Challenges and Opportunities in Gene Delivery - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 46

With increased understanding of the genetic and molecular basis of diseases, the
promise of gene therapy has grown exponentially. Gene therapy has shown a great
promise over conventional chemotherapy with respect to the toxicity, treatment speci-
ficity, and in permanent cure of diseases such as cancer, cystic fibrosis, hemophilia,
and so on, in which only symptomatic drug therapy has been used. The applications of
gene therapy have been advanced in clinical studies, with DNA-based vaccines such
as prostate-specific membrane antigen (PSMA) DNA vaccine, designed for targeting
prostate cancers expressing the PSMA antigen. VGX™-3100 is a proprietary, thera-
peutic DNA vaccine candidate for the treatment of cervical intraepithelial neoplasias
(CIN) caused by human papillomavirus (HPV) types 16 and 18, and many more DNA-
based products approaching the market [19] . Current market focus on gene therapy
is in the treatment of ocular disease. Macugen, an aptamer for the treatment of wet
age-related macular degeneration, is the only RNA/DNA product currently available
worldwide [20] . However, in the near future the products for treatment of cardiovas-
cular disorders and cancer therapy, currently in clinical trials, may be marketed; these
hold significant therapeutic efficacy and great market potential [20] .
Gene therapy research currently focuses cancer disorders (many under clinical
investigations), monogenic diseases (hemophilia A and B, cystic fibrosis, severe com-
bined immunodeficiency syndrome), infectious diseases, vascular diseases, and DNA
vaccination [1,21] . Despite these early successes, widespread use of DNA therapeu-
tics for disease treatment is still a long way off for providing clinically effective and
safe DNA therapeutics.
Initial methods used in gene therapy involved an ex vivo approach: introduction
of a therapeutic gene using a suitable vector system into target cells removed from
the diseased patient, and then reintroduction of the transfected cells back to the host.
However, significant barriers related to complexity, cost, and time limited its clini-
cal application. Hence, the direct in vivo administration of genes to patients, with
or without carrier, to produce the desired protein selectively, at a controlled rate for
the required timeline, represents an ideal approach for clinical practice. But low effi-
ciency of the passive transport of the “genetic drug” or a DNA plasmid to reach its
target site, the desired cell nucleus, has been the biggest obstacle to the success of
gene therapy. Yet, delivery of a few molecules to the desired cell nuclei is likely to
be sufficient to achieve the desired outcome. Thus gene delivery represents a very
different challenge to scientists compared to the delivery of low-molecular-weight
drugs and protein biologicals.
The success of a gene therapy for each clinical indication completely depends on
the quantity of protein that must be expressed by the DNA to obtain the desired ther-
apeutic activity. This prospect of the therapy should be considered at an early stage
of the formulation development, and the DNA delivery strategy should be targeted in
the required dose accordingly [22] . The quantity of protein produced will be depen-
dent on the quantity of DNA expressed in the cell as well as on the successful target-
ing of the DNA to the cells and the nucleus within the cells using a suitable delivery
system.