Innovation in Retina

David N. Zacks, MD, PhD

Innovation in Retina


David N. Zacks, MD, PhD

Getting to the root cause of vision loss.


Since it was initially formed in 1872 as one of the first university-based ophthalmology departments in the United States, what is now known as the Kellogg Eye Center of the University of Michigan has been a pioneer in some of the most important developments in eye care. These include the femtosecond laser, the cofounding of an early eye bank, the role of genetics in eye disease, and the first commercial implantations of the Argus II retinal prosthesis for patients afflicted with end-stage retinitis pigmentosa.

However, the research currently being conducted on photoreceptor cell death and its impact on vision loss by David N. Zacks, MD, PhD, and his spin-off company ONL Therapeutics (Ann Arbor, MI), may prove to be the most important ophthalmic research ever undertaken at the university. This work centers on Dr. Zacks’ more than 15 years of study of photoreceptor cell death and his conclusion that inhibiting the FAS pathway through medical intervention is key to stopping unwanted photoreceptor cell death (apoptosis) in retinal detachment, wet and dry AMD, geographic atrophy, and diabetic retinopathy.

Though the first human clinical trials of the company’s neuroprotective ONL1204 peptide drug are still at least a year away, Dr. Zacks and his team have already attracted a blue-ribbon scientific advisory board that has confidence the dramatic results attained in preclinical animal studies will be transferable to humans. The target for the initial trial is the 25,000 annual US cases of “macula-off” retinal detachment. This is an area of treatment for which surgical results have been excellent but visual outcomes almost uniformly poor, with average BCVA at one year after surgery at 20/70 – with many patients’ visual outcomes much worse than that.

David N. Zacks, MD, PhD

“The photoreceptor cell death that takes place between the time the retinal detachment occurs and the reattachment surgery is significant,” says Dr. Zacks. “That lost vision is not being regained. Our goal is to get our ONL1204 drug (an analog of the small-molecule peptide Met12) injected into the patient’s eye as quickly as possible to shut off the FAS pathway and stop the cell death, which should allow much better visual outcomes in retinal detachment surgery.”

Dr. Zacks says ONL1204 should also be able to provide neuroprotection in a range of retinal diseases, treating the root cause of vision loss, which is photoreceptor cell death. Overall, the potential market opportunity for the use of ONL1204 in a variety of indications exceeds $12 billion annually. The FDA has already given ONL1204 orphan drug designation.


For Dr. Zacks, the creation of ONL Therapeutics (ONL stands for outer nuclear layer) and the prospect of soon-to-begin clinical trials is the culmination of work that began when he was a medical student and developed a deep interest in visual physiology and sensory biology.

“Going into ophthalmology was a natural choice for me,” says Dr. Zacks. “It was the perfect fit for my research interests and offered just the right blend of clinical and research experiences.”

But whereas a group of brilliant young ophthalmologists studying the critical role of angiogenesis in retinal disease coalesced around the legendary Folkman Lab at Harvard on the 1990s, Dr. Zacks did not initially attract a large following to the concept of developing neuroprotectives for photoreceptor cells.

“My primary inspiration was the groundbreaking work of Dr. Steven Fisher, PhD, who is currently professor emeritus at the University of California at Santa Barbara,” says Dr. Zacks. “He is a true pioneer in this field and I remember that just meeting him at ARVO was a big moment for me.”


As Dr. Zacks’ research on the role of the FAS pathway in photoreceptor cell death continued to progress, he accumulated a great deal of valuable intellectual property (IP) from his time at both Kellogg and previously at Mass Eye and Ear.

“I recognized that we had a potential therapy but I did not know how to make drugs and I knew that I needed help to move ahead,” says Dr. Zacks. “I got great support from my department and from the University of Michigan’s mentor-in-residence and technology transfer programs. At that point, we decided to form a company as the best way to move ahead and to ensure that all interests were aligned.”

ONL Therapeutics was formed in 2011. Dr. Zacks is an employee of the University of Michigan and the IP that’s related to his research is owned by the university, with some earlier IP owned by Mass Eye and Ear.

“As a university employee, I’m permitted to spend up to 20 percent of my time on outside activities, largely ONL,” says Dr. Zacks. “I would say I spend about 10 percent on ONL. We have a CEO, John Freshley, who has a great deal of experience in biotech startups. We have three full-time employees and about 15 people working on various projects. I’m not hindered at all in my research. It’s exciting. It’s stimulating, a good situation.”

Dr. Zacks says that one of the advantages of the academic-industry partnership is that he can call on the vast resources of the university for consultants with special expertise if and when he needs them.


Thus far, ONL’s rather modest funding needs have been covered by seed funding from the University of Michigan, a couple of Small Business Innovation Research (SBIR) grants, and significant investment from local “angels.” However, conducting a clinical trial will require millions more in funding and the company may have to turn to new sources such as venture capital.

ONL is now working on a study design for the retinal detachment trial. It will not be simple, as many retinal detachment patients are seen within hours while others wait days for their surgery. Will ONL1204 have a different level of effectiveness if the patient has to wait three days to receive an injection? RP