Technology evaluation: cystic fibrosis therapy, Genzyme

Genzyme is developing therapies to replace the defective forms of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein in CF patients. The company is developing a gene therapy, as well as a recombinant production of CFTR for protein replacement therapy. Both approaches have been granted orphan drug status by the FDA [156348]. The results of several clinical trials were discussed at the first annual meeting of the American Society of Gene Therapy in May 1998. A single dose nasal administration was well tolerated by volunteers, but had disappointing efficacy. In a study completed at the Royal Brompton Hospital, London, a single dose aerosol application of GL-67:DOPE was administered to eight patients, while another eight received GL-67:DOPE plus pCF1-CFTR. In the second group, a moderate increase in the potential difference in the lung was observed, with a slight trend towards bacterial adherence normalization in the airway cells. Seven of the patients in the second group, and three patients who received lipid alone, developed, flu-like symptoms within 24 h. A trial at the University of Alabama, using the same formulation, showed that flu-like symptoms developed in six of eight patients by day two, and in all patients by day seven [290120]. In 1995, the company began a clinical safety trial involving delivery of a normal CF gene to the patient's lungs via an adenovirus vector. The administration involves the inhalation of an aerosol containing the vector or, separately, delivery to one lobe of the patient's lung via a bronchoscope [191678]. To evaluate additional delivery methods for the gene, Genzyme has an exclusive research agreement for the use of Vical's cytofectins as non-viral delivery vectors for CFTR. Also under investigation are delivery systems for the nasal epithelium using liposomes or lipid-DNA complexes. These protocols are being developed in collaboration with the National Heart & Lung Institute, London, and an undisclosed partner [162590], [177633]. Following in vitro screenings by the company, two T-shaped molecules were identified (GL-67 and GL-53), the gene transfer activities of which could be enhanced by dioleoyl-PE (DOPE). A recently-completed clinical trial in 16 CF patients demonstrated that the GL-67:DOPE:DMPE-PEG5000-pCF1-CFTR compound accumulated in the lung with minimal toxicity and resulted in a 25% correction of CF symptoms [268093]. Genzyme has also developed recombinant cell lines that synthesize CFTR and has used transgenic expression techniques to breed mice, rabbits and goats which secrete the protein in their milk. Protein replacement therapy is currently in preclinical investigation and research efforts have been reduced infavor of the gene therapeutic approach [177633].