Personalizing LNP-Delivered RNA Payloads At Scale With Acuitas' Ying Tam

In this episode of Supplier Horizons, host Tom von Gunden discusses with Chief Scientific Officer Ying Tam from LNP platform developer Acuitas Therapeutics the use of lipid nanoparticles as RNA delivery vehicles across an expanding range of targetable indications, including outside the liver. Among the advances discussed are delivering CAR-T therapies in vivo, loading personalized therapeutic payloads into preformed vesicles, and maintaining RNA stability throughout targeted cellular delivery.

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Supplier Horizons. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader, and your host for the series.

Today, I am pleased to be joined by Ying Tam, who is Chief Scientific Officer at Acuitas Therapeutics, which is an LNP [lipid nanoparticle]-based platform delivery development organization.

Welcome, Ying.

Ying Tam, Chief Scientific Officer, Acuitas Therapeutics:

Thanks, Tom, it's great to be here.

Well, it's my pleasure to have you here.

For the Drug Delivery Leader audience, which is pretty wide-ranging, there are probably people who are very familiar with what we mean when we say LNP-based delivery platforms for RNA-type therapeutics. But there may be some people who are not as familiar.

So, could you give us a foundational start? What should we be thinking about to envision what you and I are about to talk to when we say we're talking about LNP-based delivery platforms for RNA?

Sure. I think the first thing that's important to lay out is that the RNA medicines, RNA therapies, are a relatively new class of medicines. The potential in that area to treat a really wide range of diseases is pretty profound. But one of the major challenges with [an] RNA therapeutic is the ability to protect it from being broken down and to get it delivered to the cells that it needs to get to.

And it's really at that stage that Acuitas comes into it. Acuitas is, as you said, focused exclusively on developing lipid-based delivery systems to enable RNA medicines. And it's based on a profound history of innovation and discovery by some of the scientists that have founded Acuitas. It's within that aspect that Acuitas works to develop these delivery systems that, as I said, truly enable RNA therapies.

And there are some really great examples of specific things that Acuitas has enabled. The first thing is the development of a lipid nanoparticle [for] the first approved RNA interference-based medicine that's called Onpattro. RNA interference is an approach to silence the disease-causing gene, and Onpattro is used to treat an otherwise fatal disease known as transthyretin amyloidosis (ATTR).

Acuitas has also developed the LNP [for] the first approved messenger RNA medicine. That was Comirnaty, which is, of course, the [Pfizer-BionNTech] COVID-19 vaccine.

And then, most recently, we've developed the LNP to deliver the first approved base-editing medicine to treat a baby, a newborn, that was born with an often-fatal mutation that affected its ability to metabolize and process proteins.

Gotcha, gotcha. Well, thanks for that overview.

So, obviously, we want to talk in more detail about the science and the technology and the approach that you folks are taking there. A couple of things that I think will be of interest to our audience [and] that intrigue me are the in vivo approach, and then also what I believe you folks refer to as preformed vesicles.

So, if you could elaborate on the concepts there and how they apply to targeting? That would be great.

Yes, so, for a lot of RNA-based medicines, and certainly a lot of the RNA-based medicines that Acuitas is involved in developing with our partners, they contemplate using the lipid nanoparticles to deliver the RNA medicine to the liver. As far as technologies go, that's a relatively instinctive and natural place for us to focus on, initially, because lipid nanoparticles naturally deliver very efficiently to the liver.

One thing that's been more challenging but has become more accessible in recent times is this idea of trying to deliver to cells outside the liver. And that's been a really strong focus of Acuitas. An example of something that potentially we will enable is CAR (chimeric antigen receptor) T cell therapy. It's currently done in a way where it's accessible only to people who have access to an advanced medical center. The costs are prohibitive; the technology and the infrastructure required is very profound.

And so, currently, for ex vivo CAR T cell therapy, a patient would need to go to a hospital. They would have their T cells collected. Those T cells would then be cultured outside the body, in culture and media. They would then be manipulated so that they would express this chimeric antigen receptor, which is designed largely to instruct those T cells that they should attack cancer cells. These manipulated cells are then grown up outside the body. They're activated, and then they're re-infused back into the patient.

The first thing to understand is, in certain cancers like B cell malignancies, this approach, this class of medicine is incredibly effective. But the disadvantages really relate to the incredible complexity of the manufacture and of the application, the incredible cost. These drugs typically cost in excess of half a million dollars or more, up to over a million dollars per patient. And the accessibility, based both on the cost and the requirement for all of this really complicated equipment and procedures.

And so, one of the really exciting pieces more recently about some of the work that we're doing at Acuitas is a focus on what we call delivery outside the liver and, in this case, delivery within the body but to the T cells in the body.

And so, we have created lipid nanoparticles, LNPs, that can go very specifically to those T cells, deliver an RNA that encodes the CAR, and therefore, potentially achieve expression and generation of CARs within the body, in vivo.

And that has so many advantages, the most profound one being that it potentially will give really broad access to really effective therapy to a much larger group of patients who can really use it, not limited by the available facilities and not limited by the cost.

How do you enable that in vivo approach? How do you actually do that versus harvest cells and re-infuse them?

For the in vivo approach, we have created what we call targeted lipid nanoparticles. We put a targeting ligand, a protein or at least a peptide, on the surface of the lipid nanoparticle, which recognizes something very specifically expressed on the T cell.

And when that lipid nanoparticle with that peptide on its surface finds and binds to the T cell, that binding causes the lipid nanoparticle to be taken up specifically into those T cells. And that's how we are able to achieve the specific delivery to the target cells we're trying to get to. And the RNA provides the instructions for that cell to express the CAR.

Gotcha. Okay, so, “preformed.” How does that come into the picture?

The manufacturing process [for LNP-based delivery], at least to date, largely mirrors what the typical process people use to make drugs and medicines. So, normally they're made at a specific facility at relatively large scales. And then these lipid nanoparticles are characterized. They're validated to be safe. And then they're released for distribution. And that's in a very generic way, very standard way that medicines have been produced to date.

But there are some very specific situations in which an alternative approach would be useful to alleviate some of the need and the time and the complexity and the size. An example of this is more medicines, as they are currently evolving, aimed at being personalized. So, designed for treatment of ultra-rare diseases. So, not one person, but a very small number.

Other aspects are things that are largely not efficiently addressed with the current paradigm of how drugs are typically manufactured. Another good example is probably the yearly flu vaccine, where probably a year or more in advance, they have to predict the specific type or strain of influenza, strains of influenza that will be circulating. They need to make that decision very early in order to allow that more traditional manufacturing process.

So, in order to overcome some of those limitations, we have developed something which we call the preformed vesicles, or PFVs. And, again, to orient you, the normal way we make drugs in one of those facilities I mentioned: we take the lipids, and we mix them in a controlled way with the RNA. And then, under appropriate conditions, we will form appropriate mRNA-loaded lipid nanoparticles.

For the preformed vesicles, we can simply make empty lipid nanoparticles. We make them very much the same way, except they are not mixed with the mRNA. And there are a few advantages to that. Number one is, they have very good storage stability at refrigerated temperatures. They don't require the low and ultra-low temperatures that the historic mRNA LNP made the traditional way requires.

And then, when you're ready to use them, you can just take a small aliquot of the empty lipid nanoparticles, mix them simply by inverting them, incubating them at room temperature for a few minutes. That simple mixing process with the empty lipid nanoparticles, what we call the PFVs, and the RNA, potentially at the hospital pharmacy or at the bedside, allows the RNA to be effectively loaded into the lipid nanoparticle and be available for administration.

And so, you can certainly understand how that provides a lot more flexible manufacturing. It allows us to address appropriate scale for a single patient, appropriate scale for a small number of patients. It addresses this potential need for ultra-low storage, ultra-low temperature storage. And it allows, potentially, a much more flexible way of picking the payloads.

One example, as I used before, was for the influenza vaccine. You could wait until late into the year and then find out what strains are circulating. Or another example is if you're making a personalized cancer vaccine. Based on the patient's cancer, you can make a particular payload. And then, if that cancer evolves to having new mutations in the cancer, you can then make a new mRNA and then combine it the next time with the PFVs for an evolved, personalized cancer vaccine.

So, there are a lot of different ways where PFVs address, number one, some of the existing shortcomings, and, number two, enable where a lot of this precision medicine is going, which is more personalized: designing drugs and medicines that are uniquely suited to treat a particular person.

Good.

Well, for our Drug Delivery Leader audience, I'm always interested in knowing what's the range of what we should envision — either current reality or promise or potential — for routes of administration. So, when it comes to leveraging lipid nanoparticles as vehicles for RNA payloads, are we talking only about IV or infusion, or are we also imagining things like injection or inhalation and other routes?

That's a great question, Tom.

Our role at Acuitas is to imagine delivery in as many iterations as possible, to enable RNA therapeutics in as many indications as possible and to, hopefully, develop drugs that are not just better than existing drugs, but enable drugs that are not yet available.

And so, we certainly envision developing lipid nanoparticles that can be administered through a variety of routes of administration. Currently, already, we're talking about IM [intramuscular] administration for things like vaccines. We are currently in the clinic with a number of our partners to deliver mRNA [such as] gene editing mRNA or protein replacement mRNA, largely to get to the liver.

We're now, as I described earlier, developing systems —  IV-administered systems — that will get outside the liver.

We're also looking at some really unique ways of administering. We're looking at aerosolizing the lipid nanoparticle, and we've identified and developed technology that can do that. So, we can deliver, potentially, to the lung and other mucosal surfaces, potentially to treat lung disease, potentially to have a different way of immunizing.

We're looking at direct administration into tumors, direct administration into specific tissue compartments like the eye, and maybe even the central nervous system.

So, there's a lot of things on the table. I think that there certainly is no shortage, as I tried to allude earlier, no shortage of potential benefits for RNA-based medicines. And it is Acuitas' role or desire to enable — to fully enable — the therapeutic potential of RNA by [removing] barriers to effective delivery.

Gotcha.

In the spirit of looking forward in any of those areas that you just gave an overview of — things you're looking at — could you illustrate the next-up problem to solve or question to answer or challenge to overcome that would help to illustrate what would move the dial in any of these areas that you've just outlined? And if you could illustrate to help us see what that might look like, what's right in front of the folks [as in], all right, how do we get past that? Or how do we move the dial on that?

The one area that I think is pretty much in front of us, because the first steps have been taken,  is this idea about personalized therapies. [What ] has always been a problem with the typical drug paradigm is that we produce medicines to treat a large group of patients. But often, when you take a look at the percentage of patients that benefit from the traditional way we design drugs, it’s a surprisingly low percentage of patients that receive a drug that actually benefit from it.

And so, this idea of personalized therapies Is a way, potentially, to overcome the limitations, but then we were faced with basically a whole other series of challenges related to how efficiently, how productively can we design and manufacture those medicines? From the point of view of the RNA payload, there have been a lot of advances as far as the design, the rapidity at which people can analyze a particular molecular basis for disease, and then design solutions, mRNA-encoded solutions.

From the Acuitas side, the ability to manufacture rapidly at a suitable scale, at a scale that, truthfully, is sustainable financially for our partners: those are the kind of challenges that exist to enabling personalized medicine. I look at the personalized medicine I mentioned earlier that we helped enable at the Children's Hospital of Philadelphia. To the extent that we can enable that at a broader range of facilities, and not just super advanced medical facilities — enable that through PFVs, enable that through more effective lipid nanoparticles, enable that through targeted delivery to particular cell types.

Great.

I like to end these episodes and conversations with a look out over the landscape, whether that's near or far, in terms of the patient landscape out there. And so, if these advances continue to move forward and arrive in the market at some scale, what do you envision or hope that the patient experience, either in terms of the treatment regimen and/or the outcomes themselves, might look like?

You know, I think a lot of the things we talked about, and a lot of things we haven't talked about, actually have the potential to profoundly change the — as you pointed to — the patient experience. As an example, some of the therapies are potentially one or maybe two and done. So, rather than a lifetime of chronic drugs [for] curative treatments, there’s the potential to treat inherited metabolic and other kinds of inherited diseases, which currently are not curable.

From that point of view, the ability to achieve those will, of course, require development on the mRNA payload side about what the mRNA can do in terms of things like correcting mutations, inserting corrected genes, [or] expressing proteins that can eventually eliminate a chronic disease.

On the Acuitas side, as I've alluded to a number of times during this conversation, it will require progressively more advanced and specialized delivery systems to achieve delivery to not only target cells that we can currently get to, but [also to] those that we're just on the verge of getting to.

Gotcha. Well, Ying, I want to thank you for joining me, for sharing your perspectives on the work that's underway at Acuitas Therapeutics on LNP-delivered RNA therapeutics. And I also want to thank our Drug Delivery Leader audience for joining for another episode of Supplier Horizons. And we'll see you next time.

About The Featured Guest

Ying K. Tam, Chief Scientific Officer of Acuitas Therapeutics, is a globally recognized expert in nanotechnology and immunology. He directs Acuitas’ scientific strategy and partnerships and has authored more than 100 peer-reviewed studies. He earned his MSc and PhD in developmental and molecular biology from the University of Waterloo and completed a post-doctoral fellowship in cancer immunotherapy at the BC Cancer Agency. He has also held roles in academia, including Assistant Professor at Rush-Presbyterian–St. Luke’s Medical Center in Chicago and Adjunct Professor at the University of British Columbia.