Paul Albert Sieving, M.D., Ph.D.
Section for Translational Research on Retinal and Macular Degeneration
Building 50, Room 4339
50 South Drive
Bethesda, Maryland 20892
Gene Therapy for X-linked Retinoschisis
A major goal of our lab is to develop therapy for human genetic retinal neurodegenerative diseases. Current efforts focus on X-linked juvenile retinoschisis (XLRS) and are aimed at understanding the mechanisms producing disease, including retinal structural changes and neuronal synaptic signaling deficiency, using a mouse model created in this laboratory. XLRS is an inherited retinal disease and is a leading cause of juvenile macular degeneration in human males. It is caused by mutations in the gene for retinoschisin found on the X chromosome. Development of gene transfer therapy for XLRS using an AAV8 vector that contains the human RS1 cDNA and a modified RS1 promoter is underway in our lab. Results of preclinical dosing efficacy and toxicity studies currently underway or completed will be provided to the FDA for an IND drug application.
Retinoschisin protein is located on the outer plasma membrane of photoreceptor inner segments and other retinal neurons and their synaptic membranes. Its molecular structure suggests that it acts as an adhesion protein in maintaining normal retinal structure, but its precise role is not known. Our laboratory applies the techniques of light and electron microscopy, immunohistochemistry, biochemistry, and molecular biology to the study of human and animal retinal tissue. We also assess retinal structure and function in living animals in ways similar to those used to evaluate human vision in the clinic. These techniques include the electroretinogram (ERG), optical coherence tomography (OCT) and behavioral measurements. By applying these techniques to the study of the natural history of the retinoschisin deficient mouse and its physiological response to light and gene replacement, we are probing the role of retinoschisin in photoreceptor and retinal synaptic function.
Photoreceptor Degeneration and Protection – Rac1 and CNTF
We are studying a number of other mouse and rat models of human retinal degenerative diseases to elucidate the mechanisms of retinal neural signaling deficiencies and degeneration leading to blindness. We are focusing on neurotrophic factors, such as CNTF, and on small molecules that regulate cytoskeletal growth and cell polarity, including Rac1, to understand the role these molecules play in photoreceptor plasticity and homeostasis in normal and diseased retinas. In studying the role of Rac1, we apply a molecular approach using mouse models we created which have a deficiency or a modified form of Rac1 in rod photoreceptors. A critical facet of retinal neurodegenerative disease involves the structural changes, particularly to the photoreceptor outer segments, which precede photoreceptor death causing loss of vision. As photoreceptor cells undergo primary degeneration through progressive outer segment shortening in many of these conditions, a critical question is whether the outer segment may exhibit sufficient structural plasticity to support elongation of those that have been shortened by disease states and whether this would promote survival of the photoreceptor cell.
Paul Sieving received his M.D. from the University of Illinois in 1978 and trained in ophthalmology at that institution between 1978 and 1982. He earned a Ph.D. in bioengineering from the University of Illinois in 1981. He was a faculty member at the University of Michigan Medical School for 17 years and moved to NIH in 2001. He combines laboratory research with clinical patient studies of genetic retinal neurodegenerative diseases. He is a member of the Institute of Medicine and currently serves as director of the National Eye Institute.
Tolun G, Vijayasarathy C, Huang R, Zeng Y, Li Y, Steven AC, Sieving PA, Heymann JB. Paired octamer rings of retinoschisin suggest a junctional model for cell-cell adhesion in the retina. Proc Natl Acad Sci U S A. 2016;113(19):5287-92.
Zein WM, Jeffrey BG, Wiley HE, Turriff AE, Tumminia SJ, Tao W, Bush RA, Marangoni D, Wen R, Wei LL, Sieving PA. CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Invest Ophthalmol Vis Sci. 2014;55(10):6301-8.
Raz-Prag D, Grimes WN, Fariss RN, Vijayasarathy C, Campos MM, Bush RA, Diamond JS, Sieving PA. Probing potassium channel function in vivo by intracellular delivery of antibodies in a rat model of retinal neurodegeneration. Proc Natl Acad Sci U S A. 2010;107(28):12710-5.
Ziccardi L, Vijayasarathy C, Bush RA, Sieving PA. Loss of retinoschisin (RS1) cell surface protein in maturing mouse rod photoreceptors elevates the luminance threshold for light-driven translocation of transducin but not arrestin. J Neurosci. 2012;32(38):13010-21.
Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, Bush RA. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A. 2006;103(10):3896-901.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on September 14th, 2018