Exploring the Landscape of Gene Therapy

Pharmacy Practice in Focus: OncologyDecember 2023
Volume 5
Issue 8

An overview of how gene therapy has evolved since its inception, current applications, and emerging challenges.

Gene therapy is best defined as the management of a disease or disorder through the introduction of genetic material into an individual’s cells to either correct mutated or absent genes or to modify cells by giving them new characteristics. The completion of this process has been shown to provide dramatic improvement in a patient’s burden of disease and even long-lasting cure. Ultimately, gene therapy has expanded treatment options for diseases that were once thought to be either difficult to manage or entirely incurable.

Illustration from research for genomic medicine or gene therapy.

Image credit: RFBSIP | stock.adobe.com

This novel treatment has been predominantly studied in monogenic diseases. The primary objective during this research has been to attain lasting expression of the therapeutic gene, commonly referred to as the transgene, at a level that effectively alleviates or cures disease symptoms while minimizing adverse effects (AEs).1 There are also currently 32 FDA-approved cellular and gene therapy products and at least 2600 gene therapies in clinical development, making it highly probable that additional novel therapies will emerge in the near future.2,3

The Journey of Gene Therapy

In the 1960s, the basic principles of gene transfer in bacteria were discovered and later adapted to pioneer gene transfer techniques to eukaryote cells. As scientists began learning more about how viruses transfer genetic material, viral vectors emerged as a highly promising means for inserting desired genes into DNA. Following this discovery, scientists further advanced the field of gene therapy by developing ex vivo and in vivo transduction strategies. In ex vivo transduction, hematopoietic stem and progenitor cells (HSPCs) are extracted from the patient, genetically modified with the desired gene, and reintroduced into the patient, where the newly gene-corrected HSPCs can engraft and self-renew. In contrast, the process of in vivo transduction is similar to the delivery of other types of pharmaceutical agents—the vector-gene construct is first stored frozen, and then it is thawed and administered directly into the target tissue. Initially, gene therapy was proven to be beneficial in addressing monogenic diseases, such as severe combined immunodeficiency (SCID) and β-thalassemia. In both of these diseases, the mutation is confined to one specific gene and can be corrected or replaced with a functional one.

After decades of research were plagued by challenges in trial design, breakthroughs in vector development led to the first successful clinical trial of gene therapy in 1990 when scientists at the University of Pennsylvania in Philadelphia successfully treated a girl aged 4 years who had adenosine deaminase– deficient SCID, which is a disease that is typically fatal in early childhood.4 Using a retroviral vector, a functioning copy of adenosine deaminase was transferred into her T cells via ex vivo transduction. Although she still partially relied on recombinant adenosine deaminase, she was able to live a normal life.

However, the development of gene therapy continued to experience challenges, 2 examples of which include the concerns of lethal immune reactions and insertional mutagenesis. In 1999, Jesse Gelsinger, who was aged 18 years and had a rare metabolic disease called ornithine transcarbamylase deficiency syndrome, volunteered to receive an adenoviral vector that encoded a normal copy of the ornithine transcarbamylase gene. Unfortunately, he died almost immediately after being given the therapy because of a severe coagulation disorder and multiorgan failure, and this was found to be because of an immune reaction to the adenoviral vector. Gelsinger was the first person to die as a result of gene therapy–related AEs. In 2000, European researchers reported the success of a gene therapy clinical trial that replaced the cytokine receptor IL2RG gene in patients with X-linked SCID. However, during this trial, 5 of the 20 children treated later went on to develop T-cell leukemia because of proto-oncogenes being activated as a consequence of vector integration.

Despite these setbacks, gene therapy developments have evolved rapidly. In 2017, a pivotal moment occurred when the FDA granted approval for 2 chimeric antigen receptor (CAR) products, tisagenlecleucel (Kymriah; Novartis) and axicabtagene ciloleucel (Yescarta; Kite Pharma), setting a significant precedent for future developments.4

Mechanism of Action and Transduction Strategies

Typically, therapeutic gene therapies involve the transfer of genetic material into cells with the aim of reversing an abnormal condition. Gene therapy is also utilized to introduce modified alleles into cells, giving them new characteristics. Examples include incorporating CAR structures into CAR T cells or implanting suicide genes into cancer cells.5

As discussed previously, ex vivo and in vivo are the 2 main strategies in which the transgene is delivered.6 In ex vivo transduction, cells are extracted from the patient and genetically modified with the desired gene. Prior to these modified cells being reintroduced into the patient, conditioning with low-dose busulfan or another alkylating agent is required for myelosuppression. These modified cells are then reintroduced into the patient.

An example of ex vivo transduction is betibeglogene autotemcel (Zynteglo; Bluebird Bio), an FDA-approved therapy for transfusion-dependent β-thalassemia, a genetic blood disorder characterized by a deficiency in hemoglobin production.7 The patient’s HSPCs are harvested and then undergo gene transfer using a lentiviral vector that contains the complementary DNA for β-globin, which is a hemoglobin subunit β transgene. The gene-corrected HSPCs are then reintroduced into the patient via intravenous infusion, where they engraft into the bone marrow and differentiate into all hematopoietic lineages. As a result of the vector design, the β-globin gene is expressed only in the erythroid lineage.

An example of in vivo transduction is voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics), which is a treatment for RPE65-related Leber congenital amaurosis, a severe inherited retinal degeneration that typically presents in early childhood and can rapidly result in complete blindness.8 In this approach, the RPE65 gene is delivered using an adeno-associated viral (AAV) vector by injection beneath the neural retina. During the injection, the vector is suspended in fluid and a cavity is formed beneath the retina. In this environment, the vector transduces the retinal pigment epithelial cells and corrects the mutated gene. However, in contrast to ex vivo transduction, the transgene does not integrate into the cell’s DNA but remains episomal.

CAR T-Cell Therapy

Although gene therapy is recognized as a treatment option for certain rare genetic disorders, it has also created significant advancements in cancer therapy. Perhaps the most well known and successful application of gene therapy within the cancer realm is CAR T-cell therapy. In this approach, patient-specific T cells are genetically modified to express chimeric receptors on their surface. These receptors include a specific antibody fragment, enabling CAR T cells to identify and interact with tumor-specific antigens.9

One of the first FDA-approved CAR T-cell therapies was tisagenlecleucel for the management of relapsed/ refractory (R/R) B-cell acute lymphoblastic leukemia (ALL).10 Tisagenlecleucel utilizes a lentiviral vector and ex vivo gene transduction. The phase 2, multicenter, single-cohort ELIANA trial (NCT02435849) evaluated the use of tisagenlecleucel in children and young adult patients with CD19+ R/R B-cell ALL. During the trial, the remission rate was promising at 81% within 3 months, with overall survival of 90% at 6 months and 50% at 12 months. However, grade 3 or 4 AEs that were suspected to be related to tisagenlecleucel treatment occurred in 73% of patients and primarily included cytokine release syndrome and neurologic events managed with supportive care. Overall, a single infusion of tisagenlecleucel provided durable remission with long-term persistence, although at the cost of transient high-grade toxic effects.

Another CD19-directed CAR T-cell therapy, axicabtagene ciloleucel, was FDA approved shortly after the accelerated approval of tisagenlecleucel in 2017. Similar to tisagenlecleucel, axicabtagene ciloleucel is indicated for the management of R/R large B-cell lymphoma. Since the approvals of tisagenlecleucel and axicabtagene ciloleucel, several other CAR T-cell therapies have been FDA approved, such as idecabtagene vicleucel (Abecma; Bristol Myers Squibb), for the management of R/R multiple myeloma.11,12

Limitations of Gene Therapy

There have been few reported AEs following the intravenous infusion of AAV-based gene therapy. However, some individuals have experienced mild infusion-related complaints, and more severe reactions such as hypotension and fever have been observed in clinical studies.13

The administration of AAV vectors triggers an innate immune response, subsequently leading to adaptive immune responses that result in the production of long-term neutralizing antibodies that could result in diminishing the effects of gene therapy. In addition to physical consequences, gene therapy may often carry a psychological toll as well. Results from a survey of patients with hemophilia B treated with gene therapy revealed that apprehensions regarding the duration of the treatment’s efficacy were common. Many patients expressed that psychological support would be essential if their disease were to relapse.14

As expected in the case of such innovative and personalized treatments, gene therapy carries a hefty price tag. The high cost of gene therapy stems from the demanding research and development process, intricate manufacturing requirements, limited patient populations who qualify for such personalized treatment, and the immense potential for life-changing benefit in an otherwise incurable disease. As such, the cost-benefit ratio of gene therapy is a highly debated topic. Onasemnogene abeparvovec (Zolgensma; Novartis), a one-time gene therapy indicated for the management of spinal muscular atrophy (SMA), is frequently recognized as the most expensive drug ever, at a price of $2.125 million for 1 dose. However, the intended patient population of infants born with the most severe form of SMA typically do not live past the age of 2 years.15

Another example that illuminates the cost-benefit analysis of gene therapy is seen in the management of hemophilia B caused by deficiency of factor IX, a disease characterized by spontaneous and traumatic bleeding, primarily into joints, which leads to chronic disability and pain. Current management of these patients requires costly infusions of factor replacement products several times weekly as prophylaxis against bleeding episodes.

Currently, there is one FDA-approved gene therapy for hemophilia B: etranacogene dezaparvovec (Hemgenix; Uniqure), which was approved in November 2022, and is priced between $2 million and $3 million. Another gene therapy, fidanacogene elaparvovec (Pfizer), had a Biologics License Application accepted by the FDA in June 2023, with a Prescription Drug User Fee Act goal date set for the second quarter of 2024. Fidanacogene elaparvovec will likely be priced between $2 million and $3 million. These gene therapies have demonstrated a more than 90% reduction in bleeding events and factor use, with sustained factor expression for up to 3 years.15 Although the cost of gene therapy for hemophilia B is steep, this cost is recommended to be compared with the cost of factor replacement products, orthopedic surgery, bleeding management, and hospitalization over an adult lifetime.16


The advancements made in the field of gene therapy over the past decade provide promising therapeutic options for a wide variety of diseases, spanning from fatal genetic disorders to the R/R cancer setting. Nevertheless, overcoming the challenges posed by gene therapy, including the cost-efficacy analysis, severe AEs, and patient apprehension about its efficacy will require persistent collaborative effort to optimize this novel advancement in medicine. Future goals to advance gene therapy further include better lentiviral vector design to improve safety and transgene control and the development of less toxic conditioning regimens, which would reduce further complications to improve the survival and quality of life for these patients.

About the Authors

Sean Hwang, PharmD, is a PGY2 oncology pharmacy resident at University of Washington Medicine and Fred Hutchinson Cancer Center in Seattle.

Anneliese Schuessler, PharmD, BCOP, BCPS, is a clinical oncology pharmacist at Fred Hutchinson Cancer Center in Seattle, Washington.

Samantha Culwell, PharmD, is a clinical oncology pharmacist at Fred Hutchinson Cancer Center in Seattle, Washington.


1. High KA, Roncarolo MG. Gene therapy. N Engl J Med. 2019;381(5):455-464. doi:10.1056/NEJMra1706910

2. Approved cellular and gene therapy products. FDA. Updated June 30, 2023. Accessed October 2, 2023. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

3. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: an update. J Gene Med. 2018;20(5):e3015. doi:10.1002/jgm.3015

4. Arabi F, Mansouri V, Ahmadbeigi N. Gene therapy clinical trials, where do we go? an overview. Biomed Pharmacother. 2022;153:113324. doi:10.1016/j.biopha.2022.113324

5. Seimetz D, Heller K, Richter J. Approval of first CAR-Ts: have we solved all hurdles for ATMPs? Cell Med. 2019;11:2155179018822781. doi:10.1177/2155179018822781

6. Mai D, June CH, Sheppard NC. In vivo gene immunotherapy for cancer. Sci Transl Med. 2022;14(670):eabo3603. doi:10.1126/scitranslmed.abo3603

7. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia. N Engl J Med. 2022;386(5):415-427. doi:10.1056/NEJMoa2113206

8. Daich Varela M, Cabral de Guimaraes TA, Georgiou M, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials. Br J Ophthalmol. 2022;106(4):445-451. doi:10.1136/bjophthalmol-2020-318483

9. Jayaraman J, Mellody MP, Hou AJ, et al. CAR-T design: elements and their synergistic function. EBioMedicine. 2020;58:102931. doi:10.1016/j.ebiom.2020.102931

10. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866

11. Yescarta. Prescribing information. Kite Pharma; 2022. Accessed October 2, 2023. https://www.fda.gov/media/108377/download

12. Abecma. Prescribing information. Bristol-Myers Squibb; 2021. Accessed October 2, 2023.https://www.fda.gov/media/147055/download

13. Leebeek FWG, Miesbach W. Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Blood. 2021;138(11):923-931. doi:10.1182/blood.2019003777

14. Garrison LP Jr, Jiao B, Dabbous O. Gene therapy may not be as expensive as people think: challenges in assessing the value of single and short-term therapies. J Manag Care Spec Pharm. 2021;27(5):674-681. doi:10.18553/jmcp.2021.27.5.674

15. Ragni M. Royal gene therapy at a royal cost. Blood. 2021;138(18):1645-1646. doi:10.1182/blood.2021012129

16. Bolous NS, Chen Y, Wang H, et al. The cost-effectiveness of gene therapy for severe hemophilia B: a microsimulation study from the United States perspective. Blood. 2021;138(18):1677-1690. doi:10.1182/blood.2021010864

Editor's Note: This article was update on December 18, 2023 at 1:45 PM ET.

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