Visualizing a Cure

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A Proposal for the Hear See Hope Foundation

Understanding Cone Degeneration in Usher Syndrome And Retinitis Pigmentosa
Within the retina, photoreceptors make up one of the most important and most vulnerable cell classes afflicted by retinal degenerative diseases, like those present in Usher syndrome patients. Drs. Jennifer Chao and Ramukar Sabesan, clinical and research faculty at the UW Medicine Eye Institute and Vision Sciences Center, are collaborating on a new approach to visualize what happens to the photoreceptors damaged by retinal degeneration using high-resolution advanced adaptive optics imaging – a next generation technology developed in our labs. This research is critical to advancing our understanding of these diseases and whether potential therapies aimed at preserving and restoring central vision to patients will be successful.

Research Summary

  • The goal of this research project is to better understand the mechanism of how central vision is affected in patients with Usher Syndrome and Retinitis Pigmentosa (RP) using our high-resolution adaptive optics imaging system.
  • Drs. Chao and Sabesan hypothesize that in patients with Usher Syndrome and RP, the cone photoreceptors (those responsible for our central vision) have impaired function early in the disease process — before there is loss of central vision — due to starvation of the cells.
  • At the UW Medicine Vision Sciences Center, we have designed and built an adaptive optics imaging system that can detect, measure, and map the structure and function of cone photoreceptors at an individual cell level in a living human eye.
  • With this new technology, we are now able to detect whether non-functional cone photoreceptors are present, and if they are capable of being stimulated.
  • Ultimately, this study will help us to determine whether potential therapies aimed at preserving and restoring central vision in patients with Usher Syndrome and RP will be successful.

A New Approach For Usher Syndrome
Recent approaches to treating diseases such as Usher Syndrome or RP include the use of stem cell transplants of photoreceptors, gene therapy, and chemical reanimation. However, a fundamental issue in understanding these diseases and translating potential therapies to patients is the ability to visualize their effectiveness at restoring function at the individual cell level. Until recently, the ability to study individual photoreceptor cell function in patients has been a challenge in the field because of the eye’s unique optics and because the retina is constantly moving.

The UW Medicine Eye Institute and Vision Sciences Center is one of only a few institutions in the United States to have designed and built an adaptive optics imaging system capable of imaging the human retina at a singular cellular level. Furthermore, our adaptive optics equipment has the ability to fix an image on the retina, allowing scientists to study cells that are not functioning properly and explore opportunities to stimulate those cells and measure the effects of any treatment with extreme precision.

Figure 1: Human foveal cone mosaic imaged with adaptive optics imaging system in the Sabesan lab. A) and B) are reflectance images with illumination centered at 543nm and 840nm respectively. Each spot denotes a cone photoreceptor and is about 2-4 microns in diameter. The scale bar is 20 microns.

Drs. Chao and Sabesan theorize that in patients with Usher Syndrome and RP, the central cones show signs of disruption in their structure and function before it is clinically noticeable. Several recent studies have shown that the loss of central cone function may be caused by the “starvation” of the cells following the loss of their rod photoreceptor counterparts. Using animal models with RP, researchers have shown that they can reverse some of the damage seen in cones and even restore their functionality with an injection of glucose into the subretinal space (4) (5) (6).

Using our adaptive optics imaging equipment, we propose to map the progression of cone photoreceptor dysfunction in patients with Usher syndrome and RP in order to gain a more complete picture of disease etiology, progression, and possibilities for clinical intervention. In addition, we also seek to demonstrate that cone photoreceptors are only dormant in Usher and RP patients and not completely lost. This finding in patients would confirm what has been observed in animal models and open up new avenues of research for the therapeutic reanimation of cones. The presence of dormant cones would that mean either preserving or restoring central vision in patients with late stage Usher Syndrome or RP is possible.

This new collaboration between the Chao and Sabesan Labs is an opportunity to test the feasibility of conducting these imaging studies in patients with a broad array of retinal diseases, such as will be possible in our new Retina Center at UW Medicine opening in 2018. This proposal is fundamentally distinct from the current efforts of both labs and is a natural next step in our pursuit to translate new therapies developed in the lab to new cures that can be administered clinically. With the results of this research, we intend to apply for federal NIH funding and other private grants in order to support continuing research in this new and promising area of study.

Budget
We have received initial funding support for this project from a Latham Vision Research Innovation Award, which was granted by the UW Medicine Department of Ophthalmology in August 2017.

 

With additional pilot funding of $25,000 or more from the Hear See Hope Foundation, we will be able to fund a portion of a salary for a research assistant for one year to aid in patient enrollment, image acquisition, analysis and interpretation of the data, and manuscript preparation. Additionally, these funds will be used towards the purchase of two new detectors that will allow us to acquire images of cone photoreceptors inner segments in Usher and RP patients.

We estimate that the full study will take three years to complete, with a total cost of $225,000. We envision this project as the beginning of a new field of research that will be ongoing at the UW Eye Institute and Retina Center. This funding will support the salary for a full-time research assistant ($60,000, including benefits) for three years, as well as provide partial salary for a clinical trials coordinator. It will also completely equip our current adaptive optics imaging equipment with the hardware needed to acquire images of cone inner segments or dormant cones ($30,000).

Thank You!
We are grateful for the past support of the Hear See Hope Foundation and we look forward to discussing this new proposal with you. Please feel free to contact Abbey Norris, director for philanthropy, at 206.221.8274 or abbeyn@uw.edu with any questions.

Thank you for your consideration of this request.

REFERENCES

  1. Sabesan R, Schmidt BP, Tuten WS, & Roorda A (2016) The elementary representation of spatial and color vision in the human retina. Sci Adv 2(9):e1600797.
  2. Wang Q, et al. (2015) Adaptive optics microperimetry and OCT images show preserved function and recovery of cone visibility in macular telangiectasia type 2 retinal lesions. Invest Ophthalmol Vis Sci 56(2):778-786.
  3. Tu JH, et al. (2017) Dysflective cones: Visual function and cone reflectivity in long-term follow-up of acute bilateral foveolitis. American Journal of Ophthalmology Case Reports 7:14-19.
  4. Du J, et al. (2016) Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina. J Biol Chem 291(9):4698-4710.
  5. Punzo C, Kornacker K, & Cepko CL (2009) Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 12(1):44-52.
  6. Wang W, et al. (2016) Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa. Cell Rep 15(2):372-385.

UW Medicine Eye Institute and the Hear See Hope Foundation

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Restoring Vision Loss Caused by Usher Syndrome

It is estimated that between 30,000 and 50,000 people in the United States suffer from Usher syndrome, a genetic disorder that causes deafness and blindness. Children with Usher syndrome are born with, or may develop, hearing loss. Then, as these children get older, they develop night blindness and their visual field narrows, creating “tunnel vision.” There are currently no treatments for Usher syndrome, but stem cell therapy holds great promise for restoring sight and benefiting patients worldwide.

The UW Medicine Eye Institute, the only academic Eye Institute in the five-state WWAMI region (Washington, Wyoming, Alaska, Montana and Idaho), is at the frontier of developing new techniques to restore vision loss utilizing stem cell therapy. Building on a depth of research expertise, clinicians and scientists at our institute have partnered with the Hear See Hope Foundation to develop treatments for vision loss caused by Usher syndrome. We welcome your partnership to advance this innovative research.

Advancing Stem Cell Therapy
Jennifer Chao, M.D., Ph.D., assistant professor in UW Medicine’s Department of Ophthalmology, utilizes a special technique to create undifferentiated stem cells from a patient’s own skin or blood cells. These stem cells, called induced pluripotent stem cells (iPSCs), contain a person’s entire genome and can be programmed to become almost any other cell in the body. Dr. Chao, in collaboration with Tom Reh, Ph.D., professor in the Department of Biological Structure, converts these iPSCs into retinal cells that are genetically identical to those found in the patient’s eye. Once the iPSCs have been grown into millions of copies of patient-specific retinal cells, high-throughput screening technology tests thousands of compounds on the cells in an effort to determine which of these compounds help the cells to survive. This process, called “cell rescue,” is a groundbreaking technique that could help identify already FDA-approved drugs capable of stopping or slowing the progression of vision loss in patients with Usher syndrome or other retinal degenerative diseases. While animal models exist for many other degenerative retinal diseases, this is not the case for Usher syndrome. This means that traditional basic research techniques used to test hypotheses in animal models cannot be performed for Usher syndrome. However, new techniques are being developed at UW Medicine to produce improved patient-derived cell culture models of Usher syndrome and other degenerative diseases to accelerate research. With UW Medicine’s streamlined approach, and our strong partnership with the Hear See Hope Foundation, we believe an effective cure will soon be made available to patients.

The Potential of Cell Rescue — From Concept to Cure
In 2013, the Chao Lab performed the first high-throughput screening of stem cells from patients with age-related macular degeneration (AMD). This proof-of-concept study demonstrated promising results: multiple compounds were found to have therapeutic effects, facilitating cell rescue. We are now in the process of understanding the biological mechanisms of the cell rescue, as well as the dosing of potential therapeutic compounds. In 2015, with support from the Hear See Hope Foundation, the UW Medicine Eye Institute will begin using this same method to test stem cells derived from Usher syndrome patients.

Opportunities to Invest
We can accelerate the pace of research aimed at slowing or stopping vision loss in Usher syndrome patients with your philanthropic investment. Support of the UW Medicine Eye Institute will advance:

  • Research associated with collecting and growing millions of Usher syndrome patient-specific stem cells, as well as use of the high-throughput screening equipment to test potential treatments. $500,000
  • New studies of the mechanisms, dosing and bio-availability of potentially therapeutic compounds identified through high-throughput screening. $500,000
  • Implementation of advanced imaging technology — available only at UW Medicine — for understanding the retinal degeneration caused by Usher syndrome and assessing the effectiveness of new treatments. $150,000
  • Devoted Usher syndrome research support via part-time or full-time post-doctorate fellows. $40,000 to 60,000 per year

Join Us
By investing in our partnership, you can advance groundbreaking research that will bring hope for a cure to the thousands of children and individuals suffering from Usher syndrome worldwide.

To learn more, please contact Abbey Norris, director for philanthropy at UW Medicine, at 206.221.8274 or abbeyn@uw.edu. Thank you for your interest.

More Hope than Ever!

Breaking research news – Gene Therapy provides vision to nearly blind young adults” Three young adults with virtually no vision can now read several lines on an eye chart and see better in dimly lit settings thanks to an innovative gene therapy aiming to reverse blindness in a severe form of retinitis pigmentosa known as Leber congenital amaurosis or LCA. One person was even able to better navigate an obstacle course several weeks after receiving the therapy.

The three individuals are participating in a Phase I clinical trial at The Children’s Hospital of Philadelphia.

This is an incredible milestone in curing blindness, and this advancement will help pave the way for the development of gene therapies to treat and cure a variety of retinal diseases including Usher syndrome.

Doctors working on Usher syndrome research are working to extend this incredible breakthrough to Usher syndrome. There is great hope that clinical trials for similar gene therapy for Usher syndrome is right around the corner. Future funding is needed for this important research to continue.