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.

2008/2009 Grants Funded

Vestibular Testing $40,000
Development of Cell-Based Therapies for Usher syndrome $52,000
Building a Foundation for Clinical Trials in Usher syndrome $60,000
Visual Field Modeling, Analysis, and Development of
Outcome Measures for Treatment Trials in Usher syndrome
$50,000

Development of Improved Visual Field Testing

Development of Improved Visual Field Testing as an Outcome Measure for Treatment Trials in Usher Syndrome (funded January 2007)

Grant Summary
Usher syndrome is a genetic condition causing both hearing loss and vision loss, and is the most common cause of deafblindness in the Western world.  Some individuals with Usher syndrome have moderate hearing loss, where others are born totally deaf.  With the advent and increasing availability of the cochlear implant, the hearing loss in Usher syndrome can be managed and even, in many cases, cured.  The vision loss in Usher syndrome, however, results from retinitis pigmentosa (RP), a progressive disorder of the retina for which there is no known cure or effective treatment.  The progressive vision loss resulting from RP is therefore the most disabling aspect of this condition.  Finding and delivering effective treatment for RP is the urgent mission of our research.

Accurate monitoring of retinal function in retinitis pigmentosa requires the use of several test methods, including assessment of the visual field and the electroretinogram (ERG).  The visual field test quantifies visual field loss, while the ERG measures the electrical impulses of the retina to quantify retinal cell function.  Over the last 30 years, the Oregon Retinal Degeneration Center (ORDC), under the direction of Dr. Richard Weleber, has become one of the premier centers in the world for the measurement and standardization of retinal function in RP.  As a direct result of Dr. Weleber’s passion and expertise, the ERG has evolved into a highly accurate, sensitive, and reproducible test method.  The visual field, however, while extremely informative, has a high degree of test-retest variability.  This variability decreases the utility of the visual field test in clinical treatment trials, where accurate, sensitive, and reproducible test measures are vital for monitoring treatment effectiveness.  In fact, the lack of acceptable visual field testing for retinal dysfunction is now a limiting factor in initiating clinical trials for RP and Usher syndrome.  Dr. Weleber has joined with Dr. Chris Johnson, an internationally known visual field expert with over 20 years of experience in glaucoma research and test development, to refine and develop visual field testing techniques specific to field loss in RP.

This study will assess and optimize computerized visual field test methods for patients with RP by addressing the following three specific aims: to ascertain the test-retest variability of visual field measurements in RP, to spatially characterize visual field losses specific to particular subtypes of RP (including Usher syndrome), and to develop novel testing algorithms that will enable us to move forward with clinical treatment trials.  At the conclusion of this study, we will publish our results and make recommendations to the scientific community regarding the best test strategy to use in multi-center clinical treatment trials.

Development of Methods of Usher Syndrome Gene Therapy

Development of Methods of Usher Syndrome Gene Therapy (funded January 2007)

Grant Summary
Usher syndrome is the commonest inherited cause of combined blindness and deafness.  The progressive vision loss is currently untreatable, although some hearing may be restored with cochlear implants.  Several gene mutations have been identified as causes of the disease, including mutations in the usherin, harmonin and myosin VIIa genes.  Gene therapy is a promising experimental treatment that has the potential to prevent the loss of hearing and sight in this devastating condition, but it needs to be developed and tested before it can be attempted in human patients.

The purpose of this application is to develop safe and effective gene therapy methods for Usher syndrome.  The long-term goal of this project is to facilitate human clinical trials of this therapy.  In this proposal, we have brought together a team of clinical and basic science researchers to accomplish the following goals:

(1) To design and produce a delivery system, using a harmless virus, to deliver the normal usherin, harmonin and myosin VIIa genes to the eye and the inner ear.

(2) To determine the best surgical techniques for safe and efficient delivery of this gene therapy vector to the eye and inner ear.  These studies will use a nonhuman primate, the rhesus monkey, because the structure of its eyes and ears are most similar to humans, and different in critical ways from other animals such as rodents.

(3) To test the safety of this gene therapy in monkeys by examining them for any possible side effects of the treatment.

There are no animal models that have Usher syndrome, and therefore it is not possible to test the ability of gene therapy to treat or prevent the disease.  However, these studies will be able to test the safety of this treatment in healthy animals.  Given the very serious nature of the disease and the potential benefit, clear evidence of safety would make it ethically acceptable to conduct a clinical study in human patients.
Through this project, we aim to provide the foundation for use of gene therapy for Usher syndrome.
We plan that this project will lead to the next steps required to initiate a gene therapy clinical trial:  manufacture of a safe vector suitable for a human patients, and, based on demonstration of the treatment’s safety, submission of the necessary regulatory documents to the FDA and other federal agencies.  With the experience and information derived from the proposed project, our team at the Casey Eye Institute can then build on its extensive patient base and experience with human clinical trials to bring this new therapy to patients with Usher Syndrome.

Population Genetic Studies of Usher Syndrome

Pilot Project of Population Genetic Studies of Usher Syndrome (funded January 2006)

Grant Summary:
The research is being conducted at the Oregon School of the Deaf in Salem, Oregon by Dr. William Kimberling from Boystown University. The goal of this study is to determine the frequencies of known Usher syndrome subtypes and their mutations in a deaf school population and in students with varied hearing losses in special education classes. This project is nearing completion and we received a synopsis of the study from the researchers at the First Annual Usher Syndrome Symposium in Omaha, Nebraska in October 2006.Ultimately, this information is important for many reasons, including increasing awareness of Usher syndrome, improving genetic testing strategies, providing earlier diagnosis, and identifying individuals as potential treatment candidates for future clinical trials. There is an opportunity that if the pilot project is successful, the National Institute of Health will award a 2.5 million dollar grant for the full screening project. This type of research gives us great hope for a cure.