The Department of Ophthalmology at NewYork-Presbyterian and Columbia has been on the forefront of ophthalmic care since 1866, when prominent New York ophthalmologist and otolaryngologist Cornelius R. Agnew, M.D., established an ophthalmology clinic at the future Columbia University Vagelos College of Physicians and Surgeons. Over the century that followed, physicians and surgeons at the institution surpassed multiple milestones in the field, including performing one of the first human corneal transplants in the U.S. in 1933; establishing the first retina clinic in the world in 1958; performing the first human retina cell transplant in 1994; and more.
In recent years, that legacy of innovation has continued with Precision Ophthalmology™, a concept coined by the department a decade ago to describe its focus on incorporating precision medicine into ophthalmic practice by leveraging genetics, state-of-the-art diagnostics, and translational research to help develop personalized treatment plans for ophthalmic diseases and conditions.
“We combine foundational science with tools such as genome engineering, bioinformatics, and artificial intelligence to understand and leverage genetic patterns that allow us to accelerate going from ideas to actual therapies,” says Jack Cioffi, M.D., ophthalmologist-in-chief at NewYork-Presbyterian and Columbia and chair of the Department of Ophthalmology at Columbia. “We are driving the future of transformative treatments to tackle the most advanced diseases and help people restore or retain their vision.”
We combine foundational science with tools such as genome engineering, bioinformatics, and artificial intelligence to understand and leverage genetic patterns that allow us to accelerate going from ideas to actual therapies.
— Dr. Jack Cioffi
The Role of Genetics in Personalized Medicine
Discovering the genetic variations that affect the onset and progression of eye diseases is a core principle behind the department’s Applied Genetics Service, which was launched in 2019 and is one of the only programs of its kind in the New York region.
The department leads work to study the underlying genetics behind a range of diseases and conditions, including Stargardt disease, macular degeneration, and retinitis pigmentosa, and is uncovering new ways to approach gene therapy, imaging analysis, and ocular manifestations of inherited syndromes. Through the program, patients can undergo genetic testing and counseling and get connected to state-of-the art therapeutics and clinical trial options. Since its inception, the Applied Genetics team has successfully sequenced more than 1,000 patient samples, provided more than 2,000 genetic counseling sessions, and has identified patients with variants in more than 300 genes.
Researchers remain committed to uncovering how genetic variations impact the onset and progression of eye diseases. The work of Simon John, Ph.D., for example, focuses on the metabolic and molecular mechanisms behind glaucoma; most recently his team developed a mouse model with mutations in Lmx1b, a key human glaucoma gene, to replicate human glaucoma and better study mechanisms of the condition. His team has also identified genetic underpinnings behind dysfunction in the trabecular meshwork and Schlemm’s canal, which can inform future treatment.
In recent years, advancements in gene therapy have also further opened possibilities for the treatment of ophthalmic diseases, with NewYork-Presbyterian and Columbia experts paving the way. In the lab of Stephen Tsang, M.D., Ph.D., an ophthalmic geneticist in the Applied Genetics Clinic and a global leader in inherited retinal disorder research, clinicians and researchers are studying the use of CRISPR-based gene-editing technology to treat dominant retinitis pigmentosa (RP), a leading inherited cause of blindness.
Dr. Tsang and his team have been able to demonstrate the promise of several in vivo CRISPR approaches in pre-clinical models, including an “ablate and replace” strategy, which excises a mutant allele and then delivers a functional replacement gene using adeno-associated viral vectors (AAVV); and using AAVV to edit the PHD2 gene to rejuvenate the eye’s glycolic metabolome and decelerate progression of RP.
CRISPR represents the ultimate implementation of precision medicine. As it becomes more widely available, virtually any mutation could be precisely targeted for treatment.
— Dr. Stephen Tsang
“CRISPR represents the ultimate implementation of precision medicine,” says Dr. Tsang. “It has shown effectiveness for both recessive and dominant disorders, which means that as CRISPR therapeutics become more widely available, virtually any mutation could be precisely targeted for treatment.”
Artificial Intelligence and the Future of Diagnostics
The vast amount of advanced imaging and data that is captured in ophthalmic practice makes the field ripe for blending data science, bioinformatics, and artificial intelligence to gain new clinical insights that can improve patient care. Machine learning models trained on patient data and image repositories can identify biomarkers for diseases like glaucoma and macular degeneration, predict disease progression, and help physicians personalize treatment strategies.
For instance, to better interpret optical coherence tomography (OCT) scans for glaucoma and other ocular diseases, Columbia researchers Donald Hood, Ph.D., and Emmanouil Tsamis, Ph.D., harnessed AI to develop the Hood-Tsamis (H-T) index, a logistic regression modeling metric that has been shown to detect damage from glaucoma better than conventional OCT metrics, which can be prone to both false positives and false negatives. The tool has the potential to improve referrals to glaucoma clinics and clinical trials and could aid ophthalmologists in diagnosis.
In 2022, demonstrating its commitment to expanding AI tools to support clinical decision-making, Columbia also launched the Artificial Intelligence for Vision Science (AI4VS) Lab under the direction of Kaveri Thakoor, Ph.D., who oversees a multidisciplinary research team of computer scientists and biomedical engineers who collaborate with ophthalmic specialists to test potential AI-assisted solutions.
Dr. Thakoor has worked on over a dozen projects with clinicians since the inception of AI4VS, and current projects include leveraging 3D OCT images to discover novel retinal anomalies in glaucoma and other ophthalmic diseases; developing an app that can use simple external digital photographs for early screening of thyroid eye disease, with Lora Dagi Glass, M.D.; and teaching trainees to improve their imaging interpretation through an AI model trained on tracking the gazes of experienced ophthalmologists, with Royce Chen, M.D.
“Our projects all start with a clinical question that a physician wants to solve,” says Dr. Thakoor. “I see AI as having the potential to be a teammate to clinicians, almost acting like a second opinion from a colleague or a corroboration on a complicated case.”
Optical coherence tomography provides a wealth of data that AI models can learn from.
Clinical Trials and Translational Research
One of the strengths of the Department of Ophthalmology at NewYork-Presbyterian and Columbia is the strong intersection between research and patient care. For more than a decade, the Clinical Trial Unit, co-directed by Lisa A. Hark, Ph.D., and Marzhan Atakulova, M.D., has participated in numerous trials evaluating novel therapeutics and diagnostics, including for glaucoma, inherited retinal diseases, retinoblastoma, melanoma, cornea abnormalities, and thyroid eye disease. Examples of clinical trials at NewYork-Presbyterian and Columbia include:
- NYC-SIGHT, a five-year randomized clinical trial led by Dr. Hark that screened more than 700 residents living in affordable housing developments in New York City and referred more than 400 people for an in-office eye exam, showing that patient navigators in underserved communities can improve attendance for in-office exams.
- The IDEAYA trial, a multicenter Phase 2 trial that evaluates darovasertib, a protein kinase C inhibitor, as a neoadjuvant therapy before enucleation for uveal melanoma; and the AURA trial, investigating nanoparticle-laser therapy for the early treatment of small uveal melanomas or indeterminate lesions, both led by Brian P. Marr, M.D., director of Ophthalmic Oncology and a global leader in treating eye cancers.
- A Phase 3 clinical trial led by Aakriti Garg Shukla, M.D., that evaluates the efficacy of long-term nicotinamide and pyruvate supplementation in slowing the progression of glaucoma and providing neuroprotection. Results from a prior Phase 2 randomized controlled trial showed the treatment helped improve the visual field of glaucoma patients.
- A Phase 3 clinical trial to test tinlarebant, a novel oral drug developed in the lab of Konstantin Petrukhin, Ph.D., that reduces vitamin A-based toxins for the treatment of Stargardt disease and dry age-related macular degeneration.
“Our ability to turn foundational science into translational clinical trials, and the volume of trials and research studies we conduct, allows us to bring innovative therapies to patients faster,” says Dr. Cioffi. “Bringing transformative vision treatments to people is our ultimate goal, and what allows us to do that is harnessing our strength in both research and clinical practice.”
