Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes.
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.
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
Wan Seok
WS
Joo
Ji Hoon
JH
Jeong
Kihoon
K
Nam
Katherine S
KS
Blevins
Mohamed E
ME
Salama
Sung Wan
SW
Kim
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D018014:Gene Transfer Techniques; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000493:pharmacokinetics; D051379:Mice; D016688:Mice, Inbred NOD; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010957:Plasmids; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D036081:Receptors, Eph Family / Q000737:chemistry*; D014018:Tissue Distribution
D008565:Membrane Proteins; D009842:Oligopeptides; D011108:Polymers; C491217:Raet1c protein, mouse; D036081:Receptors, Eph Family