Pro-drug Design for Retinal Disease

Palo Alto, CA — The Mahajan Lab is designing small-molecule injectable drugs for a number of molecular targets they identified using proteomics, the large-scale study of proteins. The ability to surgically inject drugs directly into the eye allows retina surgeons to deliver precise therapies that are personalized, safe, and effective. But preventing small-molecule drugs from breaking down or rapidly leaking out of the eye is a major challenge.

An issue with intravitreal injection of small molecules comes to light when considering the pharmacokinetics of particular drugs, which play an important role in determining the dosage frequency. The longer time between injections, the better for patients. However, therapeutic concentrations of the desired drug must still be achieved. Dylan Parsons Ph.D., a postdoctoral fellow in the Mahajan lab, is a medicinal chemist working on this problem.

Drugs are injected into the vitreous, a fluid compartment inside the eye overlying the retina.

Dylan said, “We have to get the drug concentration to the right therapeutic level and overcome the high turnover rate in the eye and also account for a multitude of molecular and tissue barriers. For biologics, like antibodies, which are typically cleared very slowly from the vitreous, this is not a problem.”

“It’s a different story with small molecules, which are low molecular weight organic compounds that regulate a biological process,” Dylan added.

Due to their small size and higher permeability, small molecules are rapidly cleared from the vitreous after injection, typically on the order of hours making them less amenable for this method of delivery. Much effort has been put into addressing this limitation and clever solutions to the problem have emerged.

Vinit Mahajan M.D., Ph.D., professor at Stanford and vice chair of ophthalmology research, said, , “One of the most obvious methods for improving the pharmacokinetics and vitreous clearance rate is through the use of prodrugs. These are modified drugs that must go through an additional chemical conversion in the body before they become an active pharmacological. Prodrugs have proven effective for a variety of systemically administered medications. The effects of different prodrug moieties in ocular tissue is not well understood. We are just beginning to explore the vast prodrug modifications available.”

Ester prodrugs, for example, have proven quite useful in systemically delivered drugs and may be extendable to the eye. Using the antiviral Ganciclovir, researchers showed that various ester modifications were tolerated and cleaved within ocular tissues, paving the way to more extensive future research and possible utility. These ester prodrugs effect eye-specific uptake into cells and pharmacokinetic parameters, such as vitreous half-life and melanin binding. The use of lipophilic ester prodrugs has been explored and demonstrated to be efficacious in multiple animal models.

Dylan said, “The use of these prodrug modifications to optimize the properties of small molecules opens the door to their use in targeting diseases of the retina. This is important as many current treatments only target the secondary effects of disease, not the underlying biochemical pathways that cause disease.”

Mahajan said, “Injecting drugs directly into the eye prevents the drug from being processed in the gut, liver, kidney, or blood, reducing the chance of side effects developing in these organs. A highly potent drug can go straight to the diseased cells in the retina, and this is a major advantage.”

To effectively deliver drugs to the retina and retinal pigment epithelial cells, intravitreal injections have become the gold-standard, because they can deliver drugs directly to the target tissue, and the vitreous is large enough to support such injections.
Mahajan noted, “Monthly injections of VEGF-inhibiting antibodies are among the most frequently administered drugs intravitreally. We also inject steroids for inflammation and antibiotics for infections.”

The injection procedure can be completed safely in an outpatient clinic in less than 15 minutes. The most common therapies are injections of antibodies to treat wet age-related macular degeneration and diabetic retinopathy.

An important limitation, Mahajan noted is that “antibodies can be used to target extracellular proteins, but antibodies cannot get inside cells to block intracellular disease proteins. This is where small-molecules can play a critical role. Well-designed small-molecules open up a whole new landscape of disease molecules that can be therapeutically targeted.”

Mahajan said, “Our Molecular Surgery Program recognizes the opportunity for combining our refined drug delivery methods with new drug design strategies.”