Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 289

CFTR gene delivery to mouse airways resulted in sustained production of mRNA
[165,166] . However, certain reports suggested inefficiency of Ad virus to deliver the
CFTR gene in animal models [167,168] . The inefficiency of original Ad was improved
by genetic manipulations to use under in vivo conditions [169] . AAV-mediated CFTR
gene transfer in animal models demonstrated persistence of expression of CFTR for
up to 6 months [170] . Liposomal delivery of the CFTR gene also resulted in sustained
mRNA synthesis [171] . Further, in an attempt to evaluate the functional assessment
of CFTR gene transfer, transgenic mice were developed [172] . Null mice were used
for intratracheal administration of the liposome-mediated CFTR gene, and the results
showed restoration of Cl - permeability in the subject mice [173] . Liposomal formula-
tion (DC-Chol/DOPE- CFTR complexes), when nebulized in transgenic mice, resulted
in RT-PCR detectable expression of CFRT mRNA [174] . However, direct application
of DC-Chol/DOTAP- CFTR complexes to the nose and tracheal instillation of the
same transgenic mice resulted in lower CFTR expression [175] . These in vivo animal
model studies proved the principle of airway gene delivery, expression, and partial
functional correction, and paved the way for human trials.

6.4.3 Human Clinical Trials
Based on the encouraging results of in vitro and in vivo animal studies, attempts have
been made to administer the CFTR gene into human patients. The various clinical tri-
als for CFTR delivery using both viral and nonviral vectors systems are summarized
in Table 6.4 .

Table 6.4 Human Clinical Trials for CFTR Gene Delivery

No. Vector System Comments Reference

1 Adenovirus Two out of three patients exhibited CFTR mRNA,

while all the patients exhibited changes in sodium
and chloride transport toward the normal range. Local
inflammation at the site of application was seen in all
patients

[176]

2 Adenovirus One patient had detectable CFTR mRNA after

bronchoscopic nasal administration, and another patient
had detectable protein in the lung. However, the
expression was transient

[177]

3 Adenovirus For the assessment of dose response of nasal epithelium.

Patients receiving the highest dose exhibited CFTR
mRNA and no consistent changes in chloride or
sodium transport measurements, and some patients
showed inflammation

[178]

4 Adenovirus Aerosol administration of a single dose of Ad/ CFTR .

No acute toxic effects were reported at doses up to
5.4  10 8 plaque-forming units (PFU), with no
inflammation

[179]

( Continued )