Challenges and Opportunities in Gene Delivery - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 71

adaptive immune responses and thus overcome the obstacles posed by the immune
system to the long-term replacement of missing or faulty genes by the use of viral
vectors [192] .
2.6 Scale-up Barriers and FDA Approval
Development of a gene-based system at the laboratory level requires a lot of effort
and research. The challenge lies in reproducing the same formulations with similar
efficacy at the scale-up level and submission of the data to the FDA authorities for
approval and marketing. For approval, it is necessary to show the safety and effective-
ness of the gene product and process for the intended use. The process used must
be aseptically controlled and properly validated to control product quality. From the
time of development of the formulation, the scale up, clinical trials, and FDA mar-
keting approval requires a time period of approximately 8-12 years. The developed
product is required to be preclinically and clinically tested on diseased and healthy
animals for safety, toxicity, and effectiveness, followed by human clinical trials. The
major barriers for developing these products and their marketing are the safety con-
cerns of these products, which are yet to be justified and require further investiga-
tions and developments before they can be safely marketed.
2.7 Conclusion
Gene therapy has been the eventual choice for treatment of various genetic and
acquired diseases occurring because of gene malfunction. Recent studies have shown
substantial extracellular, intracellular, and biological barriers to the successful delivery
of the therapeutic gene. The efficiency of therapeutic gene delivery depends upon
overcoming the barriers successfully by means of covalently modifying the DNA to
reduce the immune response to DNA, as well as altering the physiochemical proper-
ties and composition of the delivery system. However, the contribution of each barrier
to gene delivery and its expression in different cells, as well as the ways to overcome
it, need to be deeply understood in order to enhance the transgene expression. More
attention is required in overcoming the endosomal escape and nuclear transport of
the gene alone or the gene-carrier complex for enhanced transfection. It is becoming
obvious that delivery systems must be optimized for each formulation and particular
cells, and no universal delivery system capable of efficiently delivering genes to a
variety of tissues is possible. The physical and chemical properties, vector system, and
administration route invariably affect the gene targeting and expression with reduced
side effects and are required to be optimized. Faster scale up and regulatory approval
after preclinical and clinical studies is also a requisite in launching the product
in the market, a process generally requiring up to 12 years of time. In summary,
facilitation of permanent gene-replacement therapy, which could provide the ultimate
cure for many devastating diseases, may require a multidisciplinary effort from gene-
therapy scientists, who will have to apply their vast knowledge in constructing and
manipulating vectors with enhanced gene expression and low immune response.