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Two Techniques to Create Hypoparathyroid Mice: Parathyroidectomy Using GFP Glands and Diphtheria-Toxin-Mediated Parathyroid Ablation
Published on: March 14, 2017
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Bioactive, full-length parathyroid hormone delivered using an adeno-associated viral vector
Alexandra M Burr1, Pamela Cabahug Zuckerman2,3,4, Alesha B Castillo2,3,4
1Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Experimental Biology and Medicine (Maywood, N.J.)
|June 6, 2022
Summary
This study demonstrates that adeno-associated viral (AAV) gene therapy can successfully deliver the parathyroid hormone (PTH) gene, leading to therapeutic PTH levels and potential tumor growth in vivo. This offers a promising new avenue for treating hypoparathyroidism.
Area of Science:
- Gene Therapy
- Endocrinology
- Viral Vector Technology
Background:
- Previous attempts at parathyroid hormone (PTH) gene delivery have faced challenges, particularly with full-length PTH (1-84) using adeno-associated viral (AAV) vectors.
- Achieving therapeutic levels of secreted proteins via gene therapy is difficult, necessitating research into novel delivery methods for PTH.
Purpose of the Study:
- To determine the feasibility of using AAV vectors for delivering the full-length PTH (1-84) gene.
- To assess the in vitro and in vivo bioactivity and potency of AAV-mediated PTH gene delivery.
- To explore the potential of AAV-PTH gene therapy for conditions like hypoparathyroidism.
Main Methods:
- An AAV vector was engineered to deliver the human PTH gene under a strong promoter.
- In vitro studies assessed PTH secretion from various cell types, including hepatocytes, and measured potency using osteosarcoma cell proliferation assays.
- In vivo studies involved systemic AAV administration in immunocompromised mice with osteosarcoma xenografts, followed by analysis of PTH levels, tumor growth, and bone turnover biomarkers.
Main Results:
- Engineered AAV vectors successfully mediated PTH secretion from various cell types in vitro, demonstrating potency by inducing osteosarcoma cell proliferation.
- In vivo, systemic AAV-PTH administration resulted in measurable plasma PTH concentrations above the normal range in all dose groups.
- Higher AAV-PTH doses correlated with significantly larger tumors, dose-dependent morphological changes, and significant differences in tibial growth plate width and blood biomarkers related to PTH.
Conclusions:
- AAV-mediated gene delivery of full-length PTH is feasible and demonstrates bioactivity in vitro and in vivo.
- The study establishes proof-of-concept for AAV-PTH gene therapy, showing potential for therapeutic applications in hypoparathyroidism.
- Further investigation in disease models is warranted to determine efficacy, but the current data support continued exploration of this gene therapy approach.
