Written by Jamie Saito ‘25
Edited by Surya Khatri '24
In 2019, the FDA approved the first gene therapy treatment for Spinal Muscular Atrophy (SMA). SMA is a debilitating genetic disease caused by the lack of survival motor neuron (SMN) proteins, leading to muscle weakness throughout the body. Because it is genetically linked, the development of treatments is significantly more complicated than other diseases. Only a few treatments have been FDA approved to treat SMA. Zolgensma (onasemnagene abeparvovec) is a one-time intravenous treatment that produces the SMN protein that patients lack. Spinraza (nusinersen) and Evrysdi (risdiplam) are two alternative treatments that target alternative genes to also increase the production of SMN proteins. The development of these treatments could provide an answer to one of the most prevalent genetic diseases for young children.
The Pathophysiology of Spinal Muscular Atrophy
Spinal Muscular Atrophy is caused by mutation in the SMN1 gene. This prevents the body from producing enough survival motor neuron (SMN) proteins, which are key in maintaining the health and function of motor neurons. Due to this mutation, patients with SMA have “insufficient levels of the SMN protein, which leads to loss of motor neurons in the spinal cord” [1]. Because muscles cannot respond to nerve impulses, they atrophy, “producing weakness and wasting of the skeletal muscles” [1]. The muscles closest to the body weaken first, including the shoulders, hips, thighs, and upper back [2]. However, the disease progresses rapidly, causing muscle weakness throughout the body. Eventually, patients lose the ability to perform activities such as speaking, breathing, and swallowing, which eventually becomes life threatening [1].
SMA is an autosomal recessive disease, meaning individuals have inherited two recessive SMN1 genes from their parents. This leads to the inability to produce enough SMN proteins [1]. Patients with SMA have parents who both possess the mutation. Often, parents have both a mutated, recessive gene and a normal, dominant gene. However, unlike a patient with SMA, the parent’s dominant gene functions normally and overwrites the effects of the mutated gene, allowing their SMN1 gene to function normally and produce a normal level of SMN proteins. Because of this, they are carriers of the disease and will not have symptoms [1].
There are four types of SMA, each differentiated by the age at which someone develops symptoms. Type 1 is the most severe form of the disease and develops during infancy. Type 2 develops between 6-18 months; these patients are “able to sit up, but respiratory challenges can shorten their lives as the disease progresses” [2]. Individuals with type 3 SMA, or juvenile SMA, develop symptoms after 18 months and are usually able to walk, especially in the beginning of the disease progression. However, they still show signs of muscle weakness. Finally, Type 4 affects adults and is usually not linked to death or more serious symptoms [2].
Zolgensma: The Price of Gene Therapy
Zolgensma is a gene therapy that uses an adeno-associated viral (AAV) vector to deliver the SMN1 gene. Essentially, a virus is programmed to carry the genetic code in its capsid before releasing it in the target cells. This treatment is administered via intravenous infusion, meaning that the AAV vectors are released systemically before they eventually reach the blood-brain barrier. Once there, they “deliver one or more copies of SMN1 to the nucleus of target motor neurons, where it resides as a non-integrating extra-chromosomal episome and enables continuous expression of the gene” [3]. By providing the patient with a non-mutated gene, this treatment increases the production of SMN proteins, allowing the motor neurons to function normally. This gene will stay in the patient’s cells for the rest of their life, continually producing SMN proteins. Because of this, Zolgensma is a one time dosage that may only be administered to patients younger than two years old [4]. Its dosage is calibrated based on the patient’s weight, delivering about one hundred trillion vector genomes per kilogram of body weight.
Regardless of how promising this treatment may be, Zolgensma is the most expensive FDA approved drug on the market. At $2.125 million per patient, it may be a powerful, yet inaccessible, tool for many children with SMA. As only the second gene therapy treatment to be approved by the FDA, this price reflects the novelty of this drug [5]. Zolgensma targets issues specific to the patient’s genome, categorizing it as a form of precision medicine. Though the concept of AAV gene therapy is not new to the scientific community, Zolgensma is one of the first drugs to employ this new technology for patients, meaning its manufacturing cost is particularly high [6]. The complexity of its development comes with a price tag, though its therapeutic effects appear to be incredibly promising.
Spinraza and Evrysdi: Alternative Treatment Options
There are two other treatment options approved for SMA patients. Both of which target the SMN2 gene. Humans carry two genes that produce the SMN protein: SMN1 and SMN2. The SMN2 gene is significantly less effective at producing the protein because of alternative splicing, which excludes a portion of the gene and creates a less stable protein [7]. SMA patients have a defect in their SMN1 gene, but they still have a functioning SMN2 gene. Changing the splicing, and therefore increasing the production of stable SMN protein, would allow patients to function normally and prevent further disease progression.
Spinraza became the first FDA approved drug for SMA in 2016. It is injected into the cerebrospinal fluid and increases production of SMN proteins by targeting this SMN2 gene [8]. Dosage calls for an initial four injection sequence followed by a dose every 4 months. However, because this treatment requires continuous maintenance, patients must pay for the drug for as long as they would like to continue treatment, which may be their lives. Spinraza costs $750,000 for the first year and $375,000 for every year thereafter [9]. This means that five years of continuous treatment will exceed the one-time cost of Zolgensma.
The third and newest option of treatment for SMA patients is Evrysdi, which was FDA approved in 2020. Similar to Spinraza, this drug also increases protein production correlated to the SMN2 gene. However, Evrysdi uses a different method to target this gene. This drug “modifies splicing by acting as a ‘molecular glue,’” preventing the exclusion of key portions of the gene and allowing the production of a functional SMN protein [10]. Evrysdi is administered orally once a day, which is an important option for patients because it is significantly less invasive than its alternatives [11]. This also allows patients to self administer the drug at home, as opposed to the spinal injections and intravenous infusion methods that are required for Spinraza and Zogensma, respectively. The cost for this drug is still expensive, though slightly lower than its two alternatives, at “a maximum of $340,000 per year, scaled according to body weight” [12]. However, this still means that the cost for about 6 years of Evrysdi will exceed that of Zolgensma, further illustrating the steep price for SMA treatments.
Conclusion
The development of treatments for Spinal Muscular Atrophy is a promising step toward effective care of affected patients. This debilitating disease has a high rate of mortality for children, causing muscle weakness and paralysis, and Zolgensma, Spinraza, and Evrysdi seem to be effective at slowing down or preventing disease progression. However, the cost of these drugs is an important factor for many patients. As a form of precision medicine, Zolgensma is the most expensive drug on the market, illustrating the cost of new technology and personalized treatments. Moreover, Spinraza and Evrysdi, which require doses for the rest of a patient’s life, will cost significantly more over a patient’s lifetime than the one-time treatment of Zolgensma. These drugs emphasize the work that still needs to be done to create more cost-effective treatments, especially for genetically-linked disorders.
References
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11. FDA Approves Oral Treatment for Spinal Muscular Atrophy [Internet]. FDA. FDA; 2020 [cited 2022 Oct 16]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy
12. First oral SMA drug. Nat Biotechnol. 2020 Oct 1;38(10):1111–1111.