The History, Use, and Challenges of Therapeutic Somatic Cell and Germline Gene Editing
Authors: Ryu Junghyun , Adashi Eli Y. , Hennebold Jon D. 
Published: March 2024

Gene editing is a technology that has been rapidly developing and that has many applications as well as ethical and practical implications. This article is a review that outlines the history of current technology, as well as the advantages and challenges in use for somatic cell and germline gene editing. Clustered regularly interspaced short palindromic repeat (CRISPR) was first introduced in 2002 and initially saw limited use among researchers. However, in 2012, it was discovered that a nuclease associated with CRISPR (Cas9) could be used with guide RNA to cleave double-stranded DNA in specific places, raising the potential for targeted gene editing. Immediately, the scientific community saw endless possibilities of this technology for clinical therapies and treatment of genetic disorders. Currently, more than 110 gene editing–based therapies are in clinical trials, with 2 different treatments already in phase 3 clinical trials.

To date, all gene editing therapies that have progressed to clinical trials are somatic cell editing therapies. Germline gene editing, in which changes to genes can be passed to the next generation, is attractive for inherited diseases but has many ethical considerations and challenges that must be addressed before this technology is further developed. One concern is off-target editing events that could involve DNA sequences with high similarity to the target sequence. In addition to this, DNA breaks from Cas9 can result in chromosomal instability and possible abnormalities such as large deletions, translocations, and rearrangements. This could be problematic particularly in germline editing, where the effects are passed down to the next generation.

Gene editing does, however, have great potential. Somatic cell gene editing has been successfully used to prevent and treat disease. One advantage of somatic cells is that they can be removed, edited, and returned to the patient to proliferate normally. For the therapies currently in stage 3 clinical trials, there have been few instances of failure to modify the alleles and no evidence of off-target editing using this method. Somatic cell gene editing has successfully been used in animal models and in limited human trials to treat diseases with easily accessible in vivo sites, such as the eye. Germline gene editing has advantages over somatic cell gene editing, as therapies can be developed to permanently correct heritable genetic diseases. It could also be adapted easily during an in vitro fertilization process for parents who are carriers of 1 or more diseases to eliminate the risk of their offspring manifesting the disease. However, germline editing creates changes to the DNA that is then passed to offspring, raising ethical and safety concerns.

Many trials in animal models as well as early human clinical trials show promise for these treatments, but challenges remain including costs and logistical considerations such as time, space, and expertise. Another challenge is that because these therapies are targeted, each variation of each disease must be treated differently, with a therapy developed specifically for each disease and potentially even variations of the same disease. This again represents significant challenges related to cost, time, and expertise. Ethical challenges for germline gene editing include the use of human embryos, high rates of off-target editing, and possible severe chromosomal deletions depending on the target. Large chromosomal rearrangements, as required with attempting to eradicate certain diseases, have been recently shown to be more difficult and dangerous than smaller rearrangements. This presents a unique challenge that must be overcome before implementing this technique in any therapies.

There are many possibilities and exciting opportunities with gene editing therapies, some of which are closer to fruition than others. We are potentially close to implementing some therapies, such as those for sickle cell disease, while farther from broad use for other therapies. The pace at which this technology has developed is astounding, which brings hope that this research will continue to progress quickly, and we may be closer than we think to effectively treating genetic disease with gene editing technology.