Zolgensma for Spinal Muscular Atrophy: Overview and Ethical Concerns

Image by Qimono: Syringe and Pills

What is Spinal Muscular Atrophy?

Spinal Muscular Atrophy (SMA) is caused by a faulty Survival Motor Neuron 1 (SMN1) gene, leading to progressive weakening and shrinking of muscles (atrophy) (Biology Dictionary, 2020). Specifically, a defect in the SMN1 gene prevents effective regulation of alpha motor neurons in the spinal cord, leading to alpha motor neuron degeneration (Kolb et al., 2015). Alpha motor neurons allow muscular contraction by sending signals to motor neurons attached to skeletal muscles (Medline Plus, 2018). However, the degeneration of alpha motor neurons leads to the characteristic muscular atrophy because signals to motor neurons are impeded (Kolb et al., 2015).

Zolgensma: A potential SMA treatment

The disease can be treated by increasing the amount of the SMN protein through Zolgensma, where a normal exogenous SMN1 gene is delivered through a “nonreplicating self-complementary adeno-associated viral serotype 9 (AAV9) capsid vector” (Reed et al., 2018). This normal gene replaces the defective or nonexistent SMN1 gene and promotes normal regulation of alpha motor neurons. In a study, Zolgensma was administered to mildly severe SMA patients, where 3 took a low dose and 12 took a high dose. Results show that at 20 months of age, every participant survived. This is significant compared to a baseline survival rate of 8% without Zolgensma. (Reed et al., 2018)

Zolgensma Ethical Concerns

Despite the potential of Zolgensma, adverse events such as premature death, liver toxicity, impaired cardiac function, and peripheral tissue disease occurred in humans (Xie et al., 2024). Some of these side effects are linked to the overexpression of the normal SMN1 gene facilitated by Zolgensma, causing higher than normal SMN1 presence in certain areas. In addition, Zolgensma is extremely expensive, costing 2.1 million dollars for a single dose. (Pope, 2024) The cost of Zolgensma, as well as the potential side effects is concerning. Zolgensma's price can decrease the access of the life-saving treatment to poorer populations affected by SMA. Even if certain populations could receive the treatment, potential side effects are still a concern. There are efforts to create SMA treatments based off Zolgensma that aim to minimize adverse side effects associated with Zolgensma. One way is a treatment where SMN1 expression is tailored specifically to different regions of the body, since different regions need different levels of SMN1 expression to function normally (Xie et al., 2024) It is important to consider the effects and efficacy of Zolgensma, access of the treatment to the public, and the research and development costs of the treatment.

Conclusion

Zolgensma has a great therapeutic potential, being capable of replacing a defective or absent SMN1 gene. This can allow those affected by SMA to live a more normal, fulfilling life. However, Zolgensma isn't without its ethical concerns. It is crucial to consider potentially adverse side effects, public access, and efficacy when pioneering a significant treatment like Zolgensma. Considering these factors will contribute to a healthcare system that is viewed more positively by humanity.

References

Biology Dictionary. (2020, October 28). [Spinal Muscular Atrophy (SMA)]. Biology Dictionary. https://biologydictionary.net/muscle-atrophy/ 

Kolb, S. J., & Kissel, J. T. (2015). Spinal Muscular Atrophy. Neurologic clinics, 33(4), 831–846. https://doi.org/10.1016/j.ncl.2015.07.004

Medline Plus. (2018, October 1). SMN1 gene (survival of motor neuron 1, telomeric). Medline Plus. Retrieved June 15, 2024, from https://medlineplus.gov/genetics/gene/smn1/ 

Pope, C. (Ed.). (2024, September 4). Why is zolgensma so expensive? Retrieved November 10, 2024,      from https://www.drugs.com/medical-answers/zolgensma-expensive-3552644/

Reed, U. C., & Zanoteli, E. (2018). Therapeutic advances in 5q-linked spinal muscular atrophy. Arquivos de neuro-psiquiatria, 76(4), 265–272. https://doi.org/10.1590/0004-282x20180011

Xie, Q., Chen, X., Ma, H., Zhu, Y., Ma, Y., Jalinous, L., Cox, G. F., Weaver, F., Yang, J., Kennedy, Z., Gruntman, A., Du, A., Su, Q., He, R., Tai, P. W., Gao, G., & Xie, J. (2024). Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor. EMBO molecular medicine, 16(4), 945–965. https://doi.org/10.1038/s44321-024-00037-x