Genomics: Insight

Research Question/Hypothesis: New gene and RNA therapies for Spinal Muscular Atrophy show how powerful genomic medicine can be; but extremely high costs and need for early genetic testing create challenges for families to obtain the treatment. 

Spinal Muscular Atrophy (SMA) is a genetic disease that mainly affects babies, young children, and young adults.It causes muscle weakness because the nerve cells that control movement slowly die. The reason this happens is because of a mutation in a gene called SMN1.³ This gene normally makes a protein that motor neurons need to survive. Thus, without enough of this protein, it’ll cause muscles to become weaker over time. Before modern treatments, SMA was one of the leading genetic causes of infant death; however, such changes are being made to alter that. 

SMN1 gene mutation can be classified into four types of SMA based on age of onset and severity.Type 1 is the most severe, with symptoms appearing between birth and 6 months. Infants have severe muscle weakness and breathing difficulties, often leading to death before age 2–3 without treatment. Type 2 begins between 7–18 months, where children can sit but cannot walk independently and may have a shortened life expectancy, though many live into adulthood.Type 3 begins after 18 months and causes progressive muscle weakness and difficulty walking, but life expectancy is typically normal.Type 4 begins in adulthood and causes mild muscle weakness or tremors without affecting life expectancy.

What makes SMA different from many other diseases is that scientists clearly understand its genetic backgrounds. Researchers were able to design treatments that target the problem directly instead of just treating symptoms.⁴ The two major treatments that changed everything are labeled as Spinraza and Zolgensma.

SPINRAZA TREATMENT

Spinraza is an RNA-targeted therapy. Instead of fixing the broken SMN1 gene, it augments a redundant gene called SMN2. SMN2 acts as a backup to SMN1 and produces small amounts of the SMN protein, which is important for motor neuron survival. However, the SMN proteins produced by SMN2 are usually shorter and not very functional. Spinraza modifies the splicing of the SMN2 gene, allowing it to produce more full-length, functional SMN protein. By increasing SMN protein levels in motor neurons, the treatment can slow disease progression, improve muscle strength, and increase survival. Normally, SMN1 produces these proteins, but in patients with SMA there is little or no functional SMN protein produced. The SMN2 gene is essentially a partially functional backup copy of SMN1, but its protein production is normally inefficient due to splicing differences.

This class of drugs is known as antisense oligonucleotides. These are short, synthetic nucleic acid sequences designed to bind to specific RNA sequences and regulate gene expression. Antisense oligonucleotide therapies can be used to alter RNA processing, inhibit translation, or modify splicing. In the case of Spinraza, the antisense oligonucleotide binds to a specific splicing site on the SMN2 pre-mRNA. By binding to this region, it blocks splicing factors that would normally exclude exon 7 during RNA processing. As a result, exon 7 is included in the mature mRNA transcript, allowing the SMN2 gene to produce full-length, functional SMN protein. This increased production of functional SMN protein helps compensate for the loss of functional protein caused by mutations in the SMN1 gene.

Unfortunately, this treatment is not permanent. These antisense oligonucleotides will eventually degrade and cause the SMN2 gene to begin making defective proteins again. Thus, Spinraza needs to be repeatedly taken to prevent neuron damage. 

The chart illustrates the efficacy of Spinraza (nusinersen) in infants with spinal muscular atrophy (SMA) Type I by improving both survival and motor function. The values shown, including reductions in risk and motor milestone outcomes such as head control and independent sitting, were directly taken and summarized from the clinical results presented on this site, which references studies such as ENDEAR and its extension. These graphs are student-created visual representations of existing published clinical data and do not represent original experimental findings.

In the ENDEAR study, a randomized, double-blind, sham-controlled trial involving 121 symptomatic infants with SMA Type I (with onset before 6 months of age), treatment with Spinraza reduced the risk of death or permanent ventilation by 47% compared to controls.⁶ In addition to improved survival, treated infants demonstrated significant gains in motor milestones. After several months of therapy, some infants achieved head control, and with longer follow-up, a greater proportion were able to sit independently. Although Spinraza is not a cure for SMA, these findings demonstrate its ability to slow disease progression and improve both survival outcomes and motor development in affected infants.

Graph 1: Effectiveness of nusinersen (Spinraza) in infants with SMA Type I from the ENDEAR randomized clinical trial (N=121; symptom onset <6 months; 2 SMN2 copies). The Y-axis represents the percentage of infants achieving each clinical outcome, including survival without permanent ventilation and attainment of motor milestones.

ZOLGENSMA TREATMENT

Zolgensma works differently. It is a gene therapy that delivers a working copy of the SMN1 gene into the body using a harmless virus. This allows cells to start making the missing protein. Zolgensma is given as a singular IV infusion and is often described as life-changing when dosages are given early. Most clinical trials involved with the medication include toddlers and babies.⁷  Clinical outcomes are significantly improved when treatment is administered before symptom onset. 

Graph 2: Motor milestone achievement in presymptomatic infants with SMA (treated before symptom onset) receiving Zolgensma in the SPR1NT trial. Outcomes are shown for infants with 2 SMN2 copies (n=14) and 3 SMN2 copies (n=15). The Y-axis represents the percentage of infants achieving each motor milestone, including sitting, standing, and walking independently.

This chart shows how effective Zolgensma was in the SPR1NT trial for babies treated before they developed symptoms of SMA.⁷ Graph 2 was created using the design application Canva. The data used in this graph were obtained from the official healthcare provider website for Zolgensma, specifically from https://www.zolgensma-hcp.com/clinical-trials/presymptomatic. The values shown, including motor milestone outcomes such as sitting, standing, and walking abilities in infants with 2 and 3 copies of the SMN2 gene, were directly taken and summarized from the clinical results of the SPR1NT trial presented on this site. This graph is a student-created visual representation of existing published clinical data and does not represent original experimental findings.

The results were especially strong in both groups of infants. Commonly, babies that had 2 copies of the SMN2 gene were more susceptible to severe symptoms, so the improvements seen in this group are especially significant. All babies with two copies were able to sit without support, and most were able to walk on their own. In the group with three copies, every child was able to stand alone, and almost all were walking independently. These outcomes are important because, in the past, many children with severe SMA would never reach these milestones. The data suggest that early treatment can dramatically change the course of the disease, while also showing how important early diagnosis and newborn screening are for giving families access to this therapy.

LIMITATION OF SMA THERAPIES 

While these treatments represent remarkable scientific advancements, they also raise significant ethical and societal concerns. Zolgensma, a one-time gene therapy, has a list price of approximately $2.1 million ⁶, making it one of the most expensive drugs in the world. Spinraza (nusinersen) is similarly costly, with an estimated $750,000 in the first year and $375,000 annually thereafter ⁶ due to lifelong dosing. Although most private insurance plans and Medicaid programs provide coverage for both therapies, access is not guaranteed and often requires extensive prior authorization. Insurers frequently negotiate lower payments for Zolgensma, typically ranging from $1.36 to $1.89 million, while patients are generally responsible only for their plan’s out-of-pocket maximum. For Spinraza, out-of-pocket costs can vary widely; however, eligible patients may reduce costs to as little as $0 through manufacturer assistance programs, such as Biogen’s copay program.

Despite these support systems, the financial burden on healthcare systems, insurers, and families remains substantial. In addition, Spinraza administration is invasive, requiring repeated lumbar punctures to deliver the drug directly to spinal neurons, which can be physically and emotionally taxing for patients. Although less invasive delivery methods are currently under investigation, they are not yet widely available. These challenges highlight ongoing disparities in access, particularly for individuals in lower-income communities or in countries with limited healthcare infrastructure.

Another major issue is newborn genetic testing. These treatments work best if they are given before symptoms become severe. SMA has a window of treatment that can significantly improve outcomes, but this window is in early infancy. That means babies need to be diagnosed very early, often through newborn screening programs. However, not all states or countries screen for SMA at birth. This creates differences in who gets early treatment and who does not.

There are also still questions regarding the exact causes of all variations of SMA. Not all patients have the same causes or mutations. It is believed that many specific SMA symptoms are related to things like improper splicing, improper gene suppression and other genetic regulatory mutations. Knowing the exact variant a patient has is important in finding the right treatment.

"SMA treatments show how far genomic medicine has come"

SMA treatments show how far genomic medicine has come. Scientists were able to study one gene, understand the exact problem, and create therapies that directly target it. However, the major price tag that comes with the medication needed for disease support is a massive factor that hinders families from receiving the correct care. The medication is still in ongoing clinical trials and development, not only to lower costs but also improve accessibility for families at risk of producing the gene. Ultimately, SMA therapies highlight both the power of genomic medicine and the urgent need to balance innovation with equitable access to care.

References:

1. Biogen. (n.d.). Later-onset SPINRAZA® (nusinersen) efficacy. Spinrazahcp.com. https://www.spinrazahcp.com/en_us/home/why-spinraza/later-onset-efficacy.html
2. Camelo‐Filho, A. E., Jovino, R. M., Tomaz, B. S., Nóbrega, P. R., & Holanda, M. A. (2026). Adult Survival in SMA Type 1: A 23‐Year Journey With Home Ventilation and Multidisciplinary Support. Clinical Case Reports, 14(3), e72052. https://doi.org/10.1002/ccr3.72052
3. Chancellor, D., Barrett, D., Nguyen-Jatkoe, L., Millington, S., & Eckhardt, F. (2023). The state of cell and gene therapy in 2023. Molecular therapy : the journal of the American Society of Gene Therapy, 31(12), 3376–3388. https://doi.org/10.1016/j.ymthe.2023.11.001
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5. Iwasaki, R. S., & Batey, R. T. (2020). SPRINT: a Cas13a-based platform for detection of small molecules. Nucleic acids research, 48(17), e101. https://doi.org/10.1093/nar/gkaa673
6. Pearson, S. D., Thokala, P., Stevenson, M., & Rind, D. (2019). The Effectiveness and Value of Treatments for Spinal Muscular Atrophy. Journal of managed care & specialty pharmacy, 25(12), 1300–1306. https://doi.org/10.18553/jmcp.2019.25.12.1300
7. Presymptomatic trials. ZOLGENSMA® (onasemnogene abeparvovec-xioi). (n.d.). https://www.zolgensma-hcp.com/clinical-trials/presymptomatic 
8. Hofman CR, Corey DR. Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges. Cell Chem Biol. 2024 Jan 18;31(1):125-138. doi: 10.1016/j.chembiol.2023.09.005. Epub 2023 Oct 6. PMID: 37804835; PMCID: PMC10841528.
9. Faravelli, I., Rinchetti, P., Tambalo, M. et al. Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids. Nat Commun 17, 988 (2026). https://doi.org/10.1038/s41467-025-67725-1