Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution.
A double-blind, dose escalation gene transfer trial was conducted in subjects with cystic fibrosis (CF), among whom placebo (saline) or compacted DNA was superfused onto the inferior turbinate of the right or left nostril. The vector consisted of single molecules of plasmid DNA carrying the cystic fibrosis transmembrane regulator- encoding gene compacted into DNA nanoparticles, using polyethylene glycol-substituted 30-mer lysine peptides. Entry criteria included age greater than 18 years, FEV1 exceeding 50% predicted, and basal nasal potential difference (NPD) isoproterenol responses (> or = -5 mV) that are typical for subjects with classic CF. Twelve subjects were enrolled: 2 in dose level I (DLI) (0.8 mg DNA), 4 in DLII (2.67 mg), and 6 in DLIII (8.0 mg). The primary trial end points were safety and tolerability, and secondary gene transfer end points were assessed. In addition to routine clinical assessments and laboratory tests, subjects were serially evaluated for serum IL-6, complement, and C-reactive protein; nasal washings were taken for cell counts, protein, IL-6, and IL-8; and pulmonary function and hearing tests were performed. No serious adverse events occurred, and no events were attributed to compacted DNA. There was no association of serum or nasal washing inflammatory mediators with administration of compacted DNA. Day 14 vector polymerase chain reaction analysis showed a mean value in DLIII nasal scraping samples of 0.58 copy per cell. Partial to complete NPD isoproterenol responses were observed in eight subjects: one of two in DLI, three of four in DLII, and four of six in DLIII. Corrections persisted for as long as 6 days (1 subject to day 28) after gene transfer. In conclusion, compacted DNA nanoparticles can be safely administered to the nares of CF subjects, with evidence of vector gene transfer and partial NPD correction.
Konstan
Michael W
MW
Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Davis
Pamela B
PB
Wagener
Jeffrey S
JS
Hilliard
Kathleen A
KA
Stern
Robert C
RC
Milgram
Laura J H
LJ
Kowalczyk
Tomasz H
TH
Hyatt
Susannah L
SL
Fink
Tamara L
TL
Gedeon
Christopher R
CR
Oette
Sharon M
SM
Payne
Jennifer M
JM
Muhammad
Osman
O
Ziady
Assem G
AG
Moen
Robert C
RC
Cooper
Mark J
MJ
D000281:Administration, Intranasal; D002097:C-Reactive Protein / Q000032:analysis; D002985:Clinical Protocols; D003165:Complement System Proteins / Q000032:analysis; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004311:Double-Blind Method; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D015850:Interleukin-6 / Q000097:blood; D049329:Nanostructures / Q000737:chemistry*; D017817:Nasal Lavage Fluid; D009297:Nasal Mucosa / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D013997:Time Factors
D015850:Interleukin-6; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003165:Complement System Proteins; D002097:C-Reactive Protein; D004247:DNA