Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes

Wan Seok Joo, Ji Hoon Jeong, Kihoon Nam, Katherine S. Blevins, Mohamed Salama, Sung Wan Kim

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The activating receptor NKG2D plays an important role in the development of type-1 diabetes. Exploiting a natural phenomenon observed in tumors, plasmid DNA encoding for a soluble ligand to NKG2D (sRAE-1γ) was isolated and engineered into a plasmid expression system. A polymeric gene delivery system was developed to deliver the soluble RAE-1 plasmid to the pancreatic islets. The bioreducible cationic polymer poly(cystamine bisacrylamide-diamino hexane) (p(CBA-DAH)) was modified with poly(ethylene glycol) (PEG) and the targeting peptide CHVLWSTRC, known to target the EphA2 and EphA4 receptors. We observed a higher uptake of the targeting polymer Eph-PEG-p(CBA-DAH) in the pancreas of NOD mice compared to non-targeting controls. To evaluate the efficacy of preventing diabetes, the Eph-PEG-p(CBA-DAH)/RAE-1 complex (polyplex) was intravenously injected into 6-week-old female NOD mice. Within 17 weeks blood glucose levels were stabilized in animals injected with polyplex, while those treated without therapeutic plasmid developed progressive hyperglycemia. Additionally, the degree of insulitis and the infiltration of CD8+ T-cells in the polyplex treated group were improved over the targeting polymer only treated group. The current study suggests that the therapy of the Eph-PEG-p (CBA-DAH) delivering therapeutic sRAE-1 gene may be used to protect β-cells from autoimmune destruction and prevent type-1 diabetes.

Original languageEnglish (US)
Pages (from-to)606-611
Number of pages6
JournalJournal of Controlled Release
Volume162
Issue number3
DOIs
StatePublished - Sep 28 2012
Externally publishedYes

Fingerprint

Cystamine
Hexanes
Type 1 Diabetes Mellitus
Islets of Langerhans
Plasmids
Polymers
Inbred NOD Mouse
EphA4 Receptor
EphA2 Receptor
NK Cell Lectin-Like Receptor Subfamily K
Gene Transfer Techniques
Ethylene Glycol
Therapeutics
Hyperglycemia
Blood Glucose
Pancreas
Ligands
T-Lymphocytes
Peptides
DNA

Keywords

  • Drug delivery
  • Gene therapy
  • Retinoic acid early inducible gene-1 (RAE-1)
  • Type 1 diabetes

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes. / Joo, Wan Seok; Jeong, Ji Hoon; Nam, Kihoon; Blevins, Katherine S.; Salama, Mohamed; Kim, Sung Wan.

In: Journal of Controlled Release, Vol. 162, No. 3, 28.09.2012, p. 606-611.

Research output: Contribution to journalArticle

Joo, Wan Seok ; Jeong, Ji Hoon ; Nam, Kihoon ; Blevins, Katherine S. ; Salama, Mohamed ; Kim, Sung Wan. / Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes. In: Journal of Controlled Release. 2012 ; Vol. 162, No. 3. pp. 606-611.
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