Small Molecule-based Conditional Control of Inflammation and Complement Activation in the Retina
This project seeks to determine whether dampening inflammation using a newly developed strategy can prevent a prevalent, currently untreatable inherited eye disease, Stargardt disease. Our approach is unique in that it can be ‘turned on’ or ‘turned off’ in the eye when necessary, thereby minimizing potential detrimental off-target effects associated with current similar strategies. We anticipate that this unique aspect of our strategy will make it more likely to be effectively used ultimately in humans with Stargardt disease.
The goal of our project is to slow or prevent damage to a cell layer in the eye called the retinal pigment epithelium (RPE) by conditionally controlling inflammation and complement activation in a mouse model of Stargardt disease, the most common retinal dystrophy. We hypothesize that prevention of chronic inflammation and aberrant complement activation will prevent Stargardt-related pathophysiology in the retina.
Our first aim is to optimize a small molecule-regulatable strategy that conditionally controls inflammation/complement activation in vivo in RPE cells. This regulatable strategy will be introduced into RPE cells of albino mice through subretinal injection of AAV. Next, we will confirm the ability of this strategy to prevent inflammatory signaling and complement activation in a small molecule-dependent manner. Potential detrimental effects of long-term suppression of inflammation and complement activation will be determined by visual acuity, electroretinogram and outer nuclear layer counts.
Our second aim is to test our validated strategy in abca4-/- Stargardt disease mice. We will confirm that our strategy works similarly in abca4-/- mice, and that suppression of inflammation/complement activation reduces bisretinoid autofluorescence, protects photoreceptor viability, restores 11-cis-retinaldehyde levels and reduces Bruch’s membrane thickness in aged abca4-/- mice.
One of the innovative aspects of our proposed research is that our strategy allows us to conditionally (not constitutively) prevent inflammation/complement activation. Using such an approach incorporates an appreciation for the observation that low levels of periodic inflammation (parainflammation) appear to be beneficial in maintenance of the retina and that inflammation is actually a necessity for proper organismal homeostasis. We posit that other strategies which rely on constitutive repression of inflammation, while arguably more straightforward, don’t resemble healthy physiologic conditions whereby inflammation and anti-inflammatory signaling wax and wane depending on the stimulus.
While we are testing whether inhibition of inflammation/complement activation is beneficial for alleviating phenotypes associated with Stargardt disease, we anticipate that this strategy will be more broadly applicable to other retinal diseases that are also influenced by inflammation and complement activation. Examples of diseases that fall into this category include the rare retinal dystrophy, Malattia Leventinese, and dry age-related macular degeneration (AMD).
About the Researcher
John Hulleman, PhD, is originally from Wausau, Wisconsin. He received dual undergraduate degrees in biology and chemistry at the University of St. Thomas in St. Paul, Minnesota, and graduated cum laude. He earned a PhD in Medicinal Chemistry and Molecular Pharmacology at Purdue University. There, under the guidance of Dr. Jean-Christophe Rochet, he studied how misfolded proteins cause early-onset Parkinson’s disease. Subsequently, he did postdoctoral research in the laboratory of Dr. Jeffery Kelly at The Scripps Research Institute, where he focused on how an R345W mutation in fibulin-3 causes a rare, early-onset form of macular degeneration.
In 2014, Dr. Hulleman joined UT Southwestern’s Department of Ophthalmology. His research focuses on novel therapeutic approaches for eye diseases, including AMD and other retinal degenerative diseases. Dr. Hulleman has a secondary appointment in the Department of Pharmacology and is affiliated with the Biological Chemistry Graduate Program at UT Southwestern.
I am honored to have been selected to receive a second BrightFocus Macular Degeneration Research grant, and I would like to personally thank all BrightFocus donors for their generosity. The funds provided by these grants allow my laboratory to pursue cutting edge and novel research with the ultimate goal of identifying treatments for devastating diseases such as age-related macular degeneration and Stargardt disease.
First published on: November 14, 2018
Last modified on: January 28, 2019