ARVO 2017 Day 4 Highlights

May 11, 2017

by Jennifer Phillips, Ph.D.

Defining “Failure”

The vast majority of ARVO presentations are on experiments that can fairly be described as successful: a new molecule that improves some clinical symptoms, a new test that can predict outcomes more accurately, etc. But disclosing when things don’t work and understanding WHY is a really important, though often overlooked realm of research. Here are a couple of USH1 research stories from today’s presentations that illustrate that point.

Lack of a reliable animal model for the retinal degeneration of USH1B has presented challenges for preclinical testing. The mouse model is particularly hard to work with because mouse photoreceptors have some key differences from those in mammals (and fish, and other critters that are active in daylight). In fact, the USH1B protein, called Myosin 7A, isn’t even present in the same retinal cells in mouse as it is in humans. Thus it’s not terribly surprising that mice lacking functional Myo7a protein don’t have the same retinal symptoms as human USH1B patients, but it does create a bit of a roadblock for preclinical work on this gene.

Seeking a way to test efficacy of a new viral delivery system of an USH1B rescue therapy, Kaitlyn Calabro and colleagues at the University of Florida presented work describing the development of a number of tools and analytical methods to detect some ‘rescuable’ defect in the retinas of their Myo7a knockout mouse, but every factor they tested was completely normal. While in some sense this is undeniably discouraging, I maintain that these were valuable experiments that are important to share with the research community. The methods used in this study were beautiful, reliable, and told a clear story—the fact that the outcome did not validate the use of this mouse model in future therapeutic testing does not detract from the quality of the science. Clear definitions and descriptions of approaches that don’t work are of great benefit to researchers everywhere. The Myo7a knockout mouse is not a good model system for testing efficacy of gene therapies on retinal degeneration. Now that we know that we can focus our time, energy and money on pursuing ways to model rescue in other systems that will tell us what we need to know to get more USH1B treatments in the pipeline.

If I sound slightly overwrought about this, well, there’s a reason for that. My own presentation at ARVO today described highly rigorous and successful experiments that told a clear story of something that doesn’t work. As some of you know, we’ve been developing zebrafish models of USH1F for the past few years, with the long term goal of creating an animal model for testing therapies, but a short term goal of testing a particular type of therapy, in-frame exon skipping, as a potential treatment for the R245X mutation that causes so many cases of USH1F. Using CRISPR/Cas9 we made beautiful zebrafish models of R245X, in which the protein code terminates prematurely. We made corresponding zebrafish models that cleanly deleted the exon harboring the mutated amino acid code in R245X, thus avoiding the premature termination and leaving the rest of the protein intact. We collected loads of high quality data on the eye and ear symptoms in fish larvae with truncating mutations versus exon deletions, and…we found that the exon deletion did not improve the symptoms at all.

Is it frustrating that the first thing we tried probably isn’t going to pan out as a therapy? Sure. But these experiments taught us a whole lot of new things about how to work with this target for gene therapy development, and that’s significant. It took us a relatively short time to create these models and do the analysis. With the question asked and answered, we can now move on to test alternative types of therapies, using the various tools and models that we have already developed. Science works. Science will solve this.

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