By Grace Rangel, YC 2025 

For decades, the lymphatic vascular system—a critical network that drains cellular waste and maintains immune balance—has been overlooked in biomedical research. Enter Rho Bio, a groundbreaking biotech startup spun out of Yale, poised to change that narrative and position itself as the leader in lymphatic biology innovation.

With roots in transformative discoveries by its scientific founders, Rho Bio is built on a series of game-changing insights. In 2015, neuroscientist and immunologist Jonathan Kipnis, PhD revealed the presence of lymphatic vessels in the brain, reshaping the understanding of neurodegenerative diseases like Alzheimer’s. In 2020, Eric Song MED ’22, MD, PhD and Akiko Iwasaki, PhD described a method of harnessing the same lymphatic vessels to better treat immunologically silent brain tumors. This year, Song (Rho Bio’s lead principal investigator), identified lymphatics associated with the eye, opening new frontiers for therapeutic breakthroughs. Together, these milestones form the foundation of Rho Bio’s mission to harness lymphatic biology for medical innovation.

Making Connections with Yale Ventures, Entrepreneurship, and Beyond

Rho Bio’s journey began in the Yale innovation hub. Iwasaki, Yale Sterling Professor of Immunobiology at the Yale School of Medicine, served as Song’s advisor during his MD-PhD training in her lab, where they uncovered new insights into the lymphatic system. During this time, Song also partnered with serial entrepreneur Aaron Ring YC ‘08, MD, PhD, then a professor at Yale Immunobiology, to develop a protein capable of selectively modulating the lymphatic system. As they worked on modulating the meningeal lymphatics, it was a natural outreach and collaboration to begin work with Kipnis at Washington University in St. Louis. Iwasaki, Ring, and Kipnis are a part of Rho Bio’s founding scientific team.

“Yale Ventures has been through it with us, from the very beginning, helping us with everything from IP management to introductions to different funders… it’s very helpful to have them by our side,” says Song.

Song also highlights the importance of embracing the discovery process. “It takes a lot of patience, but it’s so exciting because every little thing you do is kind of new. And you’re moving things forward, and exploring the unknown, which I think is the real beauty of science.”

Rho Bio is navigating uncharted waters, with the potential to transform the lives of millions affected by immunological diseases that currently have no drug treatments. At the same time, it is advancing the scientific understanding of the lymphatic system.

“[We’re] going to continue to grow that base of knowledge of what happens [when] we upregulate the lymphatic system… [and] what it means for human health,” Song explains.

With a diverse team of scientific founders from Yale, the Fred Hutchinson Cancer Center, and Washington University in St. Louis, Rho Bio aims to redefine how the pharmaceutical market approaches the lymphatic system and its broader role in human disease.

Photo (clockwise from top left): Eric Song, MED ’22, MD, PhD; Aaron Ring YC ‘08, MD, PhD; Jonathan Kipnis, PhD; Akiko Iwasaki, PhD

The Science Behind Rho Bio

The major scientific hurdle in developing a therapeutic for the lymphatic system has been specific targeting of its main regulator: VEGFR3. VEGFR3 engagement in the short term can increase lymphatic pumping and in the long term stimulates lymphangiogenesis, the growth of new lymphatic vessels. It’s activation is dependent upon the growth factor protein known as VEGF-C. However, VEGF-C can also activate a second receptor VEGFR2, which promotes the process of angiogenesis - a major factor in cancer growth and pathogenesis of debilitating conditions like macular degeneration and diabetic retinopathy. Despite 25 years of research, no drug molecule has specifically targeted the VEGFR3 receptor – until now.

Ring, who specializes in protein engineering, helped develop the mutant protein, LS-VEGF-C, via a method called directed evolution. So far, LS-VEGF-C has proven to specifically target VEGFR3 and enable disease modulation in multiple animal models: including decreases in eye pressure in glaucoma model, drainage of fluid in the retina, and revitalization of lymphatic drainage in a lymphedema model.

With this new lymphatic activator Rho Bio is poised to treat the many diseases that result from a dysfunctional lymphatic system.  

Broad Applications

“We really want to broaden our knowledge about the central nervous system and see how we can use this molecule to help diseases of the brain [and the eyes],” says Song.

Rho Bio’s initial focus is on treating eye diseases characterized by fluid retention and retinal degeneration. This work builds on Song’s groundbreaking discovery of lymphatics at the back of the eye, with the potential to demonstrate early neuroprotective effects. Beyond ophthalmology, the team is exploring additional therapeutic applications for Alzheimer’s disease and lymphedema.

Recent findings from Kipnis’s group and others suggest that the lymphatic system could play a pivotal role in addressing Alzheimer’s and other neurodegenerative diseases. Rho Bio’s innovative approach offers the possibility of forging new pathways to treat these debilitating, currently incurable conditions. Similarly, in lymphedema, where treatment options are limited to physical interventions like lymphatic massages or compression devices, Rho Bio’s work provides hope for the development of a targeted pharmacologic therapy.

This progress comes at a critical moment for the field of lymphatic biology, which is gaining momentum with increased attention and funding, including federal initiatives like ARPA-H to support lymphatic research. Positioned at the forefront of this growing field, Rho Bio aims to deliver the first lymphatic activator to patients, reshaping the treatment landscape for many chronic diseases.