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All You Need to Know About the Usher Syndrome and Related Disorders Conference, Part I: Potential Therapies

June 7, 2010

by Mark Dunning

Valencia, Spain is beautiful. I have to confess with my America centric view of the world I knew nothing about Valencia, outside of their football club. Incredible architecture, parks, beaches, and food. Wonderful place. The conference was held in La Ciudad de las Artes y las Ciencias (The city of arts and sciences) in the auditorium of the Science building. It was a great facility for a conference.

The hosts, too, were wonderful. Dr. Jose Millan and his staff deserve a lot of credit for putting on such an event. It's nice to know that Usher families have folks like them looking out for them.

The conference was enlightening and, at times, exciting. I'll give you as brief a summary of the two and half days as I can, highlighting what you really need to know.

The conference was broken in to multiple sessions. I'll go through the first session on the first day in this post then discuss the other sessions in later posts. This session was on potential therapies, which is probably of the most interest to this audience.

Clinical Trials for CNTF for Retinitis Pigmentosa
Paul Sieving, M.D., Ph.D.
National Eye Institute

We've known about neurotrophic factors (of which CNTF is one) for a while. These compounds seem to keep the cells in the eye from degenerating. However, targeting therapeutic compounds to the eye is a tricky business, as there is a barrier between the blood and the retina that prevents most molecules from entering retinal cells.. You can't just take a shot in the arm, like with a vaccine, and necessarily have the treatment reach the retinal cells. So CNTF has been put in to this kind of capsule that can be put in to the eye via minor surgery. The capsule then releases the CNTF over time.

They have begun phase I clinical trials and Dr. Sieving presented the preliminary results. Ten patients were involved in the study. Five got a limited dose of CNTF and five got a higher dose. All patients in the trial had very limited vision. Not all of them had Usher syndrome but there were Usher syndrome type II patients in the study.

The results are still being collected and analyzed, but it seems like it helped improve the vision in at least some of the patients, who were able to read more letters on an eye chart after the treatment.

Why you care

This is about as exciting as the science of Usher gets. This is a potential treatment for the vision component of Usher syndrome that is in clinical trials right now and has demonstrated, at least initially, that it might help. There are still more phases to go before this is available as a treatment, but it's promising enough that the Director of NEI wanted to talk about it.

Neuroprotective Effects of TUDCA and Safranal
Nicolas Cuenca
University of Alicante, Spain

Like CNTF, TUDCA and safranal both seem to have the ability to protect photoreceptor cells from degenerating. TUDCA is bear bile and has been used in traditional Chinese medicine as a treatment for eye and liver disease for centuries. Safranal is the stuff that turns rice yellow in paella (can you tell I was just in Spain?). Dr. Cuenca has found that treatment with TUDCA and safranal has slowed cell death in rat's with retinal degeneration.

Why you care

This, too, is pretty exciting stuff. The research is farther away from helping families than the CNTF research and the doses used in the study were very, very high. Much higher than you'd want to take. But it did help. More studies need to be done, but it's promising. However, until more studies are done, please don't stuff yourself or your kid full of TUDCA. We don't know enough about it. You might want to think about adding some more yellow rice to your diet, however. Any excuse to eat more paella is good with me.

The Use of Aminoglycosides as a Therapy for Usher Syndrome
Tamar Ben-Yosef
Technion-Isreal Institute of Technology, Haifa, Israel

Let me see if I can do this topic justice. Usher syndrome is caused by mutations in DNA. DNA contains the instructions on how to build certain proteins. If the instructions are wrong, you get a bad protein and cells don't work properly. There are different ways to screw up instructions (just ask my wife when she sends me to the grocery store). One particular type of mutation is called a nonsense mutation. Basically these are periods in a sentence where they shouldn't be. So when my wife says 'pick up milk and bread PERIOD' I hear 'pick up milk PERIOD' and screw up the instructions.

Aminoglycosides are drugs that allow a 'read through' of that misplaced period, hopefully allowing the full instructions on how to build a particular protein to be read.

There are some aminoglycosides that are commercially available today. The problem is that they are often toxic at the levels necessary to get the desired read-through result. Dr. Ben-Yosef has found some compounds that are more effective in getting a read through effect while reducing the toxicity. Unfortunately at the moment none of these compounds seem to work with nonsense mutations in Usher.

Why you care

If you or your family member has a nonsense mutation, you care a lot. This has the potential to treat your Usher syndrome by simply taking a pill. However, this is still in the theory stage. It hasn't even helped treat Usher in an animal model yet.

Gene Therapy for Usher syndrome Type 1B
David Williams
Jules Stein Eye Institute, UCLA School of Medicine

Jennifer has explained gene therapy much better than I can here and here. Just to give a quick synopsis, gene therapy is the act of overriding bad instructions within DNA by supplying a new set of good instructions. So going back to my wife example, she could override the entire bad instruction of 'go sit on the couch and watch TV' with the good string 'go downstairs and do the laundry'.

This is accomplished by using a virus to 'infect' the cells with the new DNA. The problem is that different genes are different sizes and viruses are like airplanes in that they have a limited payload that they can carry. There are also only a limited number of viruses that can be used in gene therapy. The virus has to be safe and not cause other problems.

One virus known to be safe is the HIV-1 lentivirus. Dr. Williams and his team have found that this virus can be stuffed with a good copy of the MYO7-A gene that causes Usher type 1b and that it can deliver that gene to cells.

Why you care

I care a lot because my daughter has type 1B. This proves that a safe virus can be used to deliver a good copy of the type 1B gene. This is an important step in moving toward clinical trials. In fact, there aren't too many more steps before we get there. Right now the hope is that Phase I clinical trials will begin in mid-2011. By the way, this estimated date was not discussed at this conference but comes from a discussion had with Dr. Stephen Rose in a Coalition for Usher Syndrome Conference Call a while back. In other words, don't write it in your calendar just yet.

USH1C Therapy Strategies in the Retina
Kerstin Nagel-Wolfrum
Johannes Gutenberg University of Mainz, Germany

The two previous subjects, those of aminoglycosides and gene therapy, were both discussed in this session as potential therapies for Usher type 1C. Preliminary data show that the gene can be delivered via a virus, which is good news for gene therapy as an option. Also 20% of all Usher cases are nonsense mutations and a particular aminoglycoside called PTC124 seemed to show promise in clinical trials for non-eye diseases.

Why you care

This is similarly good news for Usher 1C patients. While no particular date for clinical trials of gene therapy for Usher 1C were discussed, things are looking as promising for gene therapy in type 1C as they are for type 1B. On the aminoglycoside front, this just reiterated much of what Dr. Ben-Yosef had said but with a focus on Usher 1C.

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