Intra-articular nonviral gene therapy in mucopolysaccharidosis I mice.

Abstract

Mucopolysaccharidosis type I (MPS I) is caused by the lysosomal accumulation of glycosaminoglycans (GAGs) due to the deficiency of the enzyme alpha-L-iduronidase (IDUA). Currently available treatments may improve several clinical manifestations, but they have limited effects on joint disease, resulting in persistent orthopedic complications and impaired mobility. Thus, this study aimed to perform an intra-articular administration of cationic nanoemulsions complexed with the plasmid encoding for the IDUA protein (pIDUA) targeting MPS I gene therapy for the synovial joints. Formulations composed of DOPE, DOTAP, MCT (NE), and DSPE-PEG (NE-PEG) were prepared by high-pressure homogenization, and the pIDUA plasmid was associated by adsorption onto the surface of nanoemulsions (pIDUA/NE or pIDUA/NE-PEG). The physicochemical characterization showed that the presence of DSPE-PEG in pIDUA/NE-PEG formulations led to small and highly stable droplets even when incubated with simulated synovial fluid (SSF), when compared to the non-pegylated complexes (pIDUA/NE). Uptake by fibroblast-like synoviocytes (FLS) was demonstrated, and high cell viability (70%) in addition with increased IDUA activity (2.5% of normal) were observed after incubation with pIDUA/NE-PEG. The intra-articular injection of pIDUA/NE-PEG complexes in MPS I mice showed that the complexes were localized in the joints, were able to transfect synovial cells, and thus promoted an increase in IDUA activity and expression in the synovial fluid, with no significant activity in other tissues (kidney, liver, lung, and spleen). The overall results demonstrated a contained, safe, tolerable, and effective in situ approach of nonviral intra-articular gene therapy targeting the reduction or prevention of the debilitating orthopedic complications of MPS I disorder.

• Authors: Juliana Bidone, Roselena Silvestri Schuh, Mirian Farinon, Édina Poletto, Gabriela Pasqualim, Patrícia Gnieslaw de Oliveira, Michelle Fraga, Ricardo Machado Xavier, Guilherme Baldo, Helder Ferreira Teixeira, Ursula Matte
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 548 Issue 1 Pg. 151-158 (Sep 05 2018) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 29940298 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• DNA, Complementary
• Emulsions
• Iduronidase

Topics

• Animals
• DNA, Complementary (genetics)
• Emulsions
• Genetic Therapy (methods)
• Humans
• Iduronidase (genetics)
• Injections, Intra-Articular
• Mice, Inbred C57BL
• Mice, Knockout
• Mucopolysaccharidosis I (therapy)
• Plasmids
• Synovial Fluid (metabolism)