Gene therapies show promise for pediatric treatment

March 17, 2020

Gene therapies have ushered in an exciting new era of treatment for some of the most challenging pediatric conditions, and the results are most encouraging.

Approximately 20 years ago, the tragic death of a young man with ornithine transcarbamylase deficiency marked the first death related to gene therapy and sent shock waves throughout the medical community. Since then, the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA) have taken steps to ensure patient safety by modifying their guidelines and oversight with organizations such as the Recombinant DNA Advisory Committee and the Genetic Modification Clinical Research Information System (GeMCRIS).1

The vehicles used to carry genetic material also have changed, resulting in a reduction in adverse effects. For example, adeno-associated virus vectors have replaced the previously used adenovirus vectors and invoke a weaker immune response. Additionally, the development of self-inactivating (SIN) viral vectors has decreased the risk of unintentional insertions of the vector-activating proto-oncogenes. This was linked to the development of leukemia in some patients with X-linked severe combined immunodeficiency (SCID) who received earlier forms of gene therapy.2 A handful of relatively newly approved gene therapies are currently available with encouraging results. Long-term outcomes of these treatments are still unknown.

FDA-approved pediatric gene therapies

Currently, there are 3 FDA-approved gene therapies for pediatric patients (Table 1 and below), but more are in various stages of research and development (Table 2).


Acute lymphocytic leukemia (ALL) is the most common pediatric malignancy. Fifteen percent to 20% of those with B-cell ALL are not responsive to initial treatment or will have a relapse. Kymriah was the first FDA-approved gene therapy to treat patients aged to 25 years who have refractory B-cell precursor ALL or at least 2 relapses. Kymriah is a chimeric antigen receptor (CAR) T-cell therapy wherein a patient’s own cells are genetically modified ex-vivo to contain genes that code for CARs. These modified T cells are then infused back into the patient. These receptors direct the T cells to target CD19 on the B-precursor lymphoblasts.

A common and serious adverse effect is cytokine release syndrome (CRS), which can lead to hypotension, pulmonary edema, and coagulopathy.3,4 In a recent pediatric and young adult clinical study, Kymriah was shown to have an 81% remission rate at 3 months with a 90% survival rate at 6 months and 76% survival rate at 12 months. Seventy-seven percent of patients had CRS and 40% had neurologic events.5 In order to minimize reactions, administration of Kymriah is held if the patient has an active infection or inflammatory disorder. Additionally, because of these risks, only certified places are allowed to administer Kymriah. Currently there are 54 centers in the United States.6


Biallelic RPE65 pathogenic variant-associated retinal dystrophy is thought to affect between 1000 to 2000 persons in the United States. This is associated with 2 conditions that cause alterations in vision, with a large portion of these patients having Leber congenital amaurosis and a smaller portion having retinitis pigmentosa. With Luxturna, a viral vector administered via subretinal injection delivers a normal copy of the RPE65 gene.7,8 Long-term follow-up of participants who received Luxturna varies with some studies showing initial improvement in visual sensitivities with a peak between 6 months and 3 years, but this effect declined or disappeared between 3 to 6 years after treatment. Ongoing efforts aim to determine the optimal dosing schedule and timing to improve outcomes.9


Occurring in 1 in 10,000 live births, spinal muscular atrophy (SMA) is an autosomal recessive condition attributed to pathogenic mutations or deletions of the SMN1 gene. Patients with SMA have degeneration of the motor neurons and subsequent muscle weakness. Some die in early childhood secondary to respiratory failure. Zolgensma is indicated for patients with SMA aged younger than 2 years who have biallelic pathogenic mutations in SMN1. Zolgensma is a viral vector that delivers a copy of SMN1.


Clinical studies have shown that patients who received Zolgensma have prolonged survival, improved motor skills, and less dependency on permanent ventilation compared with the natural history cohort. One ongoing trial that enrolled 21 patients with the average age of 3.9 months showed survival without permanent assisted ventilation in 19 of them at 7.9 to 15.4 months after treatment. Based on natural history reports, approximately 5 patients would have survived past 14 months without permanent assisted ventilation.10 Of note, nusinersen (Spinraza) is another therapeutic option for children with SMA. It increases the production of protein required to maintain the motor neurons, but it is not a gene therapy. No clinical trials comparing Spinraza to Zolgensma have been completed.11

Note from Dr. Lee

Refinements to gene therapy technology have produced viable life-saving therapies for devastating genetic diseases such as SMA. The price of these agents may seem overwhelming at first, but their single dose regimen may actually be more cost effective than the traditional life-long chronic therapies with potentially better efficacy. We look forward to the long-term effect of these therapies with the development of additional therapies in the future. – Carlton Lee, PharmD, MPH, FASHP, FPPAG


1. Collins FS, Gottlieb S. The next phase of human gene-therapy oversight. N Engl J Med. 2018;379(15):1393-1395.

2. Kumar SR, Markusic DM, Biswas M, High KA, Herzog RW. Clinical development of gene therapy: results and lessons from recent successes. Mol Ther Methods Clin Dev. 2016;3:16034.

3. US Food and Drug Administration (FDA). FDA approval brings first gene therapy to the United States [news release]. Available at: Published August 30, 2017. Accessed January 29, 2020.

4. Tisagenlecleucel (Kymriah) for ALL. Med Lett Drugs Ther. 2017;59(1532):177-178. 

5. 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.

6. Novartis Pharmaceuticals Corporation. Find a KYMRIAH treatment center. Available at: Published March 2019. Accessed January 29, 2020.

7. US Food and Drug Administration (FDA). Cellular and gene therapy products: Luxturna. Available at: Published July 26, 2018. Accessed January 29, 2020.

8. Voretigene neparvovec-rzyl (Luxturna) for inherited retinal dystrophy. Med Lett Drugs Ther. 2018;60(1543):53-55.

9. Wright AF. Long-term effects of retinal gene therapy in childhood blindness. N Engl J Med. 2015;372(20):1954-1955.

10. Zolgensma-one-time gene therapy for spinal muscular atrophy. Med Lett Drugs Ther. 2019;61(1577):113-114.

11. Sandrock AW, Farwell W. Comparisons between separately conducted clinical trials: letter to the editor regarding Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guérin A, et al. Adv Ther (2019) 36(5):1164-1176. doi;10.1007/s12325-019-00923-8. Adv Ther. 2019;36(11):2979-2981.

12. Conditions by state. Baby’s First Test website. Available at: Published 2020. Accessed January 30, 2020.

13. website. Available at: Accessed January 30. 2020.

14. Harrison C. First gene therapy for β-thalassemia approved. Nat Biotechnol. 2019;37(10):1102-1103.


15. Bluebird bio. A study evaluating the safety and efficacy of the LentiGlobin BB305 drug product in severe sickle cell disease. Available at: Updated August 19, 2019. Accessed January 30, 2020.