Gene Therapy Delivery With Battelle's Gabe Meister And Tony Duong
A significant challenge in gene therapy delivery – particularly for in vivo approaches – has been limitations in cargo capacity of the gene payload carrier. In this episode of Supplier Horizons, host Tom von Gunden talks with technical director Gabe Meister and scientist Tony Duong from biopharmaceutical research and development company Battelle about the promise of polymer nanoparticles as delivery vehicles for treating rare diseases with in vivo gene therapies.
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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 and Community Director at Drug Delivery Leader. Today, I am joined by representatives from Battelle, a drug development and research company focusing ― for the sake of today's conversation ― on rare disease targeting, particularly with genetic therapies. And for that discussion, I am joined by Gabe Meister, Technical Director of Drug Development and Precision Diagnostics at Battelle.
Welcome, Gabe.
Gabe Meister, Technical Director of Drug Development and Precision Diagnostics, Batelle:
Thanks, Tom. Pleasure to be here.
And also, by Tony Duong, Lead Drug Delivery Scientist from Battelle.
So hello, Tony.
Tony Duong, Lead Drug Delivery Scientist, Batelle:
Thanks for having us, Tom.
Let's get started. Thanks for joining me. So, in the realm of the broad arena of genetic therapies, can we start by looking backwards a little bit ―as far back as you want to go, in terms of that arena. [Tell us] what's been made available, how we got to where we are today, and trace the trajectory of gene therapies and how you folks from Battelle think about where it has been and where it's going.
Meister: So, I'm going to give a little bit of a step back and try to put a little bit of context. I think, generally speaking, people hear the term rare or ultra rare disease, and they think, it doesn't affect me. In actuality, the definition of a rare disease is a disease that affects maybe 3,000 people. And that can seem like it's probably not that high probability of affecting me. But there are a little over 7,000 rare or ultra rare diseases that currently impact nearly 10% of the world's population.
So, you think about 1 in 10 people are impacted in some way by a rare or ultra rare disease. And so, some of these diseases can be just devastating to the quality of life, the ability to enjoy the things that many of us potentially take for granted. And so, understanding that ― that this underlying, genetic condition can lead to catastrophic challenges within someone's life has really led the scientific community to want to understand: What might be the causes of these diseases? And what may we be able to do to potentially try to correct [the disease] or improve the quality of life? And then, if we think really, really long-term over the horizon: What can we do to potentially cure these folks so that they can have a long, healthy life?
And so, from Battelle’s perspective, we've looked at this over years of experience and in many different domains, to include polymers and encapsulation, drug development, omics, machine learning — very multidisciplinary — and really assess what is there, what has there been, and what can there be.
I think, in years past, everybody has probably heard the term AAVs [adeno-associated viruses] as a genetic therapy delivery technology. Viruses evolved over years. They can very easily inject nucleic material to have a positive effect. But there are also some adverse effects associated that we will probably get into a little later. But the community at large is leveraging the learnings from AAVs to look at both viral and non-viral kinds of technologies to get these new innovations into patients. And so, I wanted to talk a little bit about historically what there has been and try to drive us into what we have today.
Duong: Yes, and as I follow the field, I think one of the biggest inflection points that I saw was probably with the approval of some of the CAR-T therapies in 2017. These were some of the first therapeutics that involved taking a patient's cells ex vivo and modifying them. In that case, it was modifying a patient's T-cells to attack and fight cancer. And so, there was this start with ex vivo engineering of cells to make engineered cell therapies. But more recently, I think there has been a lot more going on in terms of in vivo gene therapies.
Just to give some examples, just this year, ELEVIDYS was approved. This is a gene therapy that treats Duchenne muscular dystrophy. And it does this by replacing a nonfunctional dystrophin gene with a smaller but functional version of that gene. And so, that's an example of in vivo gene replacement. And then, some of the other advances include things like CASGEVY®, a gene-editing therapy.
So, this is similar to the CAR-T therapy where the cells were taken ex vivo. CASGEVY® involves treating sickle cell disease by taking a patient's bone marrow stem cells and then using CRISPR to modify the genes to increase hemoglobin production. And so, that's an example of gene editing. And there are a lot of efforts these days to take gene editing in vivo, as well. So, that's a little bit of the history of cell and gene therapies and gene editing to where we are today and why it's exciting.
So, speaking of where we are today, if you think about the challenges that need to be worked on, questions that still need to be answered, the problems that still need to be solved — whether it's things you're working on there at Battelle or just in the industry in general — what are those things that are really the needed focus of attention in today's efforts around innovation and advancement?
Meister: That's a great question. And when we think about delivery and we think about a potential cure for a disease, I think it's really important to understand that this is an incredibly complex problem that is going to take a multifaceted and multifunctional approach to figuring out. When you think about the tactical drug administration to a patient, and you want this outcome, you have to have a drug product that's stable, that can be administered safely.
Once it's actually in a patient, you need it to travel throughout the entire body, evade the immune system, evade those cells within the body that are constantly seeking out foreign things. You often have to get past really tight barriers, challenges to get to the cell types that you're trying to target. And if you think about the blood-brain barrier [BBB], we have that for a reason so that certain things can’t get into the brain. But if you're talking about tackling or trying to solve the challenge of neurodegenerative disease, you have to get a genetic medicine to the right cells. Even if you can get across that barrier, which is incredibly difficult to do, you've got to get to the right cells. And so, the delivery challenge is in the forefront of everybody's mind in this particular community.
And there have been advancements. Today, folks are looking at the traditional AAV vectors that are really good at delivering genetic material but really don't have specificity to where they might deliver. And so, you could be delivering some of these novel medicines to the wrong cells.
We all are aware of the lipid nanoparticles [LNPs] in the Covid vaccines. The one thing I would just offer is that a vaccine is there to actually create an immune response, get cells in the body to react to that foreign thing. We're talking about trying to cure a genetic disease. We actually don't want the immune system to block the effectiveness of that therapy. And so, the community at large is really trying to look at a lot of different ways to solve some of these challenges.
Tony, do you want to talk a little bit about some of the current technology that folks are really investing in trying to use to solve these problems?
Duong: Yeah, I could go into that. And just to highlight why delivery is such a challenge as we shift into these newer gene therapies, if you think about legacy drugs, these were typically small molecules rather than gene constructs. And these small molecules are generally no bigger than 1000 daltons (Da) or 1000g per mole (g/mol) in molecular weight. But the molecules that make up these gene therapies are long chains of molecules, nucleic acids, which, all together, make this construct ]what] could be more than one million Da.
So, just to paint a mental picture, that's like going from trying to deliver something the size of a grain of sand to delivering something the size of a basketball. And so, that's why these historically used delivery mechanisms aren't going to cut it. And the challenges that Gabe mentioned, like immunogenicity getting past these cells, the epithelial barriers ― that's why these become a much bigger challenge.
So, as far as the things that have been used, Gabe did mention AAVs. They're used in at least eight approved gene therapies by the FDA today. And viruses have been good at getting into human cells. But they do have some serious limitations.
The cargo capacity size has increased with genetic therapies, and AAVs have some serious cargo capacity limitations. They can only deliver things that are 5,000 base pairs — that’s the ATCGs — or less. And so, this is where we need things that can deliver larger constructs. When we look at non-viral alternatives, lipids were an intuitive choice because the cells that you need to deliver to are composed largely of lipids.
And there have been gene therapies that have used lipid nanoparticles. For example, ONPATTRO® was approved by the FDA. This is a therapy that treats a rare liver disease using RNA molecules, and those are delivered by lipid nanoparticles. As Gabe mentioned, the Covid 19 mRNA vaccines use lipid nanoparticles — with the caveat, obviously, that that's not really a gene therapy. It doesn't modify or augment the person's genome. But that was an inflection point for the field of non-virals.
And just to take us to where we are today, what we're most excited about is polymer nanoparticle delivery vehicles. And that's really the basis of the work that we're interested in at Battelle. And part of the reason is because we can use polymer chemistry to engineer nanoparticles with very specific attributes, giving them specific sizes, surface charges, mechanical modulus, hydrophilic/lipophilic balance. And a lot of the characteristics that we can engineer allow us to address these major concerns and challenges for the field of gene delivery.
I hadn't thought to ask you this, but I will: Since you have mentioned the specifics of polymers as a methodology for delivery, go ahead and say more about what actually is happening when that mechanism of action is in the world.
Meister: I think one of the things that we're really excited about, specifically in the non-viral space when we think about polymers, is there have been some concerns over legacy types of delivery vehicles potentially having an immunologic response that could lead to some unwarranted toxicity. And I'll talk about two things, and then I'll let Tony highlight a couple of other things.
When I think about being able to get more drugs or better drugs to patients faster, AAVs and LNPs have historically run into manufacturing challenges: the ability to make them at scale and/or at a quantity or quality [that] may be necessary to get to the patients that need them. I think the interesting part about polymers ― I'm really excited about looking into the future ― is it's a cell-free based synthesis process. It does allow for rapid scale. The reproducibility is much like [for] a small molecule, which many people are familiar with. They [polymers] haven't ― to date, at least ― [in] the work that we've done and [by] some colleagues that we work with, we've seen very little immune response. And so, that bodes well for trying to get to some of those hard-to-reach places.
And Tony can talk to this: I think the fine-tune ability, the ability to carry large payloads ― all of these things are really exciting when you think about some of the limitations of the viral vectors. And so, I am really excited to be part of the non-viral delivery community that includes LNPs and extracellular vesicles. But really excited about the promise that polymers bring into this view.
Duong: And just to get a little bit into the mechanism of what happens and why polymers are interesting, as soon as a nanoparticle is administered in vivo, that nanoparticle will start to interact with components of the immune system. There’s a protein complement system where serum proteins will start binding. And what binds to the nanoparticle, a lot of that is driven by things like the surface charge. So, is it positively charged, negatively charged, neutral? In fact, one of the hallmarks of lipid nanoparticles has been the use of a polymer called polyethylene glycol, or PEG.
And by putting this polymer on the surface of the lipid nanoparticles, the field has used that polymer to make what are called immune stealth polymers. Due to the non-ionic nature of that polymer, it can avoid binding to certain components of the immune system, evading certain immune cells. And really with polymer chemistry, we have an opportunity to go beyond PEG and explore lots of other polymer chemistries that can either up- or down-regulate the immune responses as desired, whether you're looking at vaccines or gene therapies. And so that's just a little bit of an insight into the mechanisms that we take advantage of.
Thanks for that deep dive. And as we move into our last segment here, I'm going to take it back up and flip it a little bit. When you think about the science, when you think about these advancements, the challenges, the problems to be solved and so forth, let's think about the future lives and health of patients. What would you anticipate and hope for in terms of the patient experience, whether it's receiving therapies and/or being cured, or having life extended by them, whatever the goal is? What do you imagine that might look like if these problems are solved and these innovations are made?
Meister: From my perspective, I think we see a vision of the future where these debilitating diseases — that, again, impact 1 in 10 people worldwide — where we're able to give hope to these people that there is work being done, there are advancements being made that could one day afford them the opportunity to live a relatively normal life, if you will, however you define normal. But bring back the quality of life, the excitement in life, and not necessarily have this anxious pit in your stomach about not having something available to you.
I also think, [since] we’re talking about delivery, many drugs often require repeat dosing. They might require long hospital stays, or family members having to live in a hotel. I think it would be really amazing in the future where a diagnosis can be met with almost a personalized medicine that leverages some of these innovative technologies so that folks can be cured. And I use the term cured and not treated in the sense that they can be confident that, for many years after that, they will be able to embrace and enjoy and effectively have the opportunity to not have that worry about this disease that has affected them up until that point in time.
Duong: I might say a few words about some of the impact that could be made by the constructs that can be delivered by some of these vehicles that we're talking about. Some of the diseases that Gabe is talking about can be treated through a gene therapy augmenting or modifying the patient's genome. But one of the advances I see that's particularly exciting is the field of epigenetics — epigenetics being the study of the information that's contained in a person's genes on top of the ATCG genes that make up their sequence.
So, just to explain that a little bit: Sometimes the letters in a person's genome, specifically the Cs, are given epigenetic marks called methylation. And as an analogy ― it may not be a perfect analogy, but I like to think of the genetic markers as kind of the punctuation marks of the genome. So, in the same way that a comma can significantly change the way that you read a sentence, these epigenetic marks can significantly change the way that the machinery of your cells read a person's genome.
And there are gene and epigenetic tools ―epigenetic regulators ― that could be used as a therapy to alter these punctuation marks and turn genes on or off. And this could potentially treat large categories of rare diseases that we were talking about. In particular, we at Battelle are using some of these epigenetic modifiers to treat neurological diseases like neurofibrillary ptosis.
And we have some collaborators at UC Davis who help us do that. But these are very challenging cargos to deliver. And so, if we are able to deliver these cargos [such as] epigenetic modifiers, it really opens up a lot of opportunity and a lot of hope for patients with diseases that can't be treated today.
Well, thank you, Tony. And to conclude, I'm going to borrow your analogy and thank you both for putting all the commas in the right places in this conversation. Thanks, Gabe and Tony, for joining me. And thanks to our audience for joining another episode of Supplier Horizons. We'll see you here next time.