The work targets a leading delivery method for the therapies, adeno-associated virus (AAV), and recently was published in the journal by UofL’s Maureen A. McCall and her colleagues from Harvard University and its Wyss Institute.

AAV is used in treating a number of conditions, including the retinal diseases McCall studies at UofL. However, it also has been known to cause serious side effects, such as elevated immune response and inflammation.

“It’s a real problem since there’s no real control,” said McCall, the Kentucky Lions Eye Research Endowed Chair and a professor in the Departments of Ophthalmology and Visual Sciences and Anatomical Sciences and Neurobiology. “Even with the best-laid plans, you see some inflammatory retinal response, and the amount can vary widely, including dangerous levels.”

The new research focuses on the role of the viral capsid, a component in AAV that’s believed to cause this response. Parts of the viral capsid interact with a protein known as Toll-like receptor 9 (TLR9), which senses foreign DNA in the body. TLR9 triggers the immune response, which causes inflammation and can reduce or eliminate the therapy’s effects.

“So, the hypothesis was that if you could change that capsid code and mask it from the Toll-like receptor, that you could build a better delivery tool,” McCall said.

The idea is to “cloak” the deleterious part of the capsid with a series of synthetic DNA “inflammation-inhibiting oligonucleotide” sequences meant to stop TLR9’s reaction. In mouse models, the researchers saw a 95% reduction in inflammation.

In many cases, gene therapies for optical diseases are delivered through the retina since the blood-retina barrier helps to mitigate some of the immune response. Ying Kai Chan, a former postdoctoral fellow in George Church’s group at the Wyss Institute, reached out to McCall in 2018 to partner on this work because of her research expertise and the experience of her UofL colleagues with these injections, especially Wei Wang, assistant professor of ophthalmology.

McCall’s work at UofL specifically focuses on the use of gene therapies to treat retinal diseases, including retinitis pigmentosa and other conditions that eventually can cause blindness. For some of these conditions, there is no known cure and many therapies are still in development and clinical trials. McCall said eliminating side effects associated with AAV delivery gets researchers one step closer to successful treatment.

“Solving this key problem with delivery is huge,” she said. “These therapies show promise in significantly increasing people’s quality of life. My hope is that one day we can use these therapies to slow – or even stop – the progression of these diseases and restore sight.”

Harvard’s “Reconnecting America” national campaign, formed following the 2016 election, identifies the root causes of national divisiveness and encourages community-based action plans that address those issues. McConnell Scholars Robert Gassman and Frank Bencomo attended the campaign kickoff and are creating programming targeted at the next generation of voters – local middle school children.

“What we want to do is instill in this younger generation how to have healthy civic dialogue and teach them how to be able to talk about important issues without having this polarized, toxic atmosphere,” Gassman said. “We thought this programming would be valuable to that age group because if we can get to them before they are polarized in high school then there would be a healthier dialogue moving forward.”

“We seem to have this sports team attitude when it comes to politics – with scoreboards and who’s winning and losing – that is dividing us,” Bencomo said. “We want to start them on a path so they can understand that these issues have history, are complex and based on policy, not just personal views.”

The two scholars have worked with local school teachers this semester to develop age-appropriate lesson plans and resources and they plan to launch the pilot program this fall as part of Constitution Week. The program will specifically target 11-and-12-year-old JCPS students.

“Robert and Frank walked away from the Harvard conference energized and ready to challenge the politically divisive rhetoric in our country,” said GlyptusAnn Grider Jones, the McConnell Center’s adviser for the Harvard IOP partnership. “They identified the U.S. Constitution as a tool to engage middle school students in the constitutional amendment process and help illustrate how student voices matter in politics.”

The McConnell Center has been part of the Harvard IOP’s National Campaign conference since 2010.

Speller, a 2015 BSN graduate from the University of Louisville School of Nursing, has been accepted to Harvard University’s , a post-baccalaureate program that aims to increase the number of underrepresented minorities in doctoral programs. Through mentored research and training, the program strengthens a scholar’s competitiveness when applying to top graduate schools.

Speller, 24, is the first UofL graduate accepted to the program, which annually admits no more than six applicants from across the country.

She will work as a research assistant with a Harvard faculty member, participate in professional development seminars and have access to undergraduate and graduate coursework.

Speller, who works as a research nurse at the UofL Clinical Trials Unit, will study health policy and plans to research ways to make hospital operations more economically efficient.

“Amanda was selected based on her long-term goals, her interests in public health research, and the overall strength of her application, including her passion for research,” said Sheila Thomas, PhD, associate dean of academic programs and diversity at Harvard’s Graduate School of Arts and Sciences.

In July, Speller will begin the program, which lasts one year with an option for a second year. She will receive a $33,000 annual stipend and tuition for up to two classes per semester.

“This is a very prestigious program and an honor for us to have a graduate accepted into it,” said Lynne Hall, DrPH, RN, UofL School of Nursing associate dean for research. “Amanda was very active in research as an undergraduate student and published and presented.”

The School of Nursing served a key role in shaping Speller’s research interests, allowing her to work as a research assistant before she was officially accepted to the upper division of the program.

She worked with Carlee Lehna, PhD, APRN-BC, School of Nursing associate professor, on two Federal Emergency Management Agency-funded grants focusing on home fire safety for parents of newborns, including those with special needs, and older adults.

A paper that Speller co-authored with Lehna and other faculty members won the 2015 American Burn Association’s Lindberg Award for the best scientific paper submitted by a non-physician.

“My professors were willing to let me be involved in every part of the research process,” Speller said. “This gave me a very clear view of the joys and frustrations of being a nurse researcher. It is also very uplifting to have a group of highly successful people believe in you.”