Self-assembling peptide hydrogel delivering `Puma` gene therapy prevents corticotroph tumor recurrence.

Recurrence of Cushing's disease is a significant challenge, primarily caused by residual corticotroph tumors after transsphenoidal surgery, with recurrence rates around 20%. Current adjuvant treatments for these residual lesions are largely ineffective or lack safety. This study addresses the critical need for targeted, safe, and effective therapies by leveraging the high activity of the POMC promoter to achieve lineage-specific gene delivery to corticotroph tumor cells.

Researchers analyzed single-cell RNA sequencing data of corticotroph tumors to identify transcriptional profiles. They designed an adeno-associated virus (AAV) vector carrying the pro-apoptotic gene Puma, with its expression controlled by the Pomc promoter for lineage-specific targeting. An injectable, self-assembling peptide hydrogel was developed for sustained local delivery of the Puma gene. Therapeutic efficacy was tested in both subcutaneous and post-resection mouse models, evaluating tumor growth, apoptosis, and systemic effects. Toxicity in major organs was also assessed.

The Pomc promoter successfully drove selective Puma expression specifically in corticotroph tumor cells, leading to mitochondrial membrane potential loss and apoptosis in vitro. In in vivo mouse models, the Puma-carrying virus significantly suppressed tumor growth and lessened systemic tumor effects. The most impactful finding demonstrated the hydrogel's potential:

When delivered via the hydrogel into surgical cavities, the gene therapy completely eliminated residual tumors without detectable toxicity in major organs. This targeted approach achieved complete tumor eradication in a post-resection setting, directly addressing the problem of recurrence.