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Published on: February 24, 2023
Hydrogel-based lineage-specific gene therapy prevents recurrence of corticotroph tumors
Junpeng Wang1,2, Zezheng Fang1,2, Jiahao Wang1,2
1Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan 250012 Shandong, China.
Abstract:
Pituitary corticotroph tumors are the primary cause of Cushing's disease. Even after transsphenoidal surgery, residual tumor cells frequently persist, leading to a recurrence rate of approximately 20%. However, safe and effective adjuvant treatments for these residual lesions are lacking. In this study, we analyzed single-cell RNA sequencing data to characterize the transcriptional profile of corticotroph tumors. On the basis of the high activity of the POMC promoter and its transcriptional regulators, we designed an adeno-associated virus vector carrying the pro-apoptotic gene Puma, with expression controlled by the Pomc promoter for lineage-specific targeting. We also developed an injectable, self-assembling peptide hydrogel for the sustained local delivery of the Puma gene and tested its therapeutic efficacy in subcutaneous and post-resection mouse models. Results showed the Pomc promoter drove selective Puma expression in corticotroph tumor cells, inducing mitochondrial membrane potential loss and apoptosis in vitro. In vivo, the virus suppressed tumor growth and lessened systemic tumor effects; when delivered via the hydrogel into surgical cavities, it completely eliminated residual tumors without detectable toxicity in major organs. This targeted, localized strategy, thus has translational potential as an adjuvant therapy for reducing the recurrence of Cushing's disease.
Insights
Researchers developed a targeted gene therapy using an adeno-associated virus to deliver the pro-apoptotic gene Puma. This approach effectively eliminated residual pituitary tumors after surgery, offering a promising new treatment for Cushing's disease recurrence.
Area of Science:
- Endocrinology
- Molecular Biology
- Gene Therapy
Background:
- Pituitary corticotroph tumors cause Cushing's disease, with ~20% recurrence post-surgery.
- Current adjuvant therapies for residual tumors are limited.
- Single-cell RNA sequencing is crucial for understanding tumor heterogeneity.
Purpose of the Study:
- To develop a lineage-specific gene therapy for residual pituitary corticotroph tumors.
- To target and eliminate persistent tumor cells after surgery for Cushing's disease.
- To evaluate the therapeutic efficacy of a novel gene therapy in preclinical models.
Main Methods:
- Analyzed single-cell RNA sequencing data of corticotroph tumors.
- Designed an adeno-associated virus vector with the pro-apoptotic gene Puma, driven by the Pomc promoter.
- Developed a self-assembling peptide hydrogel for sustained local gene delivery.
- Tested efficacy in subcutaneous and post-resection mouse models.
Main Results:
- Pomc promoter selectively drove Puma expression in tumor cells, inducing apoptosis.
- In vivo, the therapy suppressed tumor growth and systemic effects.
- Hydrogel-delivered gene therapy eradicated residual tumors in surgical cavities without organ toxicity.
Conclusions:
- Targeted, localized gene therapy with Puma shows translational potential for Cushing's disease adjuvant treatment.
- This strategy effectively reduces tumor recurrence by eliminating residual cells.
- The developed hydrogel system ensures sustained delivery and minimizes systemic toxicity.
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