Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Abstract

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.

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Citation

Published Version (Please cite this version)

10.1167/tvst.9.7.2

Publication Info

Thompson, Debra A, Alessandro Iannaccone, Robin R Ali, Vadim Y Arshavsky, Isabelle Audo, James WB Bainbridge, Cagri G Besirli, David G Birch, et al. (2020). Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium. Translational vision science & technology, 9(7). p. 2. 10.1167/tvst.9.7.2 Retrieved from https://hdl.handle.net/10161/23895.

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Scholars@Duke

Arshavsky

Vadim Y Arshavsky

Helena Rubinstein Foundation Distinguished Professor of Ophthalmology

The Biology and Pathophysiology of Vertebrate Photoreceptor Cells

Research conducted in our laboratory is dedicated to understanding how vision is performed on the molecular level. Most of our work is centered on vertebrate photoreceptor cells, which are sensory neurons responsible for light detection in the eye. Photoreceptors capture photons, produce an electrical signal, and transmit this information to the secondary neurons in the retina, and ultimately to the brain, through modulation of their synaptic release. 

The main experimental direction of our laboratory is to elucidate the cellular processes responsible for building the light-sensitive organelle of photoreceptor cells, called the outer segment, and for populating this organelle with proteins supporting its structure and conducting visual signaling. Of particular interest is the mechanism by which outer segments form their “disc” membrane stacks providing vast membrane surfaces for efficient photon capture. Outer segment membranes are continuously renewed throughout the lifetime of a photoreceptor, with new discs added to the outer segment base and old discs phagocytosed at the tip by the retinal pigment epithelium. As a result, the entire mammalian outer segment is replaced with new discs over the course of 8-10 days. One of the central goals of our current studies is to elucidate the signaling pathway that acts as a “control center” to initiate the formation of each new disc with the strikingly regular frequency of approximately 80 times per day. 

Our second major research direction explores a connection between understanding the basic function of rods and cones and practical, translational ideas aiming to ameliorate retinal degeneration caused by mutations in critical photoreceptor-specific proteins. Several years ago, we found that photoreceptors bearing a broad spectrum of disease-associated mutations suffer from a common cellular stress factor, proteasomal overload, i.e. insufficient ability of the ubiquitin-proteasome system to process misfolded and/or mislocalized proteins produced in these cells. Our more recent data demonstrate that the enhancement of protein degradation machinery in these cells causes a remarkable delay in the progression of photoreceptor degeneration. We continue investigating photoreceptor proteostasis in further mechanistic depth and seek optimal strategies to employ proteasomal activation as a means to ameliorate or cure inherited blindness. 

During our studies, we explore high-end applications of mass spectrometry-based proteomics and were the first laboratory adopting several advanced proteomic approaches to vision research. Of particular significance are the applications of so-called “label-free” quantitative proteomics for simultaneous elucidation of multiple protein distributions among different compartments of the photoreceptor cells and for identification of unique protein components of various photoreceptor membranes. Using label-free proteomics, we demonstrated that a small protein PRCD (progressive rod and cone degeneration) is a unique component of photoreceptor discs and subsequently identified several novel unique components of the plasma membrane enclosing the rod outer segment. Most recently, we adopted a highly efficient and accurate methodology for simultaneous absolute quantification of several dozen proteins, termed MS Western. This method allowed us to determine the precise molar ratio amongst all major functional and structural proteins residing in the light-sensitive outer segments of photoreceptor cells.


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