Gene Therapy: Process, Uses and Benefits

Overview

Gene therapy is a medical technology that has been recognized as one of the most important developments in medicine in recent decades. Unlike traditional medicines that manage only the symptoms of disease, gene therapy seeks to address the genetic causes of disease. Through gene therapy, researchers and physicians are able to treat many diseases that until recently were thought to be incurable. As the field continues to grow, what was once experimental gene therapy is becoming increasingly accepted as a clinical treatment option.

What Is Gene Therapy?

Gene therapy is a medical technology that aims to treat or prevent disease by modifying or replacing a faulty gene in a person's cells. Every cell in the human body contains DNA, which provides the instructions necessary for growth, function, and repair. If a mutation occurs in a gene, it can result in significant health problems.

Gene therapy addresses the cause of a problem directly. Rather than providing a prescription to manage the consequences of a flawed gene, gene therapy treats the source of the flaw. Gene therapy can introduce working versions of a gene that was missing, turn off a gene that is producing excessive amounts of protein, or edit the genetic code to restore normal functioning.

How Gene Therapy Works

Gene therapy accomplishes its goal by introducing genetic material into a person's cells to correct a malfunction. The process requires delivery vehicles called vectors, which bring the therapeutic gene to the appropriate cells. Because viruses are highly effective at entering host cells and transporting genetic material, scientists commonly use modified viruses as vectors. Scientists alter these viruses so they will not cause disease while still allowing them to deliver healthy copies of a gene into the body.

Once inside the cell, the newly introduced genetic material combines with the existing cellular DNA or operates separately to generate the needed proteins. Depending upon the nature of the illness being treated, various cells are targeted. While some therapies involve genetically altering cells outside of the body in a laboratory prior to returning those altered cells to the patient, others deliver the virus to the location of the damaged tissues and allow it to enter those tissues.

Types of Gene Therapy

While there are two main forms of gene therapy, both offer varying degrees of hope for treating different illnesses and using different delivery mechanisms.
 Somatic gene therapy targets non-reproductive cells in a patient. Any alterations to these cells will be limited to the patient and will not be transmitted to future generations. Somatic gene therapy is the most common type of gene therapy being applied clinically today.

Germline gene therapy alters reproductive cells or embryos. Therefore, any alteration would be passed on to future generations. Due to numerous safety concerns and ethics issues regarding germline modification, germline modifications remain largely prohibited from clinical application.

Within somatic gene therapy, there are several strategies.

• Gene replacement introduces a fully functional version of a mutated gene.
• Gene silencing utilizes molecular techniques to "turn off" a problematic gene.
• Gene editing utilizes tools such as CRISPR-Cas9 to precisely modify the genetic code.
• CAR-t cell therapy engineers an individual's Immune cells to recognize and attack cancerous cells.

Process of Gene Therapy Treatment

Each patient involved in gene therapy receives a combination of steps that differ based on the illness being treated and how the treatment is administered. Generally, however, all patients undergoing gene therapy treatment follow similar steps.

1. Firstly, doctors determine whether or not a patient is eligible for treatment. To do so, doctors conduct extensive evaluations including genetic studies, reviews of the patient's medical history, and overall physical examinations.
2. Doctors provide comprehensive explanations to patients detailing all aspects of the treatment plan, including the possible risks associated with the procedure, along with possible positive outcomes. 
3. After reviewing this information, patients must consent to participate in the study. 
   1. If the treatment is performed ex vivo (outside of the body), clinicians obtain samples from the patient's blood or bone marrow, which contain stem cells. Those cells are then taken out of circulation and placed in culture, and modified with gene therapy in a specialized laboratory. The modified cells are then reintroduced into the patient through an infusion. 
   2. If the treatment is performed in-vivo (inside the body), the viral vector carrying the corrected gene is administered directly to the patient through an IV infusion, direct injection into a particular tissue or organ, etc.
4. Patients are continuously evaluated after completing treatment through periodic blood tests, genetic analyses, and/or clinical assessments to monitor the efficacy of the treatment and identify any adverse reactions. Some gene therapies require only one round of treatment, whereas other therapies need multiple rounds over extended periods.

Benefits of Gene Therapy

The advantages offered by gene therapy far exceed those presented by traditional treatments. 

• Gene therapy targets the genetic basis of a disease as opposed to merely treating symptoms. This allows for the possibility of achieving long-term or possibly even permanent benefits through only one treatment regimen. For patients suffering from hereditary conditions that necessitate continuous medication and/or ongoing medical intervention throughout their lives, this presents a substantial improvement in quality of life.
• Additionally, since gene therapy enables treatment options for diseases that currently have no known effective treatment options, many diseases, such as spinal muscular atrophy, inherited retinal degenerative conditions, and some blood-related diseases, have approved gene therapy options that were unavailable just ten years ago.
• In addition to these applications in inherited diseases and disorders related to vision loss, personalized gene-based treatments utilizing CAR-T cell therapy have resulted in unprecedented responses among individuals with blood cancers that had exhausted all other treatment options.

Risks and Challenges of Gene Therapy

As mentioned above, there are very real risks associated with gene therapy that patients and practitioners should take great consideration in evaluating.
One major concern is an Immune reaction against the viral vector used to deliver the therapeutic gene. The body can perceive the virus as a foreign invader, leading to an Immune response ranging from minor inflammation to severe systemic reactions. Scientists are continuing to improve methods for delivering the vector to minimize this risk.

Another concern is off-target effects associated primarily with gene editing technologies. If incorrect sections of DNA are edited by mistake, it can lead to unintended disruptions elsewhere in the genome and potentially create new problems, including increasing an individual's susceptibility to developing cancer in certain instances.

There is also uncertainty regarding the long-term effects of treatments. There are times when the effects of a treatment wear off over time as modified cells replace unmodified cells, thereby resulting in repeated administrations.
Lastly, financial constraints and lack of access pose significant obstacles. Many approved gene therapies are priced extremely high, which limits accessibility for patients located in countries with underfunded public health systems.

What to Expect During Gene Therapy Treatment

The expectations for patients receiving gene therapy will vary greatly based upon specifics regarding the treatment plan for their illness and/or disorder. Most patients receive their treatment at specialty centers staffed by multidisciplinary teams familiarized with genetic medicine.

Prior to initiating treatment plans, patients will undergo extensive preparatory phases. Possible pre-treatment medications may include immunosuppressive drugs designed to suppress Immune responses which might be triggered by exposure to vectors, and conditioning regimens intended to prepare patients' bodies to accept modified cells.

Administration of treatments is often relatively simple. Many therapies require nothing more than an IV infusion lasting several hours. Patient status is continuously monitored during and immediately after administration for signs of initial adverse reactions.

Post-treatment monitoring includes assessing whether or not treatments are effective via blood work and/or genetic testing, along with clinical assessments. Side effects occurring post-treatment, such as fatigue and flu-like symptoms, are common for short periods of time following treatment. Serious adverse reactions rarely occur, but when they do require immediate medical attention.

References

Cox, D. B. T., Platt, R. J., & Zhang, F. (2015). Therapeutic genome editing: Prospects and challenges. Nature Medicine, 21(2), 121–131. 

Doudna, J. A., & Charpentier, E. (2012). The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213), Article 1258096.

Cavazzana-Calvo, M., Hacein-Bey, S., de Saint Basile, G., Gross, F., Yvon, E., Nusbaum, P., Selz, F., Hue, C., Certain, S., Casanova, J. L., Bousso, P., Deist, F. L., & Fischer, A. (2000). Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science, 288(5466), 669–672.

Bouard, D., Alazard-Dany, N., & Cosset, F. L. (2009). Viral vectors: From virology to transgene expression. British Journal of Pharmacology, 157(2), 153–165. 

Yin, H., Kauffman, K. J., & Anderson, D. G. (2017). Delivery technologies for genome editing. Nature Reviews Drug Discovery, 16(6), 387–399.