In May, an interdisciplinary MUSC research team won an inaugural Blue Sky Award, which provided $100,000 in funding for its project to restore vision in patients with age-related macular degeneration (AMD) by recharging the eye cells’ batteries. The Blue Sky Award was created to encourage high-risk, high-reward research that has the potential to make a profound impact on patient care but is unlikely to attract traditional funding due to the difficulties of the projects.

The team was led by Baerbel Rohrer, Ph.D., of the College of Medicine, and Andrew Jakymiw, Ph.D., of the College of Dental Medicine, and included their graduate students Kyrie Wilson and Charles Holjencin. Rohrer is the Endowed Chair of Gene and Pharmaceutical Treatment of Retinal Degenerative Disease. Jakymiw is an expert in developing cell-penetrating peptides for drug delivery.

Together they intend to tackle a disease that affects more than 10 million Americans: AMD. The disease causes vision to worsen slowly and eventually leads to blindness. Current therapies are inadequate, as they can only lessen the symptoms and aim, at best, to postpone the loss of vision. Existing therapies also require patients to return again and again for treatment.

Team members weren’t satisfied with just slowing down the disease. They wanted to develop a curative therapy that could protect and even restore vision. 

“We knew that if we could treat the disease at the root cause, and not just the symptoms, that would be a huge step forward in regenerative medicine,” said Wilson.

At its root, AMD is caused by an insufficient supply of energy to eye cells. 

“Every single activity of a cell requires energy,” said Rohrer. “Once you lose that energy, you will lose proper function of the cells. That will eventually lead to disease and vision loss.” 

Mitochondria are the batteries that supply energy to cells, and they have their own DNA – mitochondrial DNA or mtDNA – to help them do that. When their DNA becomes damaged, mitochondria cease to function properly and cannot provide cells with the energy they need.

Over time or because of stress, errors can be introduced into mtDNA as it copies itself. Rohrer likens the process to the game of “telephone.” In the game, a person whispers a word into the ear of another person. That person then whispers the word into the ear of the next person and so on down the line.

“Whatever ends up after five people is probably not the word that you picked to start with,” said Rohrer. “And it’s pretty much the same thing with copying mtDNA.”

Instead of trying to target and fix many copy errors, Rohrer and Wilson wondered whether a better approach would be to prevent the mistakes in the first place. They could do so by providing the mitochondria a new blueprint, or template, for copying their DNA, essentially “resetting” the word in the telephone game.

“You need a new template,” said Wilson. “You need to go back and have the perfect words again and know what you’re trying to say.”

Rohrer and Wilson realized that they would need a vehicle to deliver the template to the mitochondria. It would have to be able to dodge the body’s immune system and be accepted by the mitochondria. They reached out to Jakymiw, who had expertise with small nucleic acid-based drug delivery.

“We had actually never delivered anything that large to that point,” said Jakymiw. “I mean we’re talking about like 16 kilobases, which is a pretty big molecule.”

Although the two laboratories had had initial discussions, it was the announcement of the Blue Sky Award that solidified the collaboration and jump started the project.

“Some outcomes of the preliminary work that has evolved over the last few months suggest that we can potentially deliver this large amount of DNA and target it efficiently enough to restore vision for individuals affected by AMD,” continued Jakymiw. 

Jakymiw and Holjencin decorate the surface of the mtDNA with small proteins that carry instructions for the cells and mitochondria on how to take up this newly formed nanoparticle. 

“Essentially, we have a delivery mechanism that carries its own instructions for cell delivery,” said Holjencin, who is creating the nanoparticles being used in the project. 

“You can also design the small proteins so that they can recognize a particular ‘zip code’ and deliver the cargo to that particular site within the cell,” said Jakymiw. 

These small proteins also provide a potential “invisibility cloak” to protect the nanoparticles from the body’s immune system.

To date, the team has shown that the small proteins can package the mtDNA within nanoparticles and deploy it to the struggling mitochondria. They have also shown that it persists there for at least four weeks. In previous studies, mtDNA disappeared after just 48 hours.

“We will eventually end up looking for the presence of mtDNA at probably eight weeks, maybe even out to 16 weeks,” said Wilson.

“And obviously what we would want for humans is that this translates into many years as opposed to having to repeat these treatments on a regular basis,” said Rohrer.

The hope is that introducing the template would set off a series of events that could lead to restored vision. The mitochondria might share the template with its neighbors, which could, likewise, pass it on. As the quality of mtDNA improves in more and more mitochondria, they could again supply sufficient energy to eye cells, restoring vision. 

“This new approach is like a quantum leap. If this were to work, it would significantly change not just the trajectory of my lab but the trajectory of treatment for AMD,” said Rohrer.

Progressnotes Summer 2022