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DNA-based delivery of G-CSF as a durable and efficacious approach to treat severe chronic neutropenia
Marek M Drozdz1, Andy T Thompson1, Linda Sasset1
1RenBio Inc., Long Island City, New York, NY 11101, USA.
Insights
DNA-based delivery of granulocyte-colony stimulating factor (G-CSF) using intramuscular electroporation (IM-EP) offers a long-lasting solution for neutropenia. This novel approach ensures sustained G-CSF production, improving patient compliance and reducing treatment burdens.
Area of Science:
- Biotechnology
- Gene Therapy
- Pharmacology
Background:
- Potent biologics often have short half-lives, requiring frequent administration.
- Granulocyte-colony stimulating factor (G-CSF) for severe chronic neutropenia (SCN) exemplifies this challenge, necessitating daily dosing.
- Frequent G-CSF administration impacts patient compliance and treatment costs.
Purpose of the Study:
- To evaluate DNA-based delivery of G-CSF using intramuscular electroporation (IM-EP).
- To assess the potential of IM-EP to overcome short biologic half-life limitations.
- To develop a more patient-friendly and cost-effective therapeutic strategy for neutropenia.
Main Methods:
- DNA plasmid encoding G-CSF was delivered via IM-EP in mouse and rabbit models.
- Pharmacokinetic profiles, gene expression durability, and efficacy in a neutropenia model were assessed.
- Effects on neutrophil counts and other bone marrow-derived cell types were analyzed.
Main Results:
- A single IM-EP administration resulted in sustained G-CSF gene expression for over a year in mice.
- The treatment demonstrated efficacy in a mouse model of neutropenia.
- Rabbit models confirmed scalability and specific increases in neutrophil counts without affecting other cell lineages.
Conclusions:
- IM-EP of DNA medicines provides a durable and effective method for G-CSF delivery.
- This approach offers a promising strategy to overcome the limitations of short half-life biologics.
- IM-EP holds potential for improved patient compliance and reduced healthcare costs in treating conditions like SCN.
Abstract:
Many potent biologics are limited by their short half-lives, necessitating frequent administration, which can be burdensome for patients and economically costly. Granulocyte-colony stimulating factor (G-CSF), a critical treatment for severe chronic neutropenia (SCN), known under the generic drug name filgrastim, exemplifies this challenge. SCN patients often require daily doses of G-CSF, which can adversely affect compliance and highlights the need for improved therapeutic strategies. Intramuscular electroporation (IM-EP) of DNA medicines has emerged as a promising solution by facilitating continuous and long-lasting production of the encoded therapeutic protein. Here, we employ this technology for DNA-based delivery of G-CSF. The data from mouse models demonstrate that a single administration leads to an improved pharmacokinetic profile, durable gene expression beyond 1 year, and efficacy in a neutropenia disease model. Furthermore, results from rabbit models validate the scalability of this approach and confirm that muscle-derived G-CSF specifically increases neutrophil count without affecting other bone marrow-derived cell types. These findings underscore the potential of IM-EP of DNA medicines as an effective method to overcome the limitations posed by the short half-life of some biologics, offering a more patient-friendly and cost-effective therapeutic approach.
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