Translating research from bench to clinic

Testing a new cross-linking method for corneal infections

One such clinical trial effort is seen in the work of Jennifer Rose-Nussbaumer, MD, associate professor of ophthalmology, who has spent the past decade researching effective treatment for corneal infections and is currently leading clinical efforts focused on corneal ulcers.

A corneal ulcer is a painful, open sore that typically results from infection with bacteria, fungus or other pathogens. Fungal keratitis accounts for approximately 50% of ulcers in tropical regions, and while FDA-approved topical natamycin drops often are effective treatment, in serious cases, half of those patients will experience perforation or require corneal transplantation, which carries a high rate of rejection.

Rose-Nussbaumer collaborated with N. Venkatesh Prajna, DO, DN, FRCO, from Aravind Eye Hospital in southern India, and with the University of California, San Francisco, to discover alternative treatment methods. Together they found that out of two topical treatments, natamycin and voriconazole, natamycin-treated patients had better visual acuity. They then combined natamycin with a technology called corneal cross-linking with riboflavin that some clinicians have started using on patients, and found that it increased scarring when used for fungal keratitis. 

“There is an urgent need to discover new therapies so that patients don’t have to undergo corneal transplantation,” Rose-Nussbaumer said. “We have found that fungal corneal infections are harder to treat than bacterial infections and tend to have worse outcomes.”

To improve these outcomes, Rose-Nussbaumer and Prajna are now using funding from an NIH clinical research cooperative award to identify new treatments for corneal infections by testing patients in India with a new cross-linking treatment method for corneal infection called rose bengal photodynamic antimicrobial therapy (PDAT). PDAT is an alternative method that looks at fungal infections in vitro. They will compare PDAT’s effectiveness to PDAT combined with the topical natamycin treatment to see if it improves or worsens visual acuity outcomes.

“With this study, we can gain an understanding and then implement our findings quickly,” Rose-Nussbaumer said.

The eye-brain network

Our vision depends on more than our eyes. In fact, the brain and the optic nerve, which transmits visual images from the eye to the brain, together play a vital role in vision. Damage to this visual pathway, known as optic neuropathy, can affect visual acuity and if left untreated, can lead to vision loss.

Joyce Liao, MD, PhD, professor of ophthalmology and neurology, is leading and collaborating on various clinical trials aimed at understanding disease progression and treatment for optic neuropathies.

In a first-of-its-kind study, Liao is the principal investigator for a Stanford trial of over 400 study participants, examining the natural history and risk factors for ischemic optic neuropathy, optic disc drusen, and mitochondrial optic neuropathies, compared to control patients with no diseases.

“Our goal is to gain a deeper understanding of patient details with optic neuropathy damage so that we can better comprehend who is more likely to have fast disease progression and then develop treatment accordingly,” Liao said.

Liao, who is the director of the Stanford Center for Optic Disc Drusen at the Byers Eye Institute, has spent the past three years recruiting patients and collaborating with her colleagues at the Spencer Center for Vision Research at the Byers Eye Institute at Stanford. Together, they have done a deep phenotyping on patients who have lost vision from optic nerve diseases by examining biomarkers, including advanced imaging techniques as well as the molecular signatures found in bodily tissues and fluids that indicate the body’s response to disease and to disease treatment.

“Imaging allows us to see scans of the optic nerve in microscopic detail, and hopefully determine who is at risk of vision loss," Liao said.

By extending their research to include analysis of patients’ blood, they can better understand the patient’s genetic constitution and metabolism.  

“When we look at a patient’s metabolic state, we find there are proteins in the energy pathway that when deficient, can correlate with vision loss,” Liao said. “We are now translating those findings into a clinical trial—to combat vision loss, we are testing a particular combination of vitamins and antioxidants to protect the optic nerve.”

Liao’s team has also identified several promising novel genes that may be responsible for familial optic neuropathies, specifically dominant optic disc drusen. This was achieved after sequencing the genome of hundreds of patients, totaling over 11 trillion DNA base pairs. The combination of deep phenotyping of the disease and detailed genotypic analysis can provide a complete profile of disease and risk factors, leading to precision health and treatment to protect or restore vision.

“Moving forward, our hope is that these trials can move into treatment,” Liao said. “Ultimately, this work would not be possible without the support of generous donors and patients who have traveled long distances to participate in our studies.”

Discovering cures for retinal diseases

Yasir Sepah, MBBS, assistant professor of ophthalmology, is leading studies and collaborating with other department faculty on research related to retinal diseases, including diabetic retinopathy and AMD.

Sepah has spent the last eight years targeting diabetic macular edema, which occurs when high blood sugar causes continuous damage to blood vessels in the retina. Diabetic macular edema leads to loss of vision and is the leading cause for vision loss in diabetic retinopathy patients.

Currently, monthly eye injections are used to treat these patients, but only two-thirds of the patients respond well to it.

In collaboration with Quan Dong Nguyen, MD, MSc, professor of ophthalmology and Carolyn Pan, MD, clinical associate professor of ophthalmology, they are investigating disease pathology in molecular biomarkers to better understand why some patients are non-responsive to current therapies. They are initiating a new study to discover additional targets for therapy. One of these targets is interleukin 6 (IL-6), a protein that is produced in response to infections and tissue damage.

“IL-6 has shown to be responsible for the signs and symptoms of diabetic retinopathy in patients who do not respond to their current individual therapies that are out there,” Sepah said. "If we can identify what patients will develop vision-threatening diseases at an earlier stage, then we can intervene before the disease progresses too much. Studying IL-6 therapy for eye disease is a great example of how we’re moving discoveries into therapeutic testing at Stanford.” 

Prosthetic chip provides a breakthrough for macular degeneration patients

Nearly 20 years ago, Daniel Palanker, PhD, professor of ophthalmology, set out on a mission to restore vision for AMD patients. His solution was a photovoltaic retinal prosthesis he created, called PRIMA.

The PRIMA prosthetic system includes a microchip implant—which is self-sustaining and needs no wires for external power supply—inserted under the central retina. Each pixel in the implant converts light projected from transparent augmented-reality (AR) glasses into electric current to stimulate the inner retinal neurons, restoring vision in patients’ central blind spot.

Over the years, Palanker and his collaborators in the departments of ophthalmology and electrical engineering at Stanford have fine-tuned the implant, testing it ex vivo and in animal models of retinal degeneration.

In a clinical feasibility study published earlier this year, they found that AMD patients not only regained central vision in the blind spot, but their prosthetic visual perception was integrated with the natural peripheral vision. Prosthetic visual acuity closely matched the 100-micrometer pixel size of the implant, reaching up to 20/438, allowing them to see large letters. Using electronic magnification on AR glasses, visual acuity exceeded 20/100. 

“These findings are remarkable,” Palanker said. “We demonstrated feasibility of restoring form perception with a photovoltaic substitute of the lost photoreceptors.”

Steven Sanislo, MD, clinical professor of ophthalmology, who previously collaborated on macular degeneration research with Palanker, is now a primary investigator alongside Theodore Leng, MD, FACS, associate professor of ophthalmology, on a clinical trial utilizing the PRIMA system.

This study is sponsored by Pixium Vision, which commercialized the device. It is a second phase trial that builds off the above-mentioned feasibility trial. The study now includes three U.S. sites, and they are currently enrolling patients with visual acuity below 20/460.

“As Dr. Palanker continues to make improvements to the prosthetic chip, I am hopeful that the implant will not only help patients with macular degeneration, but other retinal diseases as well,” Sanislo said. Particularly, Sanislo would like to see the chip benefit those with retinitis pigmentosa, a group of rare genetic disorders that affect the retina in various ways. The most common symptoms include losing night vision and gradual peripheral vision loss, followed by the loss of central vision and color perception.

Palanker’s lab is working on the next generation of the implant with 20-micrometer pixels, aiming for visual acuity of 20/100 prior to any electronic magnification. “Success of the first-generation implant in patients and of the new chip with five times higher resolution in preclinical testing provide hope for patients, so we are excited and motivated to move forward,” Palanker said.

Stem cells show healing properties for macular degeneration

Leng is also leading other clinical trials focused on macular degeneration, including a new treatment approach using stem cells to restore lost vision.

Leng is studying a form of late-stage dry AMD known as geographic atrophy (GA). GA typically first begins in the central vision and causes the retina cells to waste away, resulting in a visual blind spot. Pharmacological drugs that can slow the growth of GA are on the cusp of coming to market, but they can only slow vision loss and cannot restore visual function.

In hopes of not only halting GA but reversing the effects of it, Leng is involved in three different research efforts looking at improving cell function.

The first is a research project at Stanford on product and cell development through grant funding from the California Institute of Regenerative Medicine. 

“We have harvested neural stem cells from brain tissue,” Leng said. “We are going through the process of manufacturing the cells in a manner compliant with the Good Manufacturing Practices as defined by the FDA, so that they can be used in human clinical trials.”

They are also testing the survivability and the functionality of the cells, finding that these cells can successfully restore visual function. Moving forward, they hope to enter a phase 1 human trial by 2024. This would entail doing surgery on enrolled patients by injecting these cells underneath the retina.

“The injected cells would secrete tiny hormones and growth factors that would restore function to the dying retinal nerve cells, allowing patients to see better again,” Leng said.

Leng is also leveraging his experience and expertise to help lead two phase one, first-in-human clinical trials replacing the cells from the outermost layer on the retina, the retinal pigment epithelium (RPE), and investigating ways to increase cell survival. RPE are responsible for keeping the light sensing cells functioning in the retina, but degenerate when a patient has GA. They began enrolling their first subject in fall of 2022.

“I am hopeful for all three of these studies,” Leng said. “For decades, cell-based therapies have shown to be effective for blood transfusions in hematologic oncology patients. This shows we have the technologies and methods to do cell-based therapies, we just have to transfer the same restorative patterns to the eye successfully.”

Light therapy for dry age-related macular degeneration

Diana Do, MD, professor of ophthalmology, has over 17 years of experience leading clinical trials geared towards
developing cutting-edge treatment for retinal diseases. Recently, Do has devoted a significant portion of her research effort to developing more effective treatments for AMD.

“When a person loses their central vision to AMD it can make it harder to read, see faces, or drive,” Do said. “The global prevalence of AMD is estimated to increase to 243 million by 2030, which is why my research team is committed to discovering further treatment routes.”

A new, promising therapy Do is testing is photobiomodulation (PBM) light therapy for dry AMD. This therapy uses low-level red and near infrared light to promote tissue healing, stimulate cellular function, and reduce inflammation. PBM light therapy can reduce both acute and chronic pain, and has been used in physiotherapy, arthritis, and wound repair.

Do is collaborating on this LIGHTSITE III clinical trial with other retina specialists and the medical device company LumiThera, serving as the principal investigator.

Together they conducted the trial at the Byers Eye Institute and nine additional collaborating U.S. retinal centers. They enrolled 100 subjects with intermediate dry AMD and an average age of 75 in a 2:1 ratio of PBM to sham (inactive) treatment. 

“Around month 13 our data showed a significant difference between our PBM group versus our sham group,” Do said. “We found that PBM provided a sustained and improved best corrected visual acuity—a very exciting step towards therapy for patients everywhere.”

Encouraged by these positive findings, Do and her collaborators plan to conduct additional studies to further evaluate PBM in AMD and other retinal disorders.

Introducing a new laser for LASIK surgery

Edward Manche, MD, professor of ophthalmology, has more than 27 years of experience conducting ophthalmic device and drug studies in the field of cornea and refractive surgery.

Laser surgery is commonly used as an alternative for patients who find that the use of glasses or contacts interfere with their quality of life, and can be used to address varying severities of nearsightedness, farsightedness, and astigmatism. Less appreciated, laser surgery is also used to correct and even prevent certain corneal diseases from progressing.

While laser and refractive surgery are well-established, Manche continues to be involved with clinical trial and research efforts aimed at identifying treatment advances, having conducted more than 25 U.S. FDA studies involving devices and drugs.

His most recent project is focused on a new excimer laser (a form of ultraviolet laser) from Carl Zeiss Meditec, Inc. known as the MEL-90 excimer laser. 

“This is the first new excimer laser being tested for use in the U.S. in more than 15 years,” Manche said. “The laser has been used successfully internationally for several years but needs to undergo a formal FDA trial to demonstrate safety, efficacy, and stability of the LASIK treatments.”

Nine sites are involved in the clinical trial, but Manche's study represents the only academic site in the group. Patient enrollment in the clinical trial is nearly complete with 404 patients enrolled to date.

While nothing has been published yet, the data is being collected and will be analyzed and submitted to the FDA for review, with an anticipated approval in 2023.  Upon approval, the laser can be commercially launched and available to treat patients in the U.S. 

“So far our findings are promising, and I am hopeful that the new technology will improve patient outcomes with an excellent safety profile,” Manche said.