ARVO 2017 Day 2 Highlights

May 9, 2017

by Jennifer Phillips, Ph.D.

Today’s agenda was full of talks on potential therapies for RP. Quickie rundown:

Erwin van Wijk and colleagues at Radboud University Medical Center in the Netherlands have been doing great work on USH2A. They’ve had particular success in testing the effects of exon skipping, using molecular ‘roadblocks’ to skip over problematic mutations in the gene so that the USH-causing mistake in the DNA blueprint isn’t incorporated into the protein construction. This approach won’t work for every type of mutation, but there are several disease causing mutations in USH2A, that are good candidates for this kind of intervention. Getting the technique to work in human cells and testing the safety of the exon-skipping molecules are two important preclinical milestones that the van Wijk group is working on now. This is still years away from reality, if it continues on its current positive trend, but this ongoing research is a great argument for the USH community to pursue a genetic diagnosis. In most cases, USH patients have two different, disease causing things wrong with their two copies of a particular USH gene. One of the ‘perks’ of having a recessive genetic disorder is that in many cases a treatment designed to treat just one of those two problems should be sufficient to alleviate symptoms. It helps researchers to know how many people are out there who might benefit from this type of ‘allele-specific’ treatment approach, not just when it comes time for clinical trials, but to guide preclinical research directions.

That point provides me with a pretty good segue to my second ‘highlight’ of the day—a wonderful talk by Neena Haider and colleagues at the Mass Eye & Ear Infirmary. Dr. Haider’s lab is working on multiple forms of RP, due to the fact that there are so many different genetic causes of this disorder.

On the whole, the RP research field is at a point where pursuing gene-specific or even allele- specific therapies are more possible than ever before, but may not always be practical from a research and development perspective. Moreover, genetic diagnoses are not possible for everyone with USH, or RP generally—the Unraveling USH initiative is a tremendous benefit to the community, but some of the rarer variants in our population might remain elusive. Add to this the complexities of varied genetic backgrounds within the population, confirmed and suspected genetic modifiers that can lessen or worsen the symptoms of a genetic disease, and other non-genetic contributors and it gets really complicated. The fact of this complexity and variation makes a strong argument that researching general treatments, in addition to the very specific ones that van Wijk and others are pursuing, is a most worthwhile endeavor.

The gene that Dr. Haider and team are investigating, called Nr2e3, is described as a ‘master modifier’. This gene has a broad range of regulatory jobs within photoreceptor cells, activating some factors while repressing others, and working to promote a general, balanced healthy cell environment known as homeostasis. One of the common denominators of RP, whatever the specific genetic cause, is the breakdown of this healthy environment that precedes photoreceptor degeneration. Haider and colleagues reasoned that increasing the function of Nr2e3 in the photoreceptors with defective RP genes might prevent the initial descent into cell degeneration and loss of visual function, and might also keep cells that had already begun the degeneration process to decline so quickly. They tested this ‘prevent and protect’ hypothesis on a wide range of mouse models with diverse genetic causes of RP and found positive effects on all of them, which is really promising. They also tested whether added Nr2e3 was affecting cell homeostasis, and found convincing evidence that it was.

This work is really exciting, as it could offer a viable alternative to gene-specific therapies, and I’ll look forward to following the story as it, hopefully, moves into clinical testing.

There’s much to do and see tomorrow, and I’ll write it up for you here at the end of the day.

Thanks for reading!

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