PulseSight: Transferrin Shows Promise in Dry AMD

PulseSight Therapeutics has announced the publication of new peer-reviewed research that reinforces the therapeutic promise of transferrin (Tf) in treating dry age-related macular degeneration (AMD) and its advanced stage, geographic atrophy (GA). The findings, published in Cell Death & Disease, a journal from Nature Publishing Group, stem from collaborative research by scientists at Inserm, Cochin Hospital (Paris), and PulseSight's internal team.

Iron Dysregulation Identified as a Key Driver in AMD

The study presents compelling evidence that iron dysregulation plays an active, pathogenic role in early retinal degeneration, rather than serving as a secondary effect. In particular, it identifies iron imbalance as a driver of retinal pigment epithelium (RPE) and photoreceptor degeneration, with direct implications for the progression from dry AMD to GA.

Excess iron has long been linked to oxidative stress, inflammation, and ferroptosis, a form of iron-dependent cell death, known to contribute to retinal degeneration. The new findings support the hypothesis that restoring iron balance may be a viable strategy for protecting retinal cells and preserving vision in AMD patients.

Mechanistic Role of Transferrin in AMD

Transferrin is a naturally occurring glycoprotein responsible for binding and transporting iron in a non-toxic form. Its role is essential in maintaining iron homeostasis and preventing iron-induced damage to ocular tissues. The study offers new mechanistic insights into transferrin’s ability to counteract ferroptosis and limit oxidative and inflammatory injury in the retina.

“Iron can promote oxidative damage and inflammation, both central to disease progression,” said Professor Joshua Dunaief, University of Pennsylvania, and member of PulseSight’s Scientific Advisory Board. “I am very enthusiastic to see programs such as PST-611 entering clinical testing to demonstrate the value of this target in preserving vision and improving patients’ lives.”

Study Findings: Iron Imbalance in AMD/GA Patients

Among the study's key findings:

• One of the largest analyses of aqueous humor samples from AMD and GA patients to date confirmed elevated iron levels and increased transferrin saturation, signaling disrupted iron regulation.

• In in vitro models using human RPE cells, iron overload led to hallmark AMD features, including:

• Oxidative stress

• Mitochondrial damage

• Inflammation

• Complement system activation

• Ferroptosis

• Exposure to oxidized lipids also mimicked this stress environment.

• Transferrin supplementation restored iron balance and significantly reduced cellular damage, preserving RPE cell integrity.

These findings provide a robust scientific rationale for targeting iron metabolism as a disease-modifying strategy in dry AMD and GA.

PST-611: PulseSight’s Lead Candidate Targeting Iron Regulation

The research directly supports the development of PST-611, PulseSight’s lead therapeutic candidate. PST-611 is a first-in-class, non-viral gene therapy designed to deliver a plasmid encoding transferrin directly into the eye. This approach is intended to restore local iron homeostasis, reduce ferroptotic stress, and preserve retinal structure and function in patients with dry AMD and early-stage GA.

“With PST-611, we combine mechanistic relevance, long-lasting efficacy, and a de-risked delivery platform, positioning PST-611 as a potential major therapeutic option for patients with dry AMD/GA,” said Thierry Bordet, PhD, Chief Scientific Officer and Chief Operating Officer at PulseSight.

The therapy is currently being evaluated in a Phase 1 clinical trial, with initial safety and biological activity results expected in early 2026.

Reference:

Youale et al., “Transferrin is a drug candidate for the treatment of dry age-related macular degeneration (AMD),” Cell Death & Disease. 16, 692 (2025). PMID: 41053100