Desipramine/L-Cycloserine Combination Treatment for Retinitis Pigmentosa and Other Ceramide Imbalance

Article: UCI researchers discover cause, develop pharmacological treatment for reducing retinitis pigmentosa vision loss
Source: University of California, Irvine, Medicine
Published: January 26, 2022

VEP of V1 in mice showing that desipramine/L-cycloserine (blue)
corrected reduction of electrical amplitude to near normal/WT
(black) compared to saline (red)

Retinitis pigmentosa is a genetic condition that results in progressive degeneration of the retina, notably the photoreceptors and retinal pigmented epithelium (RPE). Scientist at UC Irvine are studying how accumulation of ceramides, sphingolipids essential for cell membrane stability and cell signaling, lead to the retinal degeneration seen in retinitis pigmentosa. In particular, the researchers found that the absence of an enzyme called Adiponectin receptor 1 protein (AdipoR1), a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity, results in the accumulation of ceramides, which in turn causes reduction of electroretinogram amplitudes, decreased retinoid content and cone opsin expression, and ultimately a damaging inflammatory response. A combination of desipramine and L-cycloserine lowered levels of ceramide in AdipoR1^–/– mice, thereby protecting the photoreceptors and the retina's structure and function. Additionally, the researchers found that mice treated with desipramine/L-cycloserine had improvement in cone-mediated retinal function (i.e., photopic/daylight vision), and treatment over a prolonged period corrected the reduction in electrical response in the primary visual cortex to visual stimuli, "approaching near-normal levels for some parameters." Although AdipoR1 is present in other organs, this lipid regulator is found in highest levels in neural tissues, such as the brain and retina, second only to the ceramidase ASAH1. Given the greater ease of pharmacological treatment compared to gene therapy, the researchers highlight the potential of inhibition of ceramide generation for diseases such as retinitis pigmentosa and other AdipoR1-related retinopathies, as well as systemic and neurodegenerative conditions related to ceramide imbalance.

My rating of this study: ⭐⭐⭐

Lewandowski D, Foik AT, Smidak R, et al. "Inhibition of ceramide accumulation in AdipoR1-/- mice increases photoreceptor survival and improves vision." JCI Insight.  11 January 2022. https://doi.org/10.1172/jci.insight.156301