The purpose of this study is to confirm the improvement in pulmonary function and cytokine levels observed in the recently completed multidose aerosol study for the treatment of Cystic Fibrosis (CF).

Start Date01 Jun 2003

Sponsor / Collaborator

AmpliPhi Biosciences Corp.

[+1]

100 Clinical Results associated with tgAAV-CF gene therapy(AmpliPhi Biosciences Corp.)

100 Translational Medicine associated with tgAAV-CF gene therapy(AmpliPhi Biosciences Corp.)

100 Patents (Medical) associated with tgAAV-CF gene therapy(AmpliPhi Biosciences Corp.)

Literatures (Medical) associated with tgAAV-CF gene therapy(AmpliPhi Biosciences Corp.)

01 Aug 2007·Human Gene TherapyQ2 · MEDICINE

Repeated Aerosolized AAV-CFTR for Treatment of Cystic Fibrosis: A Randomized Placebo-Controlled Phase 2B Trial

Q2 · MEDICINE

Article

Author: Waltz, David A. ; Clancy, John P. ; Martin, Dana B. ; Pian, Mark ; Heald, Alison E. ; Spencer, L. Terry ; Colombo, John ; Carter, Barrie J. ; Pilewski, Joseph ; Moss, Richard B. ; Ferkol, Thomas ; Accurso, Frank ; Milla, Carlos ; Ramsey, Bonnie ; Dorkin, Henry L. ; Zeitlin, Pamela L.

Previous studies have demonstrated that delivery of a recombinant adeno-associated virus (AAV) vector encoding the complete human cystic fibrosis transmembrane regulator (CFTR) cDNA (tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis (CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 (IL-8) levels were seen at early time points. This larger study was conducted to verify these trends. One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis (forced expiratory flow in 1 sec [FEV1]:60% predicted) were randomized to two aerosolized doses of 1x10(13)DNase-resistant particles of tgAAVCF (n=51) or matching placebo (n=51) administered 30 days apart. Although tgAAVCF was well tolerated, the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo. There were no significant differences in spirometric lung function over time, induced sputum biologic markers, or days of antibiotic use in either treatment group. Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated, but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.

01 Jan 2007·The Journal of Gene MedicineQ4 · MEDICINE

Calculating expected lung deposition of aerosolized administration of AAV vector in human clinical studies

Q4 · MEDICINE

Article

Author: Emily Louca ; Allan L. Coates ; Kitty Leung ; Pervin Anklesaria ; Keith Munson ; Benjamin Dutzar

AbstractBackgroundCystic fibrosis is an autosomal recessive disease affecting approximately 1 in 2500 live births. Introducing the cDNA that codes for normal cystic fibrosis transmembrane conductance regulator (CFTR) to the small airways of the lung could result in restoring the CFTR function. A number of vectors for lung gene therapy have been tried and adeno‐associated virus (AAV) vectors offer promise. The vector is delivered to the lung using a breath‐actuated jet nebulizer. The purpose of this project was to determine the aerosolized AAV (tgAAVCF) particle size distribution (PSD) in order to calculate target doses for lung delivery.MethodsA tgAAVCF solution was nebulized using the Pari LC Plus (n = 3), and the PSD was determined by coupling laser diffraction and inertial impaction (NGI) techniques. The NGI allowed for quantification of the tgAAVCF at each stage of impaction, ensuring that rAAV‐CFTR vector is present and not empty particles. Applying the results to mathematical algorithms allowed for the calculation of expected pulmonary deposition.ResultsThe mass median diameter (MMD) for the tgAAVCF was 2.78 ± 0.43 µm. If the system works ideally and the patient only receives aerosol on inspiration, the patient would receive 47 ± 0% of the initial dose placed in the nebulizer, with 72 ± 0.73% of this being deposited beyond the vocal cords.ConclusionsThis technology for categorizing the pulmonary delivery system for lung gene therapy vectors can be adapted for advanced aerosol delivery systems or other vectors. Copyright © 2006 John Wiley & Sons, Ltd.

01 Feb 2004·ChestQ1 · MEDICINE

Repeated Adeno-Associated Virus Serotype 2 Aerosol-Mediated Cystic Fibrosis Transmembrane Regulator Gene Transfer to the Lungs of Patients With Cystic Fibrosis

Q1 · MEDICINE

Article

Author: Alan S. Brody ; L. Terry Spencer ; Bonnie Ramsey ; David Waltz ; Nicole Hamblett ; Richard B. Moss ; David Rodman ; John P. Clancy ; Moira L. Aitken ; Pamela L. Zeitlin ; Alison E. Heald ; Carlos Milla

STUDY OBJECTIVESThe primary objective was to determine the safety and tolerability of repeated doses of aerosolized adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA (cDNA) [tgAAVCF], an adeno-associated virus (AAV) vector encoding the complete human CFTR cDNA. Secondary objectives included evaluation of pulmonary function assessed by spirometry, lung abnormalities by high-resolution CT (HRCT), airway cytokines, vector shedding, serum neutralizing antibody to AAV serotype 2 (AAV2), and gene transfer and expression in a subset of subjects undergoing bronchoscopy with bronchial brushings.DESIGNRandomized, double-blind, placebo-controlled, phase II trial.SETTINGEight cystic fibrosis (CF) centers in the United States.SUBJECTSCF patients with mild lung disease, defined as FEV(1) > or =60% predicted.INTERVENTIONSSubjects were randomized to inhale three aerosolized doses of 1 x 10(13) deoxyribonuclease-resistant particles of tgAAVCF or matching placebo at 30-day intervals using the Pari LC Plus nebulizer (PARI; Richmond, VA).MEASUREMENTS AND RESULTSOf 42 subjects randomized, 20 subjects received at least one dose of tgAAVCF and 17 subjects received placebo. No difference in the pattern of adverse events or laboratory abnormalities was noted between the two treatment groups. Improvements in induced-sputum interleukin-8 (p = 0.03) and FEV(1) (p = 0.04) were observed at day 14 and day 30, respectively, in the group receiving tgAAVCF when compared to those receiving placebo. No significant differences in HRCT scans were noted. Vector shedding in sputum was observed at low levels up to 90 days after the third dose of vector. All subjects receiving tgAAVCF exhibited an increase (by at least fourfold) in serum AAV2-neutralizing antibodies and detectable levels in BAL fluid from five of six treated subjects undergoing BAL. Gene transfer but not gene expression was detected in a subset of six tgAAVCF subjects who underwent bronchoscopy.CONCLUSIONSRepeat doses of aerosolized tgAAVCF were safe and well tolerated, and resulted in encouraging trends in improvement in pulmonary function in patients with CF and mild lung disease.

100 Deals associated with tgAAV-CF gene therapy(AmpliPhi Biosciences Corp.)

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 3	US	AmpliPhi Biosciences Corp.	01 Jun 2003

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