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Recombinant Adeno-Associated Virus Gene Therapy for Cystic Fibrosis and α1-Antitrypsin Deficiency*

Terence R. Flotte, MD
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*From the Powell Gene Therapy Center, University of Florida, Gainesville, FL.

Correspondence to: Terence R. Flotte, MD, University of Florida Gene Therapy Center, Academic Research Building, Room R1-191, 1600 SW Archer Rd, Gainesville, FL 32610-0266



Chest. 2002;121(3_suppl):98S-102S. doi:10.1378/chest.121.3_suppl.98S
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Recombinant adeno-associated vectors (rAAVs) have theoretical advantages as vehicles for human gene therapy because they are based on a virus that is nonpathogenic and has a natural mechanism for long-term persistence in human cells.13 The ability to manipulate single genes also has the potential to be a powerful research tool in animal models of human diseases. Our laboratory has developed rAAVs for the therapy of the two common single-gene disorders that affect the lung, cystic fibrosis (CF) and α1-antitrypsin (AAT) deficiency.6 In addition, we have developed vectors for either the constitutive or inducible expression of the important anti-inflammatory cytokine, interleukin (IL)-10, which could be therapeutically useful in patients with inflammatory diseases like CF, type-I diabetes mellitus, or inflammatory bowel disease. Preparations of rAAV-cystic fibrosis transmembrane conductance regulator (CFTR), rAAV-AAT, and rAAV-IL-10 have been extensively characterized in cell culture systems,79 animal models,4,1011 and early phase I trials in CF patients.1216 Studies with rAAV-CFTR and rAAV-IL-10 in CF bronchial cell cultures have been used to examine the functional consequences of CFTR complementation and IL-10 expression. In vivo studies in mice,,6,1718 rabbits,4,19 and monkeys1011 with each of these vectors have demonstrated long-term gene transfer and expression (ie, > 6 months for CFTR and > 18 months for AAT) without any detectable pathologic findings. These studies also have demonstrated that therapeutic levels of AAT can be achieved in mice by delivery to muscle, liver, or lung. Interestingly, studies of both rAAV-CFTR in monkeys and rAAV-AAT in mice indicate that the vector DNA persists in long strings or concatemers that are episomal, that is, physically separate from the host cell chromosome (in contrast with the naturally occurring form of the virus) and that host cell factors, such as the DNA-dependent protein kinase, play arole in this process.,10,18,2022 This could allow for the DNA to persist without incurring the potential risk of disrupting host cell genes. Phase I trial results in CF patients are also encouraging in that DNA transfer and expression have been observed in the sinuses and the lung without vector-related toxicity. A phase II aerosol trial of rAAV-CFTR is planned in CF patients, as is a phase I trial of rAAV-AAT in AAT-deficient patients.

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