Dispatches from ARVO 2013: Day 4

May 9, 2013

by Jennifer Phillips, Ph.D.

Whew! Day 4 is in the books, and what a day it was. I saw more excellent science presentations than I can count (and a few disappointing ones, too, but that’s a story for another day). I engaged in stimulating discussions about research directions throughout the day and managed to catch sight of a few Seattle landmarks while walking and talking with a colleague before hunkering down in my quaint little hotel room to write this up.

With such a wealth of excellent science to choose from, there’s no shortage of topics for this blog post, but in all honesty there isn’t much competition for the top spot, both in terms of relevance to our community of readers and sheer, take-your-breath-away brilliance.

At the end of yesterday’s post, I mentioned an upcoming talk on an USH2A patient study from the Tucker Stem Cell lab. Dr. Tucker has given several talks at ARVO this year about his stem cell research, and never fails to impress. The technical aspects of the science he and Dr. Ed Stone are conducting with induced pluripotent stem cells rank pretty high on the wow factor. Beyond that, though, Dr. Tucker’s approach to developing treatments for retinal degeneration is encouragingly comprehensive. On one of his introductory slides, he showed two overlapping graphs—one depicting the level of knowledge of a given disease, i.e. how much is known about the gene identity and function, and the other showing the degree of retinal degeneration suffered by the patient in a progressive disease. Superimposed on this were the different types of therapies that would best fit the degree of knowledge or degree of degeneration at any point on the continuum. For example, if we know what the causative gene is and how to work with it, AND the patient’s vision loss is still in the early stages, he or she would be a great candidate for gene replacement therapy. If, on the other hand, we don’t know much about the gene, or the patient’s degree of degeneration has advanced to the point where there are few healthy cells left to work with, cell replacement therapy, or even a retinal prosthesis would be a more beneficial approach. And, of course, there are many points along the spectrum in either direction with regard to genetic options and disease progression. This broad view of a multifaceted and time-dependent problem lays the groundwork for a customized approach to managing, and in time actually treating, the vision loss in Usher syndrome patients. 

The USH2A story Dr. Tucker presented today recounted the genetic identification of USH2A mutations in a patient with advanced retinal degeneration. We know from previous reports how challenging it can be to identify mutations that are actually causing disease in the background of the normal genetic variation on every human chromosome. How do you know if a change in the code is going to cause disease—how do you know when you’re finished looking for THE disease causing mutations? Animal models have been used to illuminate these answers, but stem cell cultures are becoming increasingly useful in this endeavor as well. Tucker and colleagues were able to study the two USH2A mutations from this patient in considerable, functional detail in cell cultures obtained from the patient's skin and induced to grow into retinal cells. Now, here’s where the converging graph model described above comes into play, as we step into the shoes of Tucker and colleagues and ask “What is the best targeted approach to treating this USH2A patient’s vision loss?” On the genetic side of things, we’ve learned a great deal about the exact nature of this patient’s mutations. We know how the mutations alter the normal shape of the Usherin (USH2A) protein, and what happens to the cells when poorly made Usherin is produced and can’t do its job. But remember the one especially challenging thing about the USH2A gene: It’s HUGE. Way too big for any of the currently available gene therapy delivery systems we’ve discussed here in the past. However, even if it were possible to deliver this incredibly large cargo, would gene replacement be the best choice for this patient? His retinal degeneration is advanced. Repairing the healthy cells, even if we were lucky enough to find a super-capacity delivery system, might not do him much good. The better choice would seem to be cell replacement, so if stem cell research continues apace, there is a possibility of introducing new, specified retinal cells into this patient’s eyes to repopulate the depleted photoreceptor layer. Implanting cells with normal copies of the USH2A gene would be a form of gene replacement as well, but Dr. Tucker made the interesting point that maybe gene replacement wouldn’t be needed. Retinal degeneration in Usher syndrome is fairly gradual. Implanting differentiated retinal cells obtained from the patient’s own donated cells might restore years of good—or at least improved—vision. Imagine a system in which your donated skin cells could tell your team of clinicians and researchers everything they needed to know about your disease genes AND provide the material to restore your vision. That’s powerful stuff, and the Tucker group has my profound admiration and thanks for taking us closer to that goal than we’ve ever been before. 

I’ll leave it there for tonight. There’s one last day of the conference tomorrow, and many more stories to tell, so check back for updates. As always, I welcome your comments, questions, and feedback.

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