Non-viral Gene Therapy - Intracellular Delivery: Fundamentals and Applications - page 672

Nearly complete ablation of the tumor was determined by video imaging in the two
human patients after treating once a week with 2 mg of pDNA-jetPEI polyplexes
for a total of 9 weeks.
Fewell et al. have developed a non-viral vector (EGEN-001) consisting of a
pDNA encoding the human gene for IL-12 and a synthetic polycation of PEI
derivative (Kendrick et al. 2008 ). This delivery system is currently being investi-
gated in phase I trial for the therapy of recurrent ovarian cancer. EGEN-001 is
designed to increase the local concentration of IL-12 in the tumor microenviron-
ment. Intraperitoneal injections of EGEN-001 resulted in an overall clinical
response of 31% stable disease and 69% progressive disease after four weekly
treatments. When patients were treated with EGEN-001 in combination with either
docetaxel or carboplatin, all patients showed partial response by CT evaluation and
reductions in CA- 125 levels following the completion of EGEN and two cycles of
chemotherapy.
DermaVir, the first dendritic cell-targeting topical HIV vaccine candidate for
topical immunization, is also a polyplex-based nanomedicine, that is fabricated by
pDNA encoding the entire HIV genome minus the integrase gene and mannose-
conjugated lPEI (Lori et al. 2005 ). Phase 1 clinical trial performed by Lori and
colleagues showed that the DermaVir patch could significantly increase the number
of HIV-specific T-cells at DNA doses varying from 0.1 to 0.8 mg. Currently, the
DermaVir patch is in a phase II clinical trial. In a randomized, placebo-controlled,
dose-ranging Phase II study conducted in Hamburg, Germany, that enrolled thirty-
six HIV-infected individuals not yet taking antiretroviral drugs, some promising
results were also obtained.
Besides PEI derivatives, PLL derivatives have been employed as nonviral vec-
tors for gene transfection in human patients. For example, Cooper and colleagues
have constructed DNA-loaded nanoparticles for the therapy of cystic fibrosis (CF)
(Konstan et al. 2004 ). PEG-PLL was used to condense a pDNA carrying the cystic
fibrosis transmembrane regulator (CFTR)-encoding gene. Twelve patients with
classic CF were intranasally administered with PEG-PLL/pDNA nano-polyplexes.
No serious adverse events occurred, and no events were attributed to polyplex nano-
formulation. There was no association of serum or nasal washing inflammatory
mediators with administration of compacted DNA. These results suggested the
safety and tolerability of the employed DNA nano-therapeutics. In addition, this
study also showed partial or complete restoration of CFTR chloride channel func-
tion for up to six days after treatment.
Davis's group has developed a b-CD containing polycation that can effectively
mediate siRNA delivery in preclinical studies (Davis 2009 ). Most recently, the
results obtained in Phase I clinical trial have been presented (Davis et al. 2010 ). The
gene delivery system employed in this trial consists of synthetic nanoparticles,
which were constructed by the complexation of siRNA (designed to reduce the
expression of the RRM2) with a linear, cyclodextrin-based polycation (CDP).
Subsequent PEGylation and targeting was implemented by host-guest interactions
between b-CD and adamantyl (Ada) group, using Ada-terminated PEG and Ada/
human transferrin protein (TF)-terminated PEG, respectively. Tumour biopsies