Curing Blindness using Stem Cells A Whitepaper for the Campaign Steering Committee

THE VISION Vision is, without a doubt, one of our most precious senses. With 40% of the brain devoted to vision and visual processing, the ability to see the world around us is crucial to the quality of life that we enjoy. Yet as remarkable as it is, the visual system is vulnerable to injury, disease and aging. Among the most difficult vision health challenges are those stemming from the retina— blindness from retinal problems is a leading cause of visual disability in the United States and worldwide. Using stem cells to restore eyesight would have a tremendous impact on patient care and mark a revolutionary advancement in regenerative medicine.

UC Davis is home to the world-class Ernest E. Tschannen Eye Center, the first in the country to obtain FDA approval to conduct adult stem cell treatment in patients with blindness from retinal disorders. We have already tested state-of-the-art techniques with autologous stem cells—cells which are taken from the patient’s own bone marrow and therefore have virtually no risk of rejection. In a promising recent clinical trial, this approach proved feasible without use of immunosuppressive medication. Some patients noted improved vision and none suffered inflammation, rejection or other side effects.

Now, we want to continue building on this important work. After some initial improvement, patients’ responses to treatment plateaued. Would higher doses of cells improve outcomes? Or increasing the frequency of treatments? Could a greater understanding of stem cells lead to non- cellular treatments that further lower the risk to patients? UC Davis is on the brink of discovering the answers to these and other critical questions.

UC Davis Health System has a vision to develop safe and effective stem cell therapies that will improve or restore sight in patients who are blind from retinal disorders, including diabetic retinopathy—the number one cause of adult blindness in the U.S.—as well as macular degeneration, retinitis pigmentosa, retinal vein occlusion and more. As the ideal model for validating the use of stem cell therapy in other systems, a breakthrough in regenerative cures for the eye would advance all other areas of regenerative medicine.

The visual system provides a window for understanding how stem cells work to heal the body. As a small and confined space, the eye loses far fewer cells to natural processes after stem cell application than other bodily systems, making it easier to maximize the effect of the cells. Most importantly, the eye permits us to directly view the behavior of the cells and the impact of the therapy. With leading-edge in vivo imaging tools, our interdisciplinary cadre of researchers is already unlocking the reparative powers of stem cells in both humans and animals. UC Davis is uniquely positioned to develop a robust, clinically relevant model for validating stem cell therapy in other systems and informing the broader field of regenerative medicine.

We have demonstrated that this stem cell therapy is feasible and without major safety concerns. A large-scale clinical trial will significantly advance regenerative therapies for patients with untreatable, blinding retinal conditions.

THE RIGHT TIME AND THE RIGHT PLACE Countless patients with irreversible vision loss are eager to try cell therapy. Not only would expanding on our recent work give these patients hope, we would also be able to better characterize how stem cells work so we can further enhance their beneficial effects on the retina.

Dr. Susanna Park, professor of ophthalmology at the Ernest E. Tschannen Eye Center, and colleagues across UC Davis have already achieved exciting progress in collaboration with one another and are poised to make a transformative impact. For example, her team developed a mouse model that showed human bone marrow cells appear to be safe long term after injection in the eye and appear to contribute to healing of the retinal blood vessels that had been damaged from a stroke. It was this study that was responsible for securing the FDA’s approval to pursue the eye center’s initial successful clinical trial.

UC Davis has become one of the premier centers for translational vision research in the country, spanning clinical and basic science, behavior and biology. It is one of the largest and best-funded biomedical research campuses in the world. Moreover, we have long fostered a culture of collaborative interdisciplinary research and are currently home to a growing pool of outstanding vision scientists.

The Ernest E. Tschannen Eye Center capitalizes on UC Davis’ capacity to bring together multidisciplinary teams of vision researchers—including veterinary ophthalmologists, neurobiologists, hematologists, imaging specialists and more—to develop promising new approaches in vision research. Our proposed clinical trial would include collaborative partners from the following colleges, schools and units:

 School of Veterinary Medicine The world’s number one veterinary school has generated new animal models and research paradigms that speed discovery of new therapies. Our veterinary ophthalmologists have established high-quality eye diagnostic instruments, such as electroretinography, for animal eye care. Their work allows us to measure the effects of stem cells on retinal function in animal eyes using the same methods that are used for eye center patients—bringing new treatments to clinical trials in a fraction of the time and at far less expense.

 Institute for Regenerative Cures After the passage of the California Stem Cell Research and Cures Act (Proposition 71), UC Davis established one of the most active and innovative stem cell research facilities in the nation: the Institute for Regenerative Cures (IRC).

The IRC is home to the nation’s second largest stem cell program, which provides leadership in bringing experimental therapies to patients for an impressive range of diseases. The IRC also oversees Northern California’s largest Good Manufacturing Practice (GMP) facility. This facility produces high-quality stem cell products for clinical applications. The proximity of the GMP facility greatly accelerates FDA approval to perform clinical trials using cell therapy.

 School of Medicine UC Davis’ nationally renowned School of Medicine provides the basic science research crucial to establishing strong evidence for our treatment strategies. By collaborating with top basic

2 scientists and using animal models of retinal disease, Dr. Park’s research team has been able to prove that there are tangible molecular-chemical changes that occur in the retina in response to cell therapy. Such studies validate the potential therapeutic effects of stem cell therapy we are noting in our study patients and provide scientific explanation for visual improvement seen among the first several patients treated with this cell therapy.

Leveraging state-of-the-art imaging equipment, researchers are able to study the retina at a cellular level in vivo. These imaging tools allow researchers and clinicians to study the effects of the treatment on the retinal cells as naturally as possible. For example, members of the Advanced Retinal Imaging Laboratory help us to visualize changes in the retina occurring at a cellular level in our study patients treated for macular degeneration. Instruments such as adaptive optics- optical coherence tomography, one of only a few in the world, will enable simultaneous assessment and imaging of individual retinal cells. Such tools are invaluable in testing the effects of therapeutic strategies for retinal diseases in animals and in humans.

The School of Medicine also established the Clinical Translational Science Center. This important facility provides resources, local guidance and oversight for clinician scientists to move translational research into clinical trials, ensuring research of the highest quality.

 Comprehensive Cancer Center Our National Cancer Institute-designated Comprehensive Cancer Center attracts the top cancer specialists in the country. Hematologists provide expertise in bone marrow aspiration so that stem cells can be harvested for eye treatments for patients enrolled in clinical trials.

THE OPPORTUNITY Imagine a grandmother being able to see her grandkids for the first time. Or a diabetic person who has suffered declining vision for over a decade finally being able to enjoy his favorite movies and hobbies again. Imagine the magnitude of the moment when someone who has lost the gift of sight is able to open his or her eyes and see again.

We are at a pivotal time in eye research. With a rapidly aging population and the rising incidence of a host of diseases that can cause vision loss, the need for life-changing research has never been greater.

UC Davis has developed a simple, five-minute procedure to inject the patient’s own stem cells in the eye. With minimal invasion, the stem cell vision scientists at UC Davis are achieving results equivalent to or better than those of higher-risk procedures. By purifying the patient’s stem cells at our GMP laboratory and injecting these cells into the patient’s eye, we create the conditions in the eye for natural healing to take place, perhaps in an accelerated manner.

Dr. Park’s team is exploring methods to enhance the effects of cell therapy on the retina, as well as non-cellular alternatives. A non-cellular approach may minimize the need for patients to undergo invasive procedures. We will also explore developing a drug that simulates the beneficial effects of stem cells. The ultimate goal is to make safe and effective treatments accessible to all.

3 MOVING FORWARD No physical space is needed.

The goal is to enroll five groups of 10 patients each to study the five most common blinding retinal conditions (hereditary retinal degeneration, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and retinal vein occlusion), for a total of 50 patients. The cost of administering the study treatment and conducting diagnostic tests would be $25,000 per patient, for a total projected cost of $1.25 million.

In addition, support to cover clinical trials salaries and the Clinical and Translational Science Center monitoring fee would be $500,000.

The total cost is estimated to be $1.75 million.

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