Newsletter - Winter 2017
Dear Friends,
As 2017 draws to a close, I want to thank you for your continued support for the Usher III Initiative. Your help has made groundbreaking research possible, and gives us hope that a cure for Usher syndrome type III will soon be within our reach!
Through the Initiative’s funding, there have been great strides made in Usher III research. Scientists have determined that a defective Clarin-1 gene causes most instances of Usher III, leading to the production of a mutated protein, CLRN1N48K. And further research from scientists at Case Western Reserve University and BioFocus, published in the journal Nature Chemical Biology, led to the development of BF844, a small molecule that could potentially slow or stop the progression of Usher syndrome type III.
Integral to this discovery was Dr. Yoshikazu Imanishi, who led the team of researchers at Case Western Reserve. So, it is with great pride and admiration that I congratulate Dr. Imanishi for winning the 2017 Pisart Award for outstanding achievements in vision science research. His work made our small molecule possible, and we are so excited for the recognition of his scientific contributions. (Below this note, you will find a short interview with Dr. Imanishi.)
We are continuing our search for pharmaceutical partners interested in taking development of our small molecule to the next level, and in the past few months, have conducted targeted outreach to groups that have overlapping interests in protein folding research. We can also report that a larger production of BF844 is near completion, and our compound will soon be available to commence pre-IND FDA required testing to make sure our compound passes all safety regulations in order to be ready for clinical trials in humans
If you are wondering how you can help, I would like to urge members of the Usher community, and for anyone diagnosed with Retinitis Pigmentosa or degenerative hearing loss, to get genotyped and to enter their data into the Usher Syndrome Registry, a secure registry administered by the Usher Syndrome Coalition. For the development of any new drug, it is essential to have an identifiable patient population to attract the interest of the pharmaceutical industry and to assure the FDA that there will be adequate access to patients for clinical trials. By taking part in the Usher Syndrome Registry, individuals will put themselves in a better position to benefit from any potential treatments.
Last, but not least, if you are able to, please consider making a tax-deductible donation to the Usher III Initiative either online, here, or by mail to the address below. Thank you again for believing in our mission and for your continuing support. Happy holidays, and may the New Year bring you good health and good luck, and find you surrounded by friends and family!
Sincerely,
Cindy Elden
Co-founder, Usher III Initiative
AN INTERVIEW WITH YOSHIKAZU IMANISHI
Earlier this year, the Lighthouse Guild, the leading not-for-profit vision and healthcare organization, announced that Dr. Yoshikazu Imanishi would be the recipient of the 2017 Pisart Award. This annual award is given to a clinician or scientist who has made noteworthy and innovative contributions to the understanding of vision loss and treatment of eye disease.
Dr. Imanishi earned his PhD in 2000 from Osaka University in Japan, and is currently an associate professor in the Department of Pharmacology at the Case Western Reserve University School of Medicine in Cleveland, Ohio. His work has dramatically increased the understanding of the etiology of Usher syndrome for which he has discovered a potential cure. In pursing the goal of discovering new therapies for the disease, Dr. Imanishi has also invented a new method of drug screening, which is applicable to inherited disorders caused by protein-destabilizing gene mutations.
Q&A WITH DR. IMANISHI:
1) Congratulations on winning the Pisart Award! How does it feel to receive such positive recognition for your work?
This is one of the highest recognitions a mid-career vision scientist can receive. Looking at the stellar list of the past recipients, I was stunned. These recipients include renowned physicians and scientists such as Drs. David G. Cogan and Paul A. Sieving. Thus, I am very humbled by such a prestigious award. I feel fortunate to work with many talented scientists who are associated with the Usher III Initiative. Special thanks to the current and past members of my laboratory who contributed tremendously to the accomplishments recognized by the Pisart Award selection committee.
2) For all of us non-scientists out there, can you tell us a little about the research that you’re being recognized for?
Early in my career, I was studying vitamin A metabolism in the eye. Vitamin A is critical for our vision, and vitamin A deficiency can lead to blindness. During my earlier studies, I invented a method (U.S. Patent No. 7,706,863) to image structures and chemical reactions within the eye using fluorescence. Using this method, I discovered the structure in the eye to which we coined the name “retinosome.” Retinosomes are responsible for the storage of vitamin A in the eye. I am hoping that my imaging method will be used for early diagnosis of eye diseases in the near future.
More recently, I’ve also developed a technology to visualize protein transport and renewal within the eye. This technique is called “photoconversion technique.” The majority of inherited blinding disorders are caused by protein transport defects in retinal cells. The technique now allows us to study the mechanistic details of how these defects occur, how we can maintain our capabilities to see the light, and apply the knowledge from these studies to come up with a therapy for such diseases.
3) Your PhD is in biological sciences from Osaka University, and you are currently an associate professor in the Department of Pharmacology at Case Western Reserve University School of Medicine. How did you become interested in pharmacology and vision research?
I have been always interested in biology, and majored in physiology for my master’s degree and biological sciences for my PhD. Pharmacology is a major subdiscipline of biology, with the goal of modulating biological pathways, and thus I’ve been always interested in pharmacology since I was an undergraduate student. Vision research is especially fascinating to me, because it is very close to our daily life. We rely so much on our vision, but there are still a lot of unknowns about our ability to see light and maintaining such ability throughout our lifespan. We still don’t know much about what we are seeing with our eyes, and how our brains interpret the information from the eyes. Fascinated by these mysteries, I started my career as a vision scientist at the age of 21, when I was still an undergraduate student at the laboratory of Dr. Fumio Tokunaga, my graduate mentor. I was also attracted to the interdisciplinary nature of the vision research area. In Tokunaga’s lab, I was able to interact with hard-core physicists. Once joining Dr. Palczewski’s lab as a postdoc at the University of Washington, I was able to interact with professional chemists and biochemists. Their interdisciplinary interactions have been critical in developing my career as a vision scientist. Right now, I am interested in cell biological and pharmacological aspects of vision research. Ocular pharmacology has advanced tremendously in the past 10 years. It is probably one the most advanced areas in the pharmacological sciences, and thus, I am fortunate to work in such an active area of research. Hopefully, we will eventually come up with a cure for inherited blinding disorders such as retinitis pigmentosa. What was considered impossible 10 years ago is now becoming feasible, at least at the conceptual level.
4) And when and how did your interest in Usher syndrome begin?
I’ve been interested in Usher syndrome research since I was a graduate student two decades ago. But I really started to think seriously about Usher syndrome when I met Cindy Elden in 2006. Until then, my knowledge about Usher was all through reading literature. After meeting with Cindy, I attended the first international symposium on Usher Syndrome and Related Disorders, which was also held in 2006. There I was able to interact with Usher patients and active investigators in the field, and understand the unmet medical needs and the issues those patients encounter in real life. These interactions allowed me to think about how I could contribute to the field as a biologist. Meeting with Usher patients was a turning point in my research career.
5) Are you working on any new research projects, and if yes, can you talk a little about them?
I am currently interested in personalized medicine as well as more generally applicable medicine. BF844 is a small molecule which was discovered through concerted efforts of the Usher III Initiative. We can say, on one hand, this is an ultimate personalized medicine, which is designed for Usher syndrome type III patients with the CLRN1N48K mutation. BF844 was designed to increase the amount of CLRN1N48K protein, which is known to be extremely unstable. In our recent study published in Nature Chemical Biology, we found that BF844 is not directly binding to CLRN1N48K. Initially, we were disappointed by the finding, because we could not come up with a simple (low-hanging) answer to how the BF844 molecule works. But then, I realized that it was actually a good thing because BF844 binds to molecular chaperones, which can stabilize proteins other than CLRN1N48K. Usher syndrome type III is caused not only by CLRN1N48K, but also by various other mutations in the CLRN1 gene. We are currently testing the idea that those other mutant CLRN1 proteins could be stabilized by BF844, and we have obtained some encouraging results.
More broadly, BF844 is potentially useful to treat other inherited disorders. The majority of inherited disorders, if not all, are caused by missense mutations in disease associated genes. Those missense mutations frequently affect the structures of the proteins slightly, rendering them more unstable. BF844 is potentially useful to stabilize a subset of these proteins. As to the vision research field, inherited blinding disorders are often caused by missense mutations of genes. We are currently testing this idea to stabilize disease associated proteins using BF844.
6) Is there any Usher-related research out there that you find particularly interesting right now?
I am particularly interested in the roles of Usher causative gene products in maintaining the primary cilia, which is the structure seen in many cell types throughout our body. There are some interesting developments in this avenue of Usher-related research. Primary cilia are often referred to as “antennas of the cells.” In the case of photoreceptor cells, cilia are used to capture photons so that we can see light. Probably many, if not all, of Usher syndrome subtypes are caused by defective ciliary functions or structures.
Thus, in addition to the research projects mentioned in the question above, my laboratory is currently studying the general cause of photoreceptor degeneration in retinitis pigmentosa. Prior to the death of photoreceptor cells, those cells lose the ciliary structures, and the major protein of the cilia (called rhodopsin) becomes mislocalized to other sites of the cells. We are currently studying why those cells die because of rhodopsin mislocalization. Once we understand the mechanism, we will be able to design novel therapies that ameliorate either the mislocalization or the toxicity of mislocalized rhodopsin.