By: Tamara Yunusova, PharmD Candidate c/o 2017

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Gene therapy? You scoff in disbelief as thoughts of designer babies, liberal eugenics, clones, and ruthless dystopian societies begin to reel in the back of your mind. Perhaps you may even stop to recall a scene or two from Jurassic Park or Star Trek. Undoubtedly, gene therapy has long been a fascination of cinema which has toyed with its numerous dilemmas and awe-inspiring promises to produce some of the most cherished science fiction films of our time.  But the ambitious road of gene therapy extends beyond a mere science fiction thrill, breakthroughs in gene therapy have increasingly come to the attention of scientists, bioethicists, politicians and healthcare professionals. Pharmacists are no exception as the vortex of biotechnology lures pharmacogenetics and gene transfer into its center.

Current drug therapy takes a “one size fits all” dosing approach. With failure rates of 20% among effective therapies, this standard dosing approach often leads to inefficacy, toxicity, and adverse drug reactions (ADRs).¹ In fact, it is estimated that ADRs result in 7,000 deaths annually, representing the fourth leading preventable cause of death in United States.¹ How can we account for such failure rates? What causes ADRs and how can we take initiative to prevent them?

Genetics has an answer. Although humans share essentially the same genome, many differences exist amongst individuals due to inherited mutations known as Single Nucleotide Polymorphisms  (SNPs).¹ While mutations, or changes in DNA are associated with certain diseases, scientific studies have shown over 1 million mutations that occur in the human gene and are not disease-related.¹ Once unnatural substances such as drugs are introduced into the body, SNPs begin to take a toll. SNPs can alter an individual’s drug response by affecting both the coding and non-coding regions of a gene.¹ In coding regions, the occurrence of SNP can terminate the production of the normal/functioning protein.¹ This occurs because the presence of an SNP alters the nucleotide sequence of a gene which results in an altered amino acid sequence thereby producing a different protein instead of the normal functioning protein.

For instance, if an SNP occurred in a gene that codes for a form of drug metabolizing cytochrome P-450 enzyme, it would alter the gene resulting in a poor metabolizer.¹ As a result, the new enzyme is metabolizing the drug at a considerably decreased rate than the normal metabolizer causing decreased drug elimination.¹ If the drug dosage is not lessened for a patient with this SNP to account for slower metabolism, the patient faces ADRs risks and potential toxicity. Likewise, an SNP that leads to an increased metabolizer can also result. In both cases, the normal dosage can no longer be administered and the dosage has to be modified in accordance to the gene charges in order to avoid any unwanted effects.

While SNPs in coding regions hinder the production of a normal protein, DNA changes in non-coding regions alter how the gene is regulated. The discovery of SNPs has underscored the importance of pharmacogenetics which is concerned with understanding how genes influence drug metabolism. Knowing a patient’s metabolizing characteristics can guide the selection of an effective drug therapy and also increase patient safety by guiding drug dosage.¹Such pharmacogenetic information can enable pharmacists to provide their patients with personalized medicine, tailoring drug therapy to a patient’s unique genetic makeup.

As current medicine veers toward individualized therapy, pharmacists are at the forefront of initiating change. Through the use of genetic screening, pharmacists can evaluate genes that encode certain drug metabolizing enzymes before dosing a drug. Such information can then be used to determine the appropriate drug as well as optimal dosing while minimizing and avoiding toxicity.

Genetic screening is only one of the targeted applications of gene therapy. Once a defective gene is found to contribute to the cause and progression of a disease, replacement genes can then be implemented. Current methods of integrating the replacement gene or transgene are performed by using vectors, which are vehicles that transport the transgene into the target cells.³ This transduction can be performed with cultured cells (ex vivo) or cells residing in the body (in vivo).³

Defective gene replacement is more than a theory. Currently, viral vector therapy has been used to treat certain cancers.  Retroviruses are a type of viral vector in which the RNA virus integrates into the host cell genome and replicates during cell division and therefore can make permanent alterations. Retroviruses have demonstrated some success in cancer patients. In 2003, a study that employed retroviral gene therapy to target cyclin G1 gene in treatment of pancreatic cancer was conducted.² The study suggests that the drug is well tolerated and may control tumor growth in patients with chemotherapy-resistant pancreatic cancer.² Retroviruses have also been used to develop cancer vaccines devised to stimulate the immune system to recognize and destroy cancer cells.² Retroviruses are not the only type of vector therapy being researched. Adenoviruses, another type of viral vector, consist of nucleic acid coated with a protective coat of protein called capsid and lack an outer lipid bilayer. Unlike retroviruses, adenoviruses do not replicate and therefore efficiently target non-dividing cells. Adenoviruses instigate alterations that are not permanent.²

Both of the vectors discussed above are known as gene delivery vectors, and as the name itself implies, both serve as agents of specific gene delivery. In order to effectively deliver a transgene into a particular cell, the genetic material must be packaged into a structure which bears a ligand specific to the cell’s receptors. Gene transcription, another method of transduction, is more selective and concerned primarily with targeting tumor cells. By utilizing a promoter that is transcriptionally active in transformed cells only, it is theoretically possible to restrict the expression to malignant cells22.

But if vector systems are to become an optimal means of combating diseases, there are many setbacks and challenges that need to be overcome. In order to produce a particular therapeutic response, sufficient amounts of transgene must be inserted into a sufficient number of recipient cells. Due to their small packaging capacities, viruses often result in inefficient gene delivery and inadequate gene expression. Also, depending upon their discrete biological characteristics, viruses are limited to tissues that express the corresponding receptor. Thus, certain viruses are compatible with certain tissues and therefore limited in their applicability. Insertional mutagenesis is another major problem. A transgene must be inserted into the correct chromosomal position of the correct cell nucleus so that it will not interfere with normal gene function and expression.

Despite some its uprising challenges, gene therapy has witnessed substantial progress promising cures for some of the most debilitating illness in the not too distant future.

SOURCES:

1. Derr, A., Kane M. D., Kisor, D. F., Likovich, M., Sprague, J. E., (n. d.).  Personalized             medicine and the future of pharmacy practice. In Pharmacy Times. Retrieved       October 27, 2012, from https://secure.pharmacytimes.com/lessons/201004-01.asp
2. Sadelain, M. & Ronald, B. G. (2001). Imaging transgene expression for gene therapy.             Journal of Pharmacy Practice, 14. Retrieved from    http://jpp.sagepub.com/content/14/5/376
3. Smith, T.J. (1996). Gene therapy: Opportunities for pharmacy in the 21st century.        American Journal of Pharmaceutical Education, 60. Retrieved from    http://archive.ajpe.org/legacy/pdfs/aj6002213.pdf