analyse it.
So, we thought that trying to put that pressure from the academic publishing and editorial side, and we all know that researchers always want to publish, they do, as editors say.
We thought it would be really important to at least improve the completeness and transparency of the data, and also allow for retrospective gender analysis or pooled and meta-analysis. And so, that could actually be improved.
But again, the same principles really applies to the research design and conduct as well. And also, evaluation of research proposal and research funding agencies. We are also having conversations to apply the same principle in the evaluation of research protocols by research ethics committees.
So, the principles are more or less the same across. So, hopefully that will also have a trickle down to all the other gatekeeping functions and research.

Stuart: James Kusena, VP Operations at MicrofluidX joined me on the podcast to share his thoughts on how advances in process analytics could accelerate the development and manufacture of cell and gene therapies?

Stuart: What have you done differently from how you might imagine the bioreactor designers of the past?
James: I mean, personally for me, obviously in the context of the company, I've spoken to a lot of people in terms of the different technologies that they look at. So, I will look at, as an example, who are the people working on metabolites? Can we do some sort of mini trial? Can we just have a conversation to understand how it works and what are the limitations?
And if you know a potential future user was to use it, would it work? What would be the limitations? What would be the challenges? And it's just thinking about that and the more people you talk about in the space of analytics and what they need from the bioreactor side, you start to understand, “Oh, actually 8 out of 10 of them need the same sort of type of connection or the same sort of sample volume or you start to see those commonalities creep up.”
Stuart: Buildups and commonalities.
James: Exactly.

Stuart: And finally here’s a clip with Matthew Durdy from the Cell and Gene Therapy Catapult. The question at the centre of this episode was; Can partnerships in the cell and gene industry transform these therapies from artisan products to mass market cures?

Stuart: What's kind of your ultimate aspiration? You look back in 10, 15 years and think this is a job well done.

Matthew: I think it's encompassed in the vision of the Cell and Gene Therapy Catapult, which is that we want to see a thriving industry in the UK but also globally, that is delivering advanced therapies across the world. And in order for that to happen, we need all of the components to work. We still need a flow of new therapeutics.
I was reading about something, about a treatment in Parkinson's disease the other day, which I didn't imagine would work as well as it looks like it does five years ago. So, I think we're going to have all of these new therapeutics coming through and then we need to work out how we deliver those therapeutics to a global population.
In 10 years’ time, I would like to see patients across the world, not just in the highly developed economies benefiting from cell and gene therapy, because there's a thriving industry that is delivering those therapeutics to them.
To use one of our plug words, one of our values, it's about collaboration. It's about everybody coming together and recognizing all of the things that we need to do to realise this. And if we do that, then we really will be seeing the benefits of it.

Stuart: Matthew raises a great point. In order for the life sciences industry to have a real-world impact, collaboration is needed between the clinicians, the manufacturers, the scientists and the regulators.
Thank you so much to all of our guests from this series. It has been fascinating to get your insights as we have dived into the impactful work of life scientists, who are enabling therapeutic innovations, developing cell and gene manufacturing platforms, and improving our understanding of fundamental biology. And thanks to them, we will be able to get better medicines, to more people, sooner.
And thank you to ..you, the listeners, for joining us on this journey. You can listen to the full series wherever you get your podcasts. And we hope you join us again soon for more from Invent: Life Sciences.
Invent: Life Sciences is a podcast from TTP, produced by Message Heard. It was hosted by me, Stuart Lowe, Head of Biotechnology, Cell and Gene Therapy at TTP. It was produced by Bill Griffin, with additional production from Emma Crampton, and Blu Posner. The Executive Producers were Sandra Ferrari, from Message Heard and Adam Roberts from TTP. TTP’s social media executive was Ursula Somers.