Re-Setting the Epigenetic Clock To Reverse Cellular Aging
Epigenetic reprogramming restored vision in preclinical studies—the first clinical trial patient has now been dosed.
Aging—the progressive decline in our physiological function as we get older—is something many of us hope to slow, stop, or even reverse. Of course, this process is inevitable and something we cannot truly intervene with.
Until now.
Efforts to reverse cellular aging began decades ago, when researchers reprogrammed the epigenetic system—the genome’s instruction manual—back into a pluripotent state. The approach transformed adult cells into a blank slate, erasing epigenetic changes that occur over time, including those that contribute to aging.
This total reprogramming approach also enabled the transformed cells to differentiate into any cell type. While this ability is essential for the development of a growing fetus, in adults it leads to the production and proliferation of unwanted cell types in undesirable locations.
Researchers have since worked to restore aged cells to a youthful state without losing cellular identity. Today, partial epigenetic reprogramming (PER) can achieve this.
To learn more about PER and its potential, Technology Networks spoke with Dr. Sharon Rosenzweig-Lipson, chief scientific officer at Life Biosciences. Ahead of the first-in-human trial, investigating the application of ER-100 for optic neuropathies, Rosenzweig-Lipson discussed the underlying science and explained how this therapy could be “more than meets the eye” as indications extend beyond vision restoration.
What led you to pursue aging biology and rejuvenation therapies?
Sharon Rosenzweig-Lipson, PhD (SRL):
My scientific roots are in behavioral neuroscience, and I began my research career studying Alzheimer’s disease (AD). I focused on receptor-based changes in AD and targeting AD symptomatology. At AgeneBio, while working on an AD program that was rooted in aging biology rather than a more traditional endpoint, the idea that we needed to focus more broadly on aging biology to reverse and prevent age-related diseases began to resonate with me.
When I encountered the science of epigenetic restoration at Life Biosciences, it felt like a turning point. The approach had potential to restore cells across multiple cell types and organ systems to a more youthful state, rather than just manage individual disease symptoms. The prospect of targeting aging biology for cellular rejuvenation—via epigenetic restoration—was a tremendous scientific opportunity to transform how we reverse age-related disease, with immense potential to improve healthy aging.
IH:
What were the key scientific trade‑offs that led to a focus on partial rather than complete epigenetic reprogramming across the PER platform?
SRL:
Complete reprogramming using all four Yamanaka factors can take a cell all the way back to a pluripotent, embryonic-like state. This sounds powerful, but it is therapeutically a problem. When all four factors are injected into animals, unless done very briefly, teratomas form because the cells lose their identity.
Yamanka factors
Yamanaka factors are a group of proteins capable of “rewinding” the genetic clock of cells, reprogramming them into a pluripotent state. The factors are named after Dr. Shinya Yamanka, who discovered them.
It is critical that we do not turn the cells in our body into stem cells. We want our eyes, heart, lungs, and liver to stay eyes, heart, lungs, and liver. A retinal ganglion cell that loses its identity is no longer a retinal ganglion cell. The key insight underpinning our epigenetic restoration platform was that using just three factors enables you to reset the epigenetic landscape and restore more youthful gene expression without erasing cell identity, thus reducing the risk of teratoma formation.
The ability of OSK to reset the degraded epigenetic code to a young, healthy state can be likened to buffing a scratch out of a record—music plays well again without destroying the recording.
OCT4, SOX2, and KLF4 (OSK)
OSK refers to the three transcription factors capable of epigenetic reprogramming: OCT4 establishes and maintains pluripotency; SOX2 works with OCT4 to bind chromatin and commence genome remodeling; and KLF4 assists in structural remodeling of DNA packaging and regulation of gene expression.
IH:
ER-100 represents the first-ever clinical study of partial epigenetic reprogramming. Can you describe its development and the underlying scientific rationale?
SRL:
ER-100's development has been a journey built on foundational work showing that OSK expression could reset the degraded epigenetic code to restore vision in aged and injured mice. ER-100 is not a gene correction or cell replacement, but a reset of the epigenetic program that governs how cells age. Mouse studies served as a great proof-of-concept, but to improve clinical translation, we invested in non-human primate (NHP) studies. These demonstrated that controlled OSK expression could restore DNA methylation patterns, essentially resetting the epigenetic code, leading to meaningful improvements in measures of visual function. Peer-reviewed NHP data is yet to be published.
Those studies were critical to securing US Food and Drug Administration Investigational New Drug clearance in January 2026 to begin our clinical studies. Our Phase 1 trial is enrolling patients with optic neuropathies, including both chronic and acute. The primary focus of the trial is safety and tolerability, and secondarily on characterizing immune response and ocular measures.
Optic neuropathies: Open-angle glaucoma and NAION
ER-100 is currently being investigated for open-angle glaucoma and non-arteritic anterior ischemic optic neuropathy (NAION).
Open-angle glaucoma is a progressive eye condition that causes painless vision loss. It is caused by a “back-up” in the fluid drainage system of the eye. This prevents fluid drainage, increasing pressure within the eye, which damages the optic nerve. Although irreversible, further progression can be prevented if identified and treated.
NAION is best understood through breaking it down. Ischemic optic neuropathy (ION) refers to changes in vision, including vision loss, resulting from inadequate blood flow. ION can affect the optic nerve or the optic disc that surrounds it. In anterior disease, as in NAION, the part of the optic nerve just underneath the optic disc, as well as the optic disc itself, can be affected. Finally, the non-arteritic nature of NAION means the process does not involve arterial inflammation, such as in infectious vasculitis, but rather occurs solely due to limited blood flow.
IH:
What unique safety and biological questions does a PER study raise compared with conventional first-in-human trials?
SRL:
While this is a first-in-human trial, it’s built on foundational science that is very familiar within the field. As ER-100 delivers the genes for OSK using an AAV2 viral vector, the safety approach follows typical gene therapy practices.
AAV2 has been well studied in the eye, so the inflammatory risks are well known and can be readily mitigated with appropriate steroid use. Our safety program was built on safety learnings from earlier mouse and NHP studies and was designed to ensure that ER-100 was appropriately assessed to enable advancement to human clinical trials.
IH:
What made ocular conditions favorable indications for early studies, and how realistic is it to extend epigenetic reprogramming to other organ systems in the future?
SRL:
The eye was a logical starting point for several reasons. First, vision loss has a tremendous impact on healthy aging. As people lose their vision, they become less independent, lose their ability to work, often have to give up their hobbies, have an increased fall risk, and are at increased risk for mental health issues and cognitive impairment. Reversing or preventing vision loss should markedly improve healthy aging. The age-related diseases we're targeting first, glaucoma and NAION, also represent serious unmet needs where current options do not target the underlying mechanisms resulting in vision loss.
Moreover, proof-of-concept studies originated in ocular models; intravitreal injection gives localized delivery that limits systemic exposure, and we can monitor outcomes non-invasively with real precision.
As for expansion, I'm genuinely optimistic. Our preclinical work has already shown epigenetic restoration activity in liver disease models. The biology of epigenetic aging is universal, meaning it has the potential to work across many organ systems. The delivery strategies will differ organ by organ, but the ocular program is our proof point for a much broader platform.
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