Yuanyuan Chen, PhD, has a lab that is developing drugs for retinal diseases. Morgan V. DiLeo, PhD, has a lab that is developing new delivery methods for these drugs.
Both labs were represented in the Eye & Ear Foundation’s June 30 webinar, “Improving Drugs and How They’re Delivered for Eyecare.”
Chen Lab
Dr. Chen, Assistant Professor of Ophthalmology in the Systems Pharmacology Laboratory at the University of Pittsburgh School of Medicine, said it was an honor to present the progress of her lab over the past six years. The lab had five people when it was first created; now there are 11.
Dr. Chen’s research interests include:
- Pharmacological studies of RHO-associated retinitis pigmentosa (R01)
- Drug discovery of MYOC-associated primary open-angle glaucoma
- Oral 8-aminopurine in age-related retinal degeneration (resubmission of RO1)
Ocular Disease
One genetic mutation affects the proper folding of a protein with three different consequences: aggregation/degradation, loss of normal function, or abnormal function. All lead to the same end result: disrupted cell function or cell death.
These proteins can be seen in diseases like ALS, Alzheimer’s, Cystic Fibrosis, Type II diabetes, RHO-RP, and MYOC-Glaucoma.
Retinal Degeneration
Retinal degeneration is a progressive series of events and is not a simple disease, Dr. Chen said. Depending on the early need and advancement of the disease, there are different events happening in the eye.
In the early stage, there is photoreceptor cell stress, gliosis and immune response, and epigenetic changes of photoreceptors.
In the middle-advanced-end stages, there is remodeling of inner retinal cells, and switched retinal metabolism.
Preventative treatments can be applied to preserve vision in the early to advanced stages. If advanced to end, then the focus is on regenerative medicine to rebuild vision.
Research Interests and Tools
In the Chen Lab, research interests and tools include:
- Understanding how and why retinal degeneration happens
- Developing pharmacological treatments for retinal degeneration
- Understanding how the chemicals work in the eyes
The lab uses high-throughput drug screening to discover new drug candidates and high-content immunofluorescence imaging and biochemical methods to validate the compounds they have discovered. They also use computational structural docking to understand how the drug binds to the target and chemical genetic analysis to understand drugable molecular pathways for new treatments. Medicinal chemistry is used to improve the potency and efficacy of the lead compound, and preclinical studies are conducted using mouse or rat models of ocular diseases. “Even failed trials count, as they lead to the future success,” Dr. Chen said.
Accomplishments
During her lab’s six years of existence, Dr. Chen has turned out 23 research publications, three patents and two new invention disclosures for eye diseases, one licensed patent by Aldeyra for a clinical trial in retinitis pigmentosa patients carrying the RHO mutation and received NIH grants and the Weigand Entrepreneurial Research Award. Mentorship has been important, which includes being the ophthalmology site head for the Hillman Summer Scholar Program for high schoolers from underrepresented communities.
Breaking News
Dr. Chen announced news she had just received the day before: Aldeyra Therapeutics announced improvement from baseline in retinal function in Phase 2 clinical trial of ADX-2191 in patients with RP. Among the findings:
- Best corrected and low-light visual acuity statistically significantly improved
- As assessed by electroretinography, time to retinal response statistically significantly improved
- As assessed by macular and dark-adapted perimetry, retinal sensitivity statistically significantly improved
- ADX-21-91 was well tolerated and no safety concerns were identified
- Planned phase 2/3 clinical trial to be discussed with regulatory authorities
Dr. DiLeo
Dr. DiLeo, Assistant Professor of Ophthalmology, Bioengineering, and Clinical & Translational Sciences at the University of Pittsburgh School of Medicine, and Director of the Ophthalmic Biomaterials Laboratory, said she works on drug delivery. This means approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect.
“The key words are safety and efficacy,” she said. “We want to make sure we are delivering drugs in a way that’s extremely safe and effective. Those two properties matter most in drug delivery.”
Drug Delivery
The role of drug delivery in vision research is to offer solutions to a number of common issues with ocular drugs, for example:
- Physician: “My patients have to take Drug X 4x/day to treat their disease, but their vision is at risk b/c they often forget to take them.”
- Researcher: “I’ve developed a new drug, Drug Y, that works really well, but it is degraded before it absorbs into the eye.”
- Company: “Sales of Drug Z are really poor b/c patients don’t like how red their eyes get when they use it.”
According to Dr. DiLeo, the best way to describe her work is to think of the difference between Blockbuster and Netflix. Both are providing the same content, but the method of getting it where it needs to go is very different. In the case of video stores, the difference led to the success of one company and the failure of another. Drug delivery is the same concept. Oftentimes the delivery component is the difference between the success and failure of a drug.
Eye Drop Administration
The advantages of eye drops: they are easy, painless, and can be self-administered. The disadvantages: It is hard to reach the site of interest, they must be taken frequently (like multiple times a day every day) and can often cause side effects. They can also be incompatible with other drugs the patient needs to take and can cause systemic side effects like drowsiness, nausea, or dizziness.
Eye Drops for Chronic Conditions
Usually there is a desired range for the drug. Below that drug level, it will not be effective. If you go above that range, you will not be doing it in a safe way and are at risk for side effects. When eye drops are administered, you are constantly going above and below that desired range. Every time it is administered, the concentration will rise dramatically and then quickly drop back to zero.
Eye Drops for Glaucoma
With glaucoma, a lot of the above issues mentioned are present. The first line of defense is to use topical eye drops. There are lots of different options and combinations. These are administered daily, often multiple times a day.
Glaucoma is a set of conditions associated with damage to the optic nerve. Often times, patients experience an increase of pressure inside the eye. The eye is a closed system and the pressure has to go somewhere. It travels back toward the optic nerve, which is extremely sensitive to increased pressure, and that can lead to irreversible damage. This is a progressive chronic condition that if left untreated will get worse. Getting worse means the vision starts to go away. Progression is controlled if eye drops are properly used. The problem is these eye drops have a lot of disadvantages.
Eye Drop Disadvantages
Poor adherence rates are one barrier to eye drops, with a less than 50% rate (or even lower, depending on the study). While there is no pain associated with glaucoma, that means there is no physical reminder to take these drugs.
A second barrier is low bioavailability, with 1-10% absorption. This means patients are only getting 1% of the drug and will have to keep readministering. What causes low bioavailability of eye drops? The blinking that occurs when the drops are administered. An entire drop can not fit in the tear film. The eye is made up of many different layers of tissues. Every tissue needs to pass through every cell layer, which will lead to some barrier for drugs to get through. Drainage is another issue – the drops can go places besides the eyes.
Solution
Imagine a solution where you have the desired drug range, where you are able to hit it right in the middle and have it stay there for a long time. Getting the right amount of drug and not having to constantly administer drops is an ideal scenario.
Controlled release formulation systems release drugs:
- For long periods of time (days to months)
- Release rates are only weakly influenced by environmental conditions
- Fixed predetermined pattern for a definite period of time
- Increase bioavailability
- Make the drug go where you want it
- Increase patient adherence
- Decrease dosing frequency
- Minimize side effects
The proposed solution is a system that would provide longer-term delivery with simple and convenient application methods.
So, the goals are to make the eye drops:
- Topical
- Comfortable
- Patient administered
- Monthly
Splitting the issue into two different categories enabled the lab to come up with a two-phase system that accomplishes this list of goals: Drug encapsulation in a controlled release vehicle.
Dr. DiLeo showed an animation that described how a drug trapped inside the polymer matrix escapes over time to actually treat a disease. She explained that the first thing that happens when a drug is put into a type of water-based environment like the eye, anything trapped on the surface will be released. The drug on the surface will come out immediately and the concentration increases.
The next thing that happens is the pores get bigger, grow, and start to form throughout the matrix. What is really happening in terms of the drug release is that most of the drug is still trapped, with nothing coming out. It is a pore formation that controls how much drug is presented to the eye.
A drug that was once trapped is able to escape the matrix, leading to positive drug release, controlled by degradation. Dr. DiLeo’s lab has developed drug-loaded microspheres that use this principle to achieve 30 days of drug release with a single dose. The microspheres are suspended in a thermoresponsive hydrogel that responds to temperature change. It starts as liquid and when it reaches body temperature on the ocular surface, it goes from liquid to a gel-like solid. As temperature decreases, it turns back into liquid – a reversible change.
This is the science used to create SoliDrop – a long-term gel eye drop that’s self-administered monthly. Temperature changes cause it to be retained in the proper space, located beneath the eyelid. Having the drug in the form of eye drops makes it convenient, comfortable, and familiar. Dosing frequency, risk of blindness, and side effects all decrease.
SoliDrops
A single SoliDrop is equal to 56 standard drops. They have the same drop in pressure, which means the same therapeutic effect – the drug is working. There is no effect in the untreated eye, so the drug is going where it needs to be. If it went to the untreated eye, there would be side effects.
Additional advantages: there is no need for preservatives, and it is easy to see and remove (just flush out with some saline).
“Beyond glaucoma, the way that we engineer these means we can deliver lots of different drugs,” Dr. DiLeo said. “Proteins, antibodies, even viruses for doing things like gene therapy.” It can work for dry eye, pediatrics, anti-inflammatory drugs, anti-infective drugs, and other glaucoma drugs.
Within a couple of years, hopefully the lab will be able to use this technology for patients in a clinical trial.