PMID- 11589832
OWN - NLM
STAT- MEDLINE
DCOM- 20011207
LR  - 20121115
IS  - 1043-0342 (Print)
IS  - 1043-0342 (Linking)
VI  - 12
IP  - 15
DP  - 2001 Oct 10
TI  - A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis 
      subjects with mild lung disease.
PG  - 1907-16
AB  - Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in 
      North America, leading to significant morbidity and early mortality. The defect 
      in the cystic fibrosis transmembrane conductance regulator protein (CFTR) 
      function can be corrected in vitro by gene replacement with a wild-type gene. A 
      Phase I, single administration, dose escalation trial was designed and executed 
      to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector 
      encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four 
      cohorts of three subjects each were administered increasing doses of the study 
      agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in 
      log increments up to 10(13) DRP. Sequential bronchoscopies were performed to 
      gather analytical samples throughout the study. All 12 subjects completed the 
      study. There were a total of 242 adverse events (AEs), six of which were defined 
      as serious and three of which were defined as possibly being related to the study 
      drug. A clear dose-response relationship was observed in vector gene transfer. A 
      maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 
      30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this 
      declined to nearly undetectable levels by day 90. Vector gene transfer was evenly 
      distributed throughout the fourth airway generation following single-dose 
      administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I 
      trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal 
      airways of CF subjects by nebulization.
FAU - Aitken, M L
AU  - Aitken ML
AD  - Department of Medicine and Pediatrics, University of Washington, Seattle, 98195, 
      USA. moira@u.washington.edu
FAU - Moss, R B
AU  - Moss RB
FAU - Waltz, D A
AU  - Waltz DA
FAU - Dovey, M E
AU  - Dovey ME
FAU - Tonelli, M R
AU  - Tonelli MR
FAU - McNamara, S C
AU  - McNamara SC
FAU - Gibson, R L
AU  - Gibson RL
FAU - Ramsey, B W
AU  - Ramsey BW
FAU - Carter, B J
AU  - Carter BJ
FAU - Reynolds, T C
AU  - Reynolds TC
LA  - eng
PT  - Clinical Trial
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (CFTR protein, human)
RN  - 0 (Cytokines)
RN  - 0 (DNA, Complementary)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
SB  - IM
MH  - Adult
MH  - Alleles
MH  - Cells, Cultured
MH  - Cystic Fibrosis/genetics/*therapy
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/*genetics
MH  - Cytokines/metabolism
MH  - DNA, Complementary/metabolism
MH  - Dependovirus/genetics
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - *Gene Transfer Techniques
MH  - Genetic Therapy/*adverse effects
MH  - Genetic Vectors
MH  - HeLa Cells
MH  - Humans
MH  - Immunohistochemistry
MH  - Lung/physiology
MH  - Lung Diseases/*therapy
MH  - Male
MH  - Mutation
MH  - Nebulizers and Vaporizers
MH  - Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Time Factors
EDAT- 2001/10/09 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/10/09 10:00
PHST- 2001/10/09 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/10/09 10:00 [entrez]
AID - 10.1089/104303401753153956 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2001 Oct 10;12(15):1907-16. doi: 10.1089/104303401753153956.