This blog post examines how the side effects of viral vectors and the potential for mutations impact the safety and future prospects of gene therapy. It provides a balanced analysis of the risks emerging alongside the technology’s potential.
In today’s aging society, where human lifespan continues to extend, life and health have become major concerns shared by all citizens of the Republic of Korea. Among these, diseases that were previously considered incurable are now drawing significantly heightened attention. While some of these incurable diseases, like baldness, cause relatively minor dissatisfaction in daily life, others are severe enough to determine the length and quality of an individual’s life. A significant portion of these incurable diseases are genetic disorders. This includes not only classic genetic disorders like Myeloid Dysplasia Syndrome or Down Syndrome, but also diseases like dementia, cancer, and leukemia, where genetic factors alone do not guarantee 100% onset, but where the likelihood of developing the disease is significantly influenced by genetics. Gene therapy holds the key to treating these incurable diseases, which have long been perceived as requiring lifelong caution once contracted. Simply put, the principle of gene therapy involves replacing abnormal genes with normal ones to eliminate the root cause of genetic diseases or the adverse effects on individuals carrying those genes. This treatment is conducted through two approaches: somatic cell gene therapy and germline gene therapy. Recently, stem cell gene therapy has also been actively developing. This therapy has steadily advanced over approximately 30 to 40 years since the 1980s, and its potential and scope of application continue to expand through diverse research today. So, let’s now take a closer look at this groundbreaking treatment.
Begun by scientist Martin Klein in 1980, this research faced a crisis where gene therapy risked being buried in indifference after repeated failures in early clinical trials. However, as gene therapy began to be utilized for treating various diseases such as optic atrophy and ADA-deficient severe combined immunodeficiency (SCID), it regained prominence as a highly anticipated biomedical technology. The principle of gene therapy can be simply summarized as using a viral vector as a carrier to introduce the necessary gene sequence (DNA or RNA) into the patient’s genome. Initially, viruses were primarily used as vectors. However, concerns arose that viral vectors could cause additional harm to patients, such as infection or immune reactions. Consequently, non-viral carriers, which differ from viral vectors, have recently begun to be used. While non-viral carriers have the advantage of reducing harm from infection or immune reactions, they have not yet become widely adopted due to the disadvantage of lower gene expression efficiency. Non-viral gene therapy methods include electroporation, gene guns, ultrasonic perforation, and magnetic injection. While early gene therapy focused on treatment through changes in protein expression, recent gene therapy is moving towards directly modifying the genome.
Classifying gene therapy by target, the first method is somatic cell gene therapy. As the name implies, this method treats genes in somatic cells, which constitute the majority of the human body. Its key difference from germline gene therapy, discussed later, is the presence or absence of heritability. Somatic cell gene therapy targets genes in somatic cells, which have no potential for inheritance. This approach is currently the most actively used method among gene therapies and is primarily applied to treat severe genetic diseases like immunodeficiency or hemophilia. These genetic diseases share the common feature of being single-gene disorders. Since current gene therapy technology has not yet reached a level capable of completely curing multi-gene disorders, single-gene disorders make highly suitable experimental candidates for somatic cell gene therapy.
The second approach is germline gene therapy. If fully successful, this therapy can pass on the normal gene directly to offspring, fundamentally eliminating the possibility of the genetic disease manifesting in descendants. This makes it a highly promising treatment. Consequently, it is primarily applied to diseases with a very high likelihood of inheritance and those primarily expressed in germ cells. In this therapy, functional genes (genes that actually function, such as those expressed, also called exons) are inserted into the genome of the germ cells to replace the disease-causing gene with a normal one. While this therapy holds the significant advantage of potentially curing genetic diseases, it is also banned in many countries due to the risk of abuse, as the modified gene could be passed on unchanged. Thus, while germline gene therapy holds immense potential, it remains a contentious field due to the ethical and societal issues it raises.
However, this therapy still faces several limitations. When viral vectors are used, immune responses can potentially act as a side effect, occurring consistently. While injecting viruses for therapeutic purposes may be perceived as positive by the human brain, the immune system interprets it entirely differently. It is only natural for an immune response to occur when a substance unfamiliar to the body enters the system. Attempts are being made to utilize non-viral carriers to solve these problems, but non-viral carriers have not yet reached a level of sufficient utility. If such immune rejection intensifies, it can lead to death; indeed, three deaths have already occurred in clinical trials. Furthermore, the fact that the therapeutic effect is maintained for only a very short period is also raised as a significant problem. DNA introduced for therapeutic purposes must remain in the genome in a persistent and stable manner. However, if this stability is not ensured, patients face the problem of needing repeated treatments. While various issues exist, the most serious concern is the potential for mutations. Mutations refer to the alteration of specific genes relative to the standard genetic makeup of the same species. Since gene therapy technology has not yet reached a level where it can selectively modify only the desired gene region with the desired precision, there is a risk that fatal symptoms could be induced if modifications occur in regions related to tumor suppressor genes or hormone expression.
To address these issues, a new treatment method called stem cell gene therapy has been introduced and is currently receiving significant attention. This approach was specifically proposed to address the issue of increased treatment frequency due to short treatment duration, among the various problems outlined earlier. Targeting stem cells with self-renewal capabilities, this therapy helps ensure the desired gene persists long-term within the body. It is generally applied to various stem cell types, including hematopoietic stem cells, neural stem cells, and mesenchymal stem cells. The potential to reduce treatment frequency is significant from the patient’s perspective, as it lessens both the financial and time burdens and alleviates the psychological pressure associated with the treatment process. Therefore, this approach is evaluated as a method with great potential to significantly contribute to the future advancement of gene therapy.
Utilizing gene therapy allows for the direct surgical repair or replacement of specific mutated gene segments with normal genes. This technique holds significant importance as a fundamental cure that eliminates the root cause of disease, unlike conventional treatments used until now, which merely suppress symptoms or provide alternative measures to make outward appearances normal. Advances in gene scissors technology have opened the possibility of treating various genetic diseases long considered incurable, and even conditions previously regarded as relatively minor, such as baldness. In modern society, rapidly aging and increasingly spotlighting the life and medical industries, gene editing technology holds great promise. It could become a useful tool for increasing the average human lifespan and act as a kind of savior for those living with the risk of incurable diseases due to congenital factors or family history. Furthermore, its significance is amplified by its high potential for application not only in the medical industry but across diverse fields.
However, like all technologies, gene therapy can be a double-edged sword. It is still impossible to guarantee with absolute certainty that gene therapy can selectively and precisely modify only the desired DNA base sequences at specific locations within the human genome. Moreover, it is difficult to predict what new mutations might arise when altering human genes using this technology. Furthermore, there is no guarantee that gene therapy will always proceed as intended, and the potential for technical errors remains quite high. Therefore, this technology can only be perfected as a useful tool for humanity through continuous development and research to minimize potential side effects, while simultaneously establishing ethical and legal safeguards to prevent its misuse.
