Demonstration of Safety in Wild Type Mice of npFOXF1, a Novel Nanoparticle-Based Gene Therapy for Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins

Fatemeh Kohram; Zicheng Deng; Yufang Zhang; Abid A Al Reza; Enhong Li; Olena A Kolesnichenko; Samriddhi Shukla; Vladimir Ustiyan; Jose Gomez-Arroyo; Anusha Acharya; Donglu Shi; Vladimir V Kalinichenko; Alan P Kenny

doi:10.2147/BTT.S400006

Demonstration of Safety in Wild Type Mice of npFOXF1, a Novel Nanoparticle-Based Gene Therapy for Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins

Biologics. 2023 Mar 20:17:43-55. doi: 10.2147/BTT.S400006. eCollection 2023.

Authors

Fatemeh Kohram^{1

2

3}, Zicheng Deng^{1

2

3

4}, Yufang Zhang^{1

2

3}, Abid A Al Reza^{1

2

3}, Enhong Li^{1

2

3}, Olena A Kolesnichenko^{1

2

3}, Samriddhi Shukla^{1

2

3}, Vladimir Ustiyan^{1

2

3}, Jose Gomez-Arroyo^{1

2

3}, Anusha Acharya^{1

2

3}, Donglu Shi⁴, Vladimir V Kalinichenko^{1

2

3}, Alan P Kenny^{1

2

5

6}

Affiliations

¹ Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
² Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Center for Lung Regenerative Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA.
⁵ Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Abstract

Introduction: Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins (ACDMPV) is a fatal congenital disease resulting from a pulmonary vascular endothelial deficiency of FOXF1, producing abnormal morphogenesis of alveolar capillaries, malpositioned pulmonary veins and disordered development of lung lobes. Affected neonates suffer from cyanosis, severe breathing insufficiency, pulmonary hypertension, and death typically within days to weeks after birth. Currently, no treatment exists for ACDMPV, although recent murine research in the Kalinichenko lab demonstrates nanoparticle delivery improves survival and reconstitutes normal alveolar-capillary architecture. The aim of the present study is to investigate the safety of intravenous administration of FOXF1-expressing PEI-PEG nanoparticles (npFOXF1), our pioneering treatment for ACDMPV.

Methods: npFOXF1 was constructed, validated, and subsequently administered in a single dose to postnatal day 14 (P14) mice via retro-orbital injection. Biochemical, serologic, and histologic safety were monitored at postnatal day 16 (P16) and postnatal day 21 (P21).

Results: With treatment we observed no lethality, and the general condition of mice revealed no obvious abnormalities. Serum chemistry, whole blood, and histologic toxicity was assayed on P16 and P21 and revealed no abnormality.

Discussion: In conclusion, npFOXF1 has a very good safety profile and combined with preceding studies showing therapeutic efficacy, npFOXF1 can be considered as a good candidate therapy for ACDMPV in human neonates.

Keywords: ACDMPV; FOXF1; mouse; nanoparticle; safety; toxicity.

Grants and funding

R01 HL141174/HL/NHLBI NIH HHS/United States