Autosomal dominant polycystic kidney disease (ADPKD) affects millions globally, yet no existing therapy addresses its underlying cause. The disorder is defined by expanding fluid-filled cysts that progressively impair kidney function, ultimately necessitating dialysis or transplantation. Transplant availability remains constrained, but emerging research indicates therapies could stop or even reverse cyst growth before kidneys suffer permanent harm.
Estuary Biotherapeutics, a startup founded to develop gene therapies, targets the genetic defects driving ADPKD. Its approach focuses on repairing proteins disrupted by these mutations—primarily polycystin-1 (PC1) and polycystin-2 (PC2), encoded by the PKD1 and PKD2 genes. Mutations in PKD1, which account for roughly 80% of cases, represent a key focus.
The company’s development pipeline stems from preclinical work by its founders, Stefan Somlo, MD, and Michael Caplan, MD, PhD, both affiliated with Yale School of Medicine. Their studies showed that reintroducing polycystin expression in mice with severe cystic disease restored both kidney structure and function. These results imply that patients with established ADPKD could still benefit from interventions capable of halting or reversing disease progression.
Estuary’s two lead programs seek to translate this research into human treatments. The first, EST-201, delivers a full-length PKD2 gene using an adeno-associated virus (AAV) vector. Clinical testing for this therapy, designed for patients with PKD2 mutations, is set to begin in 2027. The second program, EST-101, addresses PKD1 mutations by administering a functional PC1 protein segment through the same AAV platform. Trials for EST-101 are scheduled for 2028.
Challenges remain in translating these findings into effective treatments. The company’s CEO and co-founder, Wayne Sackett, acknowledged that while the biology is well understood, precisely delivering genetic therapies to kidney cells poses an engineering obstacle.
ADPKD typically advances gradually, with patients often living for decades before reaching end-stage disease. The potential to treat even advanced cases could significantly improve patient quality of life. Sackett highlighted that while early intervention offers the greatest likelihood of success, biological evidence suggests late-stage patients might also derive benefit. “We believe there is an important window of opportunity to intervene earlier in the disease course, while also exploring the potential to benefit patients with more advanced disease,” Sackett said.
To advance its programs, Estuary has raised $103 million in funding. The next few years will determine whether gene therapy can fulfill its potential. For now, the company’s strategy relies on decades of foundational research, offering a possible breakthrough in ADPKD management.
