Focus In Sound

In this edition of FOCUS In Sound, we meet Dr. Laura Ensign who is making important strides in nanomedicine for drug delivery, in a variety of therapeutic areas.

Her wide-ranging interests and research pursuits focuses on the characterization of biological barriers in health and disease in order to design more effective formulations for prophylactic and therapeutic drug delivery.

Transcription of “Interview with Dr. Laura Ensign”

00;00;02;25 – 00;00;41;06 Ernie Hood Welcome to Focus In Sound, the podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood. In this edition of Focus In Sound, we meet a remarkably accomplished young researcher who is making important strides in nanomedicine for drug delivery in a variety of therapeutic areas. Dr. Laura Ensign is the vice chair for Research and the Marcela e Wall Professor of Ophthalmology at the Wilmer Eye Institute Nanomedicine Division, which is part of Johns Hopkins Medicine in Baltimore.

00;00;41;26 – 00;01;16;26 Ernie Hood She is an associate professor in Ophthalmology, Chemical and Biomolecular Engineering, Biomedical engineering, Pharmacology and Molecular Sciences, Gynecology and Obstetrics, Infectious Diseases and Oncology. That long list of appointments reflects her wide ranging interests and research pursuits, which focus on characterization of biological barriers in health and disease in order to design more effective formulations for prophylactic and therapeutic drug delivery.

00;01;17;22 – 00;01;41;28 Ernie Hood She received funding from the Burroughs Wellcome Fund in 2015 for her project, titled The Role of Vaginal Progesterone Delivery in Cervical Remodeling and Preterm Birth, which was part of the fund’s program to encourage preterm birth research and is now called the Next Gen Pregnancy Initiative. Laura Ensign, welcome to Focus In Sound.

00;01;42;17 – 00;01;44;16 Laura Ensign Thank you. It’s fun to be here.

00;01;45;12 – 00;02;02;13 Ernie Hood Laura, I’d like to concentrate first on your work on preterm birth and then will widen out to include much of your other research. Tell us about your recent study of a vaginally delivered nano medicine method for preventing preterm birth.

00;02;03;11 – 00;02;26;13 Laura Ensign So one of the major issues with preterm birth is that there are not many therapeutic options. So we don’t have good ways of preventing preterm birth using drug products. And there’s really only one approved product on the market. And even that product recently had a failed confirmatory clinical trials. And it’s quite possible that that drug will even get removed from the market.

00;02;26;25 – 00;02;48;25 Laura Ensign And so one of the things that we actually sought out to do here was not just to improve drug delivery. So often the research idea we’re maybe looking at better targeting or making drugs more effective, reducing side effects. But in this case, it’s both that. But then also there’s just not a lot of options to begin with. And so we started with progesterone.

00;02;48;25 – 00;03;13;03 Laura Ensign And because that’s something that has been shown to work, it’s progesterone is kind of the pregnancy hormone. And so we were looking at ways to better deliver progesterone vaginally, which has shown in some clinical trials to have some positive effects on preterm birth prevention. But we figured in that case we could do a more targeted, more effective drug delivery to the uterus and the upper tracts.

00;03;13;03 – 00;03;38;06 Laura Ensign And so but the interesting thing that we found in the animal model that we were working with, where we were really focused on inflammations inflammation as a cause of preterm birth, we found that the progesterone alone actually wasn’t working very well. It wasn’t very therapeutically effective. And so what we ended up having to do then was actually more of a drug discovery kind of biology type project where we were then using other molecules.

00;03;38;06 – 00;03;59;29 Laura Ensign So the molecule in particular is it’s called an attack inhibitor. Basically what it does is it changes gene expression, right? And so we ended up figuring out that if you use that drug in combination with the progesterone, then you actually see prevention of the preterm birth. But then the other thing that was interesting about it is that it was really the vaginal drug delivery.

00;03;59;29 – 00;04;34;21 Laura Ensign So the targeted delivery with the nanomedicine system that was more effective, whereas if you dosed by injection or something systemic, then it had no effect still. The other thing that was that was interesting about the work, though, is that in the context of inflammation, you’re also concerned about the developing fetus, particularly neurological development. And so if you’re prolonging then gestation in a setting where you have inflammation, you also want to make sure that your drug treatment is also addressing the inflammation and making sure that neurological development is occurring normally.

00;04;35;02 – 00;04;59;03 Laura Ensign And so that was something that was particularly exciting, is that in the mouse model, the pups that were born with the neurological and neuro motor characterizations, they they appeared to behave and develop. Neuro typically are normally compared to animals that had no inflammation and no drug treatment. And so that was something that was particularly exciting about this as a preliminary observation.

00;04;59;27 – 00;05;12;14 Ernie Hood Well, that certainly sounds like a very exciting result. Do you anticipate moving this approach into human studies? If so, when? And will you conduct that phase of the research?

00;05;12;28 – 00;05;41;26 Laura Ensign Yeah. So actually, one of the things that we’re looking to do now, now that we’ve looked at kind of the role of gene expression and modifying gene expression, this is an area called epigenetics. And so that’s actually something that’s coincidentally become very a very hot topic even in clinical studies. So looking at epigenetics and epigenetic markers and and women and patient samples, and that’s something that Burroughs Wellcome is very interested in at this stage as well.

00;05;42;06 – 00;06;01;02 Laura Ensign The idea then is that, you know, maybe it’s not your genetics, not your DNA, it’s it’s how your DNA is being free. And so can you change things about that if there are things turned on that need to be turned back off, you know, and Vice versa. And so one of the things that we’re actually trying to do now is even kind of grow the drug screening.

00;06;01;02 – 00;06;23;26 Laura Ensign So use the preclinical animal models and and and do drug screening as a tool then to identify potentially more therapeutic options and then also ones that may be safer for use in pregnant women in pregnancy because that’s, of course, is a major concern. Whenever you’re talking about treating a pregnant woman, you’re worried about safety for both the mother and the fetus.

00;06;24;09 – 00;06;50;13 Laura Ensign And so we’re trying to kind of build a pipeline. And we have these research tools now we can build this pipeline and then determine, you know, best candidates that might be feasible to move into clinical studies. But then as far as clinical translation, the thing that’s perhaps exciting about the Nanomedicine approach and the formulation approach is that this is actually a it’s a very similar approach to what was what was.

00;06;50;13 – 00;07;16;16 Laura Ensign We also spun out into a company a number of years ago. I’m sorry. Center We started a company that’s called Cullin Pharmaceuticals, probably now has two approved products, coincidentally eyedrops that use very similar formulation approaches. And so should we end up identifying a drug candidate? Yet the potential for moving into clinical studies and actually doing the translational stuff is is it’s much it’s actually realistic.

00;07;16;24 – 00;07;24;02 Laura Ensign So we’re not talking about nanotechnology as science fiction. You know, there’s already approved products that are based on these kinds of formulation approaches.

00;07;25;00 – 00;07;35;21 Ernie Hood Laura, you are also using Nanomedicine to advance drug delivery in ophthalmic settings. Mm hmm. Also, about some of the work you’ve been doing in that area here.

00;07;35;24 – 00;08;05;00 Laura Ensign I often get questions about that. So I like working on the eye and being in the summer institute and then also having an appointment and gynecology and obstetrics and working on women’s health. What’s the crossover? Right? Like, what’s the similarity? And so it’s really the underlying similarity is just we’re talking about mucosal surfaces and so mucosal surfaces being, you know, any of the external epithelial surfaces, there’s several, including the airways and the gut.

00;08;05;00 – 00;08;27;16 Laura Ensign And so then the reproductive tract in the eye. And so the idea then is that these formulation approaches, if you’re if you’re able to increase, you know, kind of drug absorption and delivery through mucosal barriers and into epithelial tissues, then there’s actually a lot of similarity and what can be beneficial for directly for the eye as for the reproductive tract and the formulation approaches.

00;08;27;17 – 00;08;56;29 Laura Ensign And some of the cases are actually quite similar. So we do work on a number of drop formulations as well. So for various ocular indications, we’ve done work and published in surgery for glaucoma and for age related macular degeneration and all sorts of eye diseases, other kinds of corneal diseases, neovascularization, all these kinds of things. So basically any drug that you would want to increase, the amount that gets into the eye, it’s a it’s something that we work on.

00;08;57;12 – 00;09;26;14 Laura Ensign And so in various different kinds of formulation approaches. But then interestingly, the underlying approach and the engineering aspect and these carriers that we make for the drugs, we’re using the same ones for the eye as we are for the reproductive tract and vice versa. But the drugs are different, right? Like the therapeutics are different, but then the idea of targeting the specific cells and then decreasing your off target or systemic exposure, it’s all very similar kind of logic.

00;09;27;10 – 00;09;48;04 Ernie Hood One of the aspects of your work that I found most interesting was reading about the challenges associated with eye drops. Yeah, that, that those are very difficult to to use in many cases. What are some of those challenges that nanomedicine and nano delivery may be able to overcome?

00;09;48;24 – 00;10;13;11 Laura Ensign The surface of the eye is is very exquisitely designed to really prevent any kind of outside material from getting in. And so there’s several ways that the eyes protected. So so one that’s kind of obvious is blinking, right? So the blinking of the eyelids blinks many times per minute. And even talking about it, usually you start to blink more frequently.

00;10;14;07 – 00;10;36;00 Laura Ensign And so that’s really it’s kind of like a wiping process that wipes the eye that works in concert with your tier production. So you have micro glands that are producing tears continuously and so that every time you blink the tear film on the surfaces is completely regenerated. And so the tears are actually a form of mucus as well.

00;10;36;06 – 00;10;56;13 Laura Ensign It’s something that maybe you don’t think about, but it is clear because it’s a low concentration of mucins, but it is a mucus layer and it’s sticky. And so any time something any kind of foreign debris or anything touches your eye, don’t get trapped up in your tear film and then drain through your nasal alcohol duct, which goes kind of into your into your nose.

00;10;56;25 – 00;11;17;17 Laura Ensign And so this process is just constantly occurring. And then if you’ve ever used eyedrops before, you know that when you use them, you reflexively start blinking and tearing. And so the process is actually kind of accelerated right after you use an eyebrow. And so usually eye drops, you have to use multiple times per day, depending on if it’s a serious infection or something like that.

00;11;17;17 – 00;11;36;07 Laura Ensign You may even be told to use it once every hour, once every 2 hours, you know, while you’re awake. And so as you can imagine, that’s you know, it’s really hard for for patients to adhere to those kinds of guidelines. And and because of all this clearance, it’s you know, it’s often cited that maybe less than 5% of the drug will actually get into your eye.

00;11;36;08 – 00;12;03;20 Laura Ensign The rest of it gets, you know, cleared through your ducts potentially. That way even you get systemic exposure of the drug or I don’t know if you’ve ever used an eye drop where immediately you can taste it afterwards. Right. Because when it goes through that duct, it goes into your mouth and into your gastrointestinal tract as well. So, you know, eye drops, they seem simple and, you know, in your eyes seems to be very accessible, but it’s actually, you know, like getting therapeutic levels of drug into your eye is actually difficult to do.

00;12;04;06 – 00;12;39;11 Laura Ensign And it takes a lot of repeated dosing. And so one of the things that we work on is just using your nano formulations, using, you know, gel forming polymers and things like that to create eye drops that both have prolonged resonance time So those so that it’ll stay on your eye for longer, but then also really make that initial absorption very rapid, get through the tear film, get through those cell barriers and get as much drug as possible into the eye before you’re blinking and tearing and everything can wash away.

00;12;39;23 – 00;13;06;13 Laura Ensign And so through multiple kinds of processes where the nanoparticle approach, like I said, has been developed by colored pharmaceuticals, and then we have these other hydrogel kind of approaches that we we recently started in your company as well to develop some of that as eye drops for clinical use. So there’s a lot there’s actually a lot of exciting things going on with the eye work because it’s and it’s also something where, you know, vision is kind of underappreciated in terms of an ocular.

00;13;06;13 – 00;13;20;23 Laura Ensign Diseases are kind of underappreciated as a things to be working on rate and ways to improve. But our vision is very important to us, you know, So it perhaps makes a lot of sense to focus on eye diseases, but it’s kind of an underappreciated area.

00;13;21;18 – 00;13;38;16 Ernie Hood Where you have characterized delivering drugs to the retina as one of the holy grails of ocular drug delivery. Tell us about a little bit more about the topical gelling eyedrops you’ve been working on that would seem to be the Holy Grail.

00;13;38;24 – 00;13;54;17 Laura Ensign Yeah, absolutely. I would like to say upfront, though, that that, you know, there was a lot about that that was really surprising to us. You know, we never saw it out saying, I’m going to be the one to make an eye drop that delivers drug effectively to the retina. This is like this is what I’m setting out to do.

00;13;55;07 – 00;14;21;24 Laura Ensign So we were actually really focused on, you know, diseases of the front of the eye when we were first developing the drilling eye drop and things like glaucoma and dry eye and things like that. But it was actually along the way when we were kind of studying the pharmacokinetics or, you know, the way the drug would distribute and clearance and things that we just started seeing surprising amounts of of drug that was being delivered to what we call the posterior segment.

00;14;21;24 – 00;14;44;29 Laura Ensign So like the retina and the choroid, you know, things that are in the back portion of the eye. It was one of those things that was unexpected, but just it just kind of being there. Yeah. And thinking, you know what, what is happening. And so with this gelling, I drop it’s a it’s a known material. So the polymer itself is, is actually something that is an approved drug product, just that lower concentrations.

00;14;44;29 – 00;15;07;05 Laura Ensign But the way that we’re using it, it’s it’s actually an interesting material that has this interesting behavior that when when you increase temperature, it undergoes a gel transition. And so when it’s in just the tube at room temperature, it’s a liquid. But then once you actually apply it to the ocular surface, it will spread and then undergo this gel transition.

00;15;07;13 – 00;15;40;21 Laura Ensign And it’s a clear gel. But then it but then it kind of hugs the surface of your eye and will stay there and kind of fits underneath your eyelid when you’re blinking. So it’s just it’s kind of like a contact lens in that way, but much, much thinner. And so it just holds the drug there. And on the surface of the eye for much longer, where also the polymer itself has these properties where it can increase the solubility of drugs and kind of increase the penetration in through into the tissue, but not in a way that’s irritating or or toxic to the cells.

00;15;41;02 – 00;16;18;29 Laura Ensign And so here we can get this tremendous drug absorption that can occur, you know, into the front of the eye that then is able to know through fluid flow and things like that, reach the back of the eye and then we’ve also been kind of studying the particular drug properties. So it’s it’s not just the eye drop itself, it’s not just the delivery vehicle, but there’s also unique things about the drug properties themselves, like once they’re in the eye, how they behave, where they go, and you can kind of maximize the combinations of those those properties to where then you’re getting sustained and therapeutic drug delivery to the retina and to the the posterior segment

00;16;19;20 – 00;16;45;19 Laura Ensign that we’re seeing is actually effective in disease models and in even animals as large as pigs, which have eyes that are similar size to humans. So, yes, it’s very exciting. We’re you know, we’re doing a lot of work then different retinal degenerative conditions, like I mentioned, age related macular degeneration, also retinitis pigmentosa and also, you know, just kind of retinal degeneration that occurs in glaucoma and doing kind of neuroprotection.

00;16;45;19 – 00;17;08;15 Laura Ensign So, you know, so once we kind of saw that, we started expanding out into every therapeutic area that we could think of where it could be applicable. And so, yeah, so it’s very exciting because there’s not there’s not any eyedrops available on the market now that are for retinal degenerative diseases. And so for AMD in particular, those patients, they have to get intraocular injection.

00;17;08;15 – 00;17;33;04 Laura Ensign So a needle into the globe of your eye once every six or eight weeks they have to go back to the doctor to get these injections. And and so the idea that, you know, an eye drop even at once, daily eye drops could replace the need for the injections. And, you know, that could be really exciting for some patients who would be looking forward to not having to keep going back to the doctor and keep getting those injections.

00;17;33;20 – 00;17;42;24 Ernie Hood Overall, this is all about overcoming barriers to drug delivery, isn’t it? Is that why nanomedicine for drug delivery is so promising?

00;17;43;10 – 00;18;12;11 Laura Ensign Absolutely. We think of nanoparticles as kind of like shuttles, you know, So they you know, they take their drug cargo and you can seek out or find, you know, cells and things where, you know, you’re only then delivering the drug to those cells and to those tissues. And then there’s there’s ways that you can manipulate nanoparticles to to look like other types of naturally occurring biological materials, like viruses and things like that.

00;18;12;26 – 00;18;47;16 Laura Ensign And so then you can imagine then you can really manipulate and take advantage of natural biological processes, really deliver drugs in a way that’s more targeted at concentrated. And and then also just kind of reduce the amount of drug that just is freely going everywhere in the body. And that’s where all the side effects come from. And so, yeah, so that is really the whole problem is nanomedicine and all of it and the concept of drug delivery, it really is, you know, the promise of, of overcoming these biological barriers and then, you know, making drugs more effective and decreasing side effects and things.

00;18;47;16 – 00;18;55;22 Laura Ensign And so the, the goal is always overall just improving treatment, efficacy, you know, improving quality of life, you know, things like that.

00;18;56;12 – 00;18;59;07 Ernie Hood What got you interested in this line of research?

00;18;59;29 – 00;19;32;14 Laura Ensign Yeah, that’s a good question. So actually, I’m one of those people that when I was younger I wanted to be a doctor. And so I actually I was I wanted to be a neurosurgeon, right? So I was very serious about this when I was a kid. And, and it was actually when I was a teenager, I did some some volunteer work at a hospital and realized that, you know, emotionally speaking, I was, you know, the concept of of, you know, having to interact with patients and families and things and death and, you know, like I was just like, I’m not emotionally cut out for this.

00;19;32;15 – 00;19;52;01 Laura Ensign Right? And so so the way that I actually got into engineering and biomedical engineering in particular was just on the promise of being able to work on things and develop things that, you know, patients will use and that people will use and will and will improve their quality of care and their quality of life from, you know, from afar.

00;19;53;00 – 00;20;13;10 Laura Ensign And so so it’s really that. And so that’s how I really got that’s how I got into biomedical engineering in general. And so that was one of the main things that really interested me about drug delivery and nanomedicine was that it was it was all about this promise of of improving the way that we care for patients and in how we treat and prevent diseases.

00;20;13;13 – 00;20;31;06 Laura Ensign And so, yeah, and that’s still what it is. And that’s how I even got interested at all in, you know, in startup companies and things like that, and trying to do translational work where you’re ultimately trying to to get to the product level because that’s that’s the ultimate goal, right? You want the product to be available and you want people to be able to use it.

00;20;31;20 – 00;20;36;10 Laura Ensign That feeds into the whole motivation to be doing the work in the first place.

00;20;36;10 – 00;20;51;28 Ernie Hood Dr. Laura Ensign You’re doing some important and valuable research in nanomedicine for drug delivery, and it’s been great chatting with you and learning about this fascinating area. Best of luck for continued success and thank you so much for speaking with us.

00;20;52;15 – 00;20;56;27 Laura Ensign Thank you for having me. It’s a lot of fun.

00;20;56;27 – 00;21;05;04 Ernie Hood We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time. This is really good. Thanks for listening.