The Critical Importance of Early and Combination Treatment for Spinal Muscular Atrophy Type

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease that until recently was one of the leading causes of infant mortality. With the advent of disease-modifying therapies, specifically gene therapy and survival motor neuron (SMN) enhancing medications, the therapeutic landscape for SMA has been transformed. Onasemnogene abeparvovec, nusinersen, and risdiplam have all been shown to significantly enhance motor function and improve survival in all infants with SMA. However, patient outcome remains highly variable, even when treatment is initiated early [1]. A recent multicenter retrospective cohort study on early-treated infants with SMA [2] provides critical insights into this issue, emphasizing the need for both rapid intervention and the strategic use of combination treatments to optimize outcomes. The study reinforces the importance of early identification and prompt intervention for infants with SMA. Initiating treatment in the earliest stages of SMA is critical due to the irreversible loss of motor neurons that begins within the first months of life. Without treatment, symptoms rapidly progress and the majority of infants with 3 or fewer copies of SMN2 gene die before 2 years of age from respiratory failure. Data was analyzed from 66 infants with SMA treated with either onasemnogene abeparvovec or nusinersen within the first 6 weeks of life. All children in the cohort achieved independent sitting and most achieved walking, achievements that historically have been unthinkable for infants with SMA. Notably, no child in the cohort required permanent ventilatory support. These findings align with previous research, including NURTURE and SPR1NT clinical trials [3, 4], which also demonstrated survival without the need for permanent ventilation in most patients treated < 6 weeks of life. However, this study goes a step further by highlighting the ongoing challenges faced by children with two copies of SMN2, even with early treatment. One of the most important conclusions from the study is the impact of SMN2 copy number on treatment outcome. SMA is caused by a deficiency of survival-motor neuron (SMN) protein, which is primarily produced by the SMN1 gene. The SMN2 gene also contributes to SMN protein production but generates a significantly reduced quantity of functional protein. The SMN2 copy number is a strong predictor of SMA phenotype, with an inverse relationship between copy number and disease severity: a greater copy number of SMN2 correlates a with milder form of SMA, whereas a low copy number is associated with severe disease. In this study, infants with two copies of SMN2 were more likely to experience gross motor delays compared to those with three or more copies despite both groups receiving early treatment. Only 68% of infants with two copies of SMN2 achieved walking, compared to 100% of those with three copies or more. Moreover, only 26% of infants with two copies of SMN2 walked within the typical developmental window, compared to 94% of those with three or more copies. Unlike the SPR1NT and NUTURE clinical trials, which excluded patients with SMA-related symptoms, more than half of patients in this cohort with two copies of SMN2 were clinically symptomatic prior to receiving initial treatment. These findings have critical implications for the counseling and clinical care of patients with SMA, suggesting that monotherapy within the first 6 weeks of life may not sufficiently rescue motor neurons in infants with only two copies of SMN2. The approach of using multiple medications, often referred to as combination therapy, is still in its early stages of exploration. Considering the divergent outcomes based on SMN2 copy number, this study highlights its potential role [1]. In this cohort, nearly half of the infants with two copies of SMN2 ultimately received combination therapy due to suboptimal outcomes following monotherapy. For example, children who were initially treated with onazemnogene abaparvovec later received nusinersen or risdiplam if they failed to achieve expected motor milestones. No patient received combination therapy preventatively. The study did not find an immediate inflection in motor function scores following additional treatment, but it also did not observe any significant adverse events related to combination therapy. Longer monitoring may be necessary to fully assess the benefits of combination therapy; however, it is also plausible that initial treatment with dual therapy would provide a more significant improvement in outcome. While providing valuable insights, this study highlights various challenges and opportunities for future research. One of the primary challenges is the persistent disability observed in patients with two copies of SMN2. This underscores the need for further investigation into the optimal timing of treatment and the use of combination therapies. It is widely recognized that early treatment is paramount; however, the efficacy and safety of combination therapy have yet to be fully explored. Additionally, the study's findings raise important questions about the current utilization of prenatal testing. Although treatment was initiated somewhat earlier in patients with two copies of SMN2, over half of these patients were symptomatic at the time treatment began. In contrast, only 10% of patients with three copies of SMN2 showed symptoms at the time of treatment initiation. Considering that infants with two copies of SMN2 experience a rapid rate of disease progression within the first weeks of life, it is noteworthy that 77% of patients in this cohort were identified through newborn screening, while only 11% were detected by prenatal testing. This suggests that prenatal testing is being underutilized, as prenatal testing would allow for treatment to begin shortly after birth and before symptoms manifest. Furthermore, it is possible that initiating treatment even earlier—perhaps in utero—could further improve outcomes. This approach requires careful consideration of the risks and benefits and will also require development of new delivery methods for current SMA therapies. Another area of future research is the exploration of non-SMN modifying treatments. Current therapies focus on increasing SMN protein levels, but there are other therapeutic targets that may complement these treatments. For example, therapies that enhance muscle function could potentially be used in combination with SMN-modifying treatments. Myostatin inhibitors are a class of drugs designed to block myostatin, which is a protein that negatively regulates muscle growth. In SMA, the loss of motor neurons leads to muscle atrophy and weakness. By inhibiting myostatin, it is possible that muscle function in SMA patients can be preserved or even restored. Three different myostatin inhibitors are currently in clinical trials to treat children with SMA (NCT05337553, NCT5115110, NCT03921528); however, the trials include patients older than 2 years of age. This is well after many children with SMA have failed to reach normal motor milestones, especially those with two copies of SMN2, and therefore early treatment to preserve motor neurons remains essential. For clinicians, the study underscores the importance of early and aggressive treatment for infants diagnosed with SMA. This includes not only initiating therapy as soon as possible but also being vigilant about monitoring treatment efficacy and being prepared to adjust treatment plans. Clinicians should particularly be aware of the potential need for early use of combination therapy in children with two copies of SMN2 and counsel families accordingly. The study also demonstrates the importance of individualizing treatment plans based on each patient's genetic makeup and response to therapy. Children with two copies of SMN2 may benefit from closer monitoring and a more aggressive treatment approach, including rapid introduction of treatment and initial use of combination therapy. In contrast, children with three or more copies of SMN2 may achieve normal motor function with monotherapy and the need for dual therapy to be regularly assessed. However, it is important to note that further research is critically needed to validate this hypothesis, better understand outcomes, and refine treatment strategies. The outcomes of early-treated infants with SMA, as detailed in this multicenter retrospective cohort study, provide compelling evidence for the importance of early and combination treatment. The study also highlights the ongoing challenges faced by children with two copies of SMN2, thus providing a more comprehensive understanding of the complexities involved in the treatment of SMA. Moving forward, the SMA community must continue to explore new treatment strategies, which include initiating treatment earlier, combining SMN-enhancing therapies, and employing treatments that target different pathways. It is crucial that both clinicians and researchers remain focused on optimizing outcomes for all patients, regardless of genetic profile. This will require ongoing collaboration, innovation, and a commitment to pushing boundaries of what is thought to be possible in the treatment of this devastating disease. Through these efforts, we can move closer to the goal of ensuring that every child with SMA can live a full and healthy life. Marie Sweat: writing – review and editing. Andrew Skalsky: conceptualization, project administration, supervision, writing – original draft, writing – review and editing. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. A.S. has participated in industry-sponsored clinical trials with compensation of time for Scholar Rock, Biogen, Genentech, and Sarepta. The authors have nothing to report.