Chapter 14 - Gene therapy: advocacies, perspectives, and ethical provocations

Abstract

It has been a desire in medicine to be able to alter precise locations in the human genome ever since it was discovered that genes are the fundamental unit of inheritance. In 1990, the National Institutes of Health approved the first case of gene therapy for severe combined immunodeficiency, bringing attention to the potential future use of genes for therapeutic purposes. Numerous therapies have been accepted, started, or finished since that time. Gene therapy is now possible because of genetics and bioengineering, which have made it possible to employ vectors (or carriers) to transfer extrachromosomal material to target cells. Gene therapy kills cells by introducing killer genes, replaces dysfunctional or damaged genes with good ones, and inhibits gene expression. Additionally, single nucleotide polymorphisms (SNPs) account for 90% of all variations, demonstrating that genetic diversity is produced daily by changes in the nucleotide sequence. SNPs offer a high-density biological identifier that can be used to locate genes linked to human disease. Familial disorders are caused by many gene variants that are passed down to offspring (known as heritable or germline mutations) and persist in particular human lineages. Innovative strategies for preventing the transmission of dangerous defects from parent to child have become more popular as a result of the prevalence of genetic diseases. Somatic cell gene therapy, germline gene therapy, in-vivo gene therapy, and ex-vivo gene therapy are now categories for gene therapy procedures based on the cell type involved in the process. During early embryonic development, when the mutation is present in a small number of embryonic cells, germline gene therapy has the ability to transform disease-causing mutations into wild-type variants. Somatic gene therapy refers to experimental gene therapy procedures that treat people’s damaged somatic tissues or organs. Today, a wide range of diseases, including cancer, cardiovascular, monogenic, neurological, ophthalmic, and metabolic problems, are treated with gene therapy. The use of germline gene therapy to repair mitochondrial DNA mutations, which if left untreated may result in a wide range of chronic, irreversible disorders in both children and adults, is on the rise. Today, gene therapy is also utilized to repair DNA double strand breaks brought on by stress from the environment or errors in DNA replication during the S phase of the cell cycle. Numerous new prospects for the management and treatment of previously incurable diseases are now available because to recent advancements in gene therapy techniques. Gene delivery techniques are vital for employing gene therapy to cure human genetic illnesses. Gene therapy is only effective if the genetic material is successfully incorporated into the cell’s nucleus. The capacity for viruses to stick to their hosts and effectively transfer their genetic material into the host cell is a natural trait. Herpes simplex virus, lentivirus, adenovirus, and adeno-associated virus are a few examples of viral vectors that have demonstrated efficacy and safety in delivering drugs. The immunogenicity, cytotoxicity, and insertional mutagenesis—the ectopic integration of viral DNA into chromosomes—of viral vectors are just a few of their downsides. The creation of nonviral systems is the result of these limitations. Physical nonviral systems include plasmids, DNA bombardants, electroporation, hydrodynamic ultrasound, and magnetofection (chemical: cationic lipids, different cationic polymers, and lipid polymers). Nonviral vectors have a far lower immunogenicity and are less likely to result in homologous recombination or insertional mutagenesis after being taken up by the cells. Their clinical usefulness is restricted by low transfection efficiency, which is brought about by nonspecific vector uptake by epithelial barriers and extracellular matrix as well as poor transport into therapeutic target cells. Since gene therapy entails changing the DNA of a patient’s inherent genetic makeup, it raises ethical questions in the eyes of some. One of the many challenges that must be solved in order to develop medicine is these ethical issues. As an illustration, human germline gene therapy, which modifies the DNA of human germ cells rather than somatic cells to prevent the disease in future generations, is not without danger. Eugenics and the uncertainty of safety and results trump the treatment’s original intended goal in situations like these. Human trials for these medicines cannot be permitted until there is clear evidence that the benefits outweigh the side effects. Issues related to medical ethics deal with much more than just diseases and their prevention and treatment because there are often divergent schools of thought in science about a particular conundrum and people may not agree with one another. Instead, they also take into account human sentiments, economic viability, and equal accessibility for the general public. The goal of this chapter is to discuss the ethical concerns associated with genome editing, while highlighting the many types of gene therapies and vectors used.