The scientific foundation for this transformation was laid in 1995, when a landmark study identified SMN1 as the disease-causing gene. The authors found that SMN1 was deleted in 98.7 percent of patients in a 229-person cohort and mutated in the remainder. Crucially, humans carry a nearly identical backup copy called SMN2, which differs by a single base-pair transition from C to T in exon seven. That single nucleotide inactivates an exonic splicing enhancer and introduces an exonic splicing silencer, causing roughly 90 percent of the protein produced from SMN2 to be truncated and degraded by cellular machinery. Because SMA severity is inversely related to the number of SMN2 copies a patient carries, this backup gene became the central target for drug development.

Three FDA-approved disease-modifying therapies now anchor the treatment landscape. Nusinersen, marketed as Spinraza, is an antisense oligonucleotide that binds to a specific site within SMN2 pre-mRNA to promote inclusion of exon seven, restoring production of full-length SMN protein. Its development traced back to the discovery of an intronic splicing silencer called ISS-N1, and animal studies showed that blocking this element dramatically increased exon seven inclusion. The pivotal Phase 3 ENDEAR trial demonstrated significant improvement in infants with SMA Type 1, leading to accelerated FDA approval in 2016. Notably, in early 2026 the FDA approved a higher-dose regimen based on the DEVOTE study, with a safety profile consistent with more than a decade of clinical data.

Onasemnogene abeparvovec, known commercially as Zolgensma, takes a fundamentally different approach. It is a non-replicating adeno-associated virus serotype 9 vector that delivers a full-length SMN1 gene under the control of a hybrid promoter, capable of crossing the blood-brain barrier to reach spinal motor neurons after a single intravenous injection. A meta-analysis conducted four years after the drug’s release found mostly positive results, particularly in patients treated early in life, with motor milestone improvements that in many studies exceeded those achieved with nusinersen. A biodistribution study of post-mortem patient tissue confirmed vector genome presence throughout the central nervous system and in peripheral organs including skeletal muscle, heart, lung, and stomach.

Risdiplam, sold as Evrysdi, is the most recent addition and the first orally administered small-molecule SMN2 splicing modifier. The compound stabilizes the interaction between the 5-prime splice site on exon seven and the U1 small nuclear ribonucleoprotein, strengthening the splice site and reducing degradation. Unlike nusinersen, risdiplam crosses the blood-brain barrier because it does not bind to multi-drug resistant protein 1 and therefore cannot be pumped out of the central nervous system. A striking case study even documented prenatal therapy, with the drug administered orally to a mother carrying a confirmed SMA Type 1 fetus beginning at 32 weeks and 5 days of gestation; at 30 months of age, the child showed no manifestations of the disease. In a matching-adjusted indirect comparison, risdiplam-treated Type 1 patients showed a 78 percent reduction in mortality relative to historical nusinersen cohorts.

Despite these remarkable gains, the review emphasizes that the therapies are not curative. In 2024, approximately 75 percent of patients in the CureSMA database had received at least one disease-modifying therapy, yet only 47 percent of children and 19 percent of adults with SMA are ambulatory. Since the dawn of the therapy era, SMA mortality has dropped by nearly 80 percent, but 36 percent of patients still require some form of breathing support, and 89 percent of adults report that reaching new motor milestones remains their greatest unmet need. As patients live longer, a constellation of comorbidities has come into sharper focus, reshaping the clinical agenda.

Orthopedic complications illustrate this shift vividly. Between 60 and 90 percent of children with SMA develop scoliosis, which can complicate the intrathecal injections required for nusinersen and, if untreated, lead to chest deformities that further impair pulmonary function. Respiratory failure remains the leading cause of death, implicated in 72 percent of known SMA fatalities in a recent review. Gastrointestinal problems, including chronic constipation, dysphagia, and gastroesophageal reflux, are common, and eating difficulties can produce metabolic abnormalities such as glucose intolerance and insulin resistance. Cardiac irregularities, though less frequent, have been documented in infantile patients, ranging from congenital heart defects to cardiomyopathy.

The review also delves deeply into why motor neurons are selectively vulnerable to SMN deficiency, a question that remains only partially answered. SMN protein is best known for assembling small nuclear ribonucleoproteins, the complexes essential for recognizing splice sites and removing introns from pre-mRNA. Motor neurons harbor disproportionately high numbers of Cajal bodies, the nuclear structures where snRNP maturation is completed, likely reflecting their extraordinary demand for RNA metabolism to sustain constant electrical signaling. Low SMN reduces Cajal body numbers and, by extension, ribosome production. SMN also interacts with mRNA-binding proteins such as HuD, IMP1, and beta-actin that govern axonal transport and growth, and its deficiency disrupts neuromuscular junction maturation before symptoms even appear.

Looking forward, the authors survey a rich pipeline of alternative strategies. Induced pluripotent stem cells derived from patient skin fibroblasts have become powerful tools for drug screening and disease modeling, revealing pathways such as Fas ligand-mediated apoptosis and calcium dysregulation in cardiomyocytes. Gene editing approaches are particularly striking: a one-time base editing technique achieved an average of 87 percent permanent conversion of the disease-causing point mutation in mouse models with no detected off-target effects, while CRISPR-based prime editing of the ISS-N1 silencer sequence restored full-length SMN2 production in patient cells. Epidural spinal cord stimulation in a small cohort of adults produced a 40 percent increase in mean step length over four weeks, with benefits persisting even when the stimulator was switched off.

The review closes with a call for combination treatment strategies that build on existing therapies while addressing residual disease burden. Investigational agents such as apitegromab, a monoclonal antibody that blocks myostatin’s inhibition of skeletal muscle growth, are already being tested alongside approved drugs. The authors stress that SMA is fundamentally a multi-organ disease requiring multifactorial management, and that future research must ensure patients of all ages, including the growing population of adults living with the disease, are represented in treatment development. What began as a uniformly fatal diagnosis has become a chronic, manageable condition for many, but converting survival into truly restored function remains the defining challenge of the next decade.

Subject of Research: Disease-modifying therapies and future treatment directions for spinal muscular atrophy

Article Title: Spinal muscular atrophy in the disease-modifying therapy era: successes, limitations and future directions

Article References: Sexton, M. M., Crow, E. W., & Peng, C. A. (2026). Spinal muscular atrophy in the disease-modifying therapy era: successes, limitations and future directions. Frontiers in Molecular Medicine, 6, Article 1901311. https://doi.org/10.3389/fmmed.2026.1901311

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1901311

Keywords: spinal muscular atrophy, SMN1, SMN2, nusinersen, onasemnogene abeparvovec, risdiplam, gene therapy, motor neurons, antisense oligonucleotide, comorbidities, base editing, iPSCs

Mary Ellen Avery’s legacy provides the intellectual template for this kind of work. In the 1950s, Avery demonstrated that respiratory distress syndrome in premature newborns was caused by a deficiency of pulmonary surfactant, the lipoprotein mixture that keeps the tiny air sacs of the lung from collapsing with each breath. That insight, derived from careful basic science, eventually produced surfactant replacement therapy, one of the most consequential interventions in modern neonatology. The lesson embedded in her career is that a mechanistic discovery, pursued patiently over decades, can be converted into a system delivered to every infant who needs it. It is precisely that conversion, from knowledge to infrastructure, that the award celebrates.

Chung’s own work sits at the intersection of genetics, pediatrics, and public health. As a human geneticist who has led large-scale genomic medicine initiatives, she has focused on a question that sounds simple but is operationally formidable: which conditions should be looked for in every newborn, and how should the results be delivered to families in a way that changes outcomes rather than merely generating anxiety? The answer determines whether a diagnosis arrives in time to alter the course of a disease or only in time to explain it retrospectively.

The clearest recent example comes from spinal muscular atrophy, a genetic disorder that was, until recently, the leading inherited cause of infant mortality. SMA is caused by loss or mutation of the SMN1 gene, which produces a protein survival motor neurons require. Infants with the most severe form lose motor neurons progressively in the first months of life, and before effective therapy existed, most died of respiratory failure before their second birthday. The disease, however, has a crucial property that makes it an ideal target for newborn screening: intervention is dramatically more effective when it begins before symptoms appear, because motor neurons that have not yet been lost can be preserved.

The therapeutic landscape changed with the development of disease-modifying treatments, most prominently nusinersen, an antisense oligonucleotide that alters splicing of the related SMN2 gene so that it produces more functional survival motor neuron protein. The pivotal randomized trial published in the New England Journal of Medicine in 2017 showed that infants treated with nusinersen had significantly better motor-function outcomes than those receiving a sham control procedure. Suddenly, a fatal diagnosis became a treatable condition, but only if it was identified early enough. Screening became the bottleneck: without systematic detection at birth, infants would still present with established weakness, at which point the therapeutic window had narrowed.

Chung and colleagues addressed this directly in New York State, where a pilot study of population-based newborn screening for spinal muscular atrophy demonstrated that molecular screening could be integrated into existing public health infrastructure. The technical approach relies on detecting the homozygous deletion of SMN1 in dried blood spots, the same heel-prick specimens already collected from every newborn for dozens of metabolic and genetic conditions. The pilot study, published in Genetics in Medicine, established feasibility, laboratory workflow, and the clinical pathway connecting a positive screen to confirmatory testing and rapid treatment initiation. New York subsequently moved from pilot to universal screening, and the model has since been adopted across a growing number of states and countries.

The same logic has been extended to Duchenne muscular dystrophy, another severe neuromuscular condition in which early identification may enable earlier access to emerging therapies. A two-year pilot study of newborn screening for Duchenne in New York, reported in Annals of Clinical and Translational Neurology, evaluated the performance of screening for elevated creatine kinase and confirmatory genetic testing in dried blood spots. These pilots illustrate a recurring pattern in Chung’s career: rigorous, unglamorous implementation science that determines whether a screening concept can actually function at population scale, with acceptable rates of false positives, clear follow-up protocols, and equitable reach across diverse communities.

Chung’s most ambitious project in this space is the GUARDIAN study, a genomic newborn screening program conducted in New York that screened tens of thousands of infants for hundreds of genetic conditions, many of which are actionable in early childhood. Unlike traditional newborn screening, which targets a fixed panel of biochemical markers, genomic screening reads the infant’s DNA directly, allowing a single platform to detect conditions ranging from metabolic disorders to hearing loss to cardiac arrhythmia syndromes. The study received in-kind contributions from GeneDx and Illumina, and its results are shaping the debate over how much genetic information should be gathered at birth and how families should be counseled about findings that range from urgently actionable to uncertain.

The GUARDIAN study also raises the ethical and logistical questions that any system of universal early care must confront. Screening an entire population inevitably identifies infants with variants of uncertain significance, conditions that may never cause symptoms, and incidental findings unrelated to the reason for testing. The design of the program, with defined gene panels focused on childhood-onset, actionable conditions, reflects an attempt to balance the promise of early intervention against the risks of overdiagnosis and medicalization of healthy infancy. Chung’s framing of the work, as building systems of care rather than simply tests, emphasizes that a screen is only as valuable as the clinical pathway behind it: confirmatory diagnostics, genetic counseling, treatment access, and long-term follow-up.

The deeper argument of the Avery Award lecture is historical and structural. Medicine tends to organize itself around the sick patient who arrives at the clinic, but the greatest gains in pediatric health have come from systems that reach children before illness declares itself: vaccination schedules, congenital hypothyroidism screening, hearing screening, pulse oximetry for critical congenital heart disease, and now genomic screening. Each of these required decades of persistence, coalition-building among scientists, public health officials, advocacy groups, and families, and a willingness to demonstrate value through pilot data before universal implementation. Chung’s career, from her leadership in identifying the genetic basis of conditions to her role in designing and executing population screening programs, exemplifies the long gestational period that careers in physician science often require before the birth of innovation reaches patients. In honoring that journey, the Society for Pediatric Research signals to the next generation of pediatrician-scientists that the highest-impact work may not be a single discovery but the patient construction of systems that ensure every child, starting at birth, benefits from what medicine already knows.

Subject of Research: Newborn screening and systems of early pediatric care, including genomic screening for treatable genetic conditions

Article Title: The journey to establishing systems of care for all children, starting at birth: the Society for Pediatric Research’s 2026 Mary Ellen Avery award

Article References: Chung, W. K. (2026). The journey to establishing systems of care for all children, starting at birth: the Society for Pediatric Research’s 2026 Mary Ellen Avery award. Pediatric Research. https://doi.org/10.1038/s41390-026-05580-6

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05580-6

Keywords: newborn screening, spinal muscular atrophy, Mary Ellen Avery, Wendy Chung, GUARDIAN study, genomic medicine, nusinersen, Duchenne muscular dystrophy, pediatric research, public health, SMN1, early intervention

The biology behind spinal muscular atrophy explains why this region has long frustrated diagnosticians. The disease is caused by loss or mutation of the SMN1 gene, which encodes a protein essential for the survival of motor neurons. Humans, however, carry a nearly identical backup copy called SMN2, distinguished by a single nucleotide change at position c.840 in exon 7. That one base difference alters how SMN2 pre-messenger RNA is spliced, so most SMN2 transcripts are translated into a truncated, unstable protein that is rapidly degraded. Each SMN2 copy produces only about ten percent of the functional protein generated by SMN1, and the proportion varies across tissues. Because the two genes are more than ninety-nine percent identical, distinguishing them requires reading across the entire roughly 28.5-kilobase locus, something short-read sequencing struggles to accomplish reliably.

Traditional testing reflects these limitations. Quantitative PCR can detect homozygous deletions of SMN1 exons 7 and 8, the molecular signature of most SMA cases, but it cannot report precise copy numbers or identify point mutations. Multiplex ligation-dependent probe amplification, or MLPA, reliably measures SMN1 and SMN2 copy numbers and detects exon rearrangements, yet it cannot resolve haplotypes or sequence-level variants. Neither method can determine whether a person with two SMN1 copies carries both on one chromosome or one on each, a distinction that matters enormously for reproductive risk. A so-called 2+0 silent carrier, with both copies on a single chromosome, appears normal on standard screening but faces the same one-in-four chance of having an affected child as a classic 1+1 carrier when paired with another carrier.

Single-molecule real-time sequencing sidesteps these obstacles through sheer read length. In the new study, researchers at Zhangzhou Municipal Hospital extracted genomic DNA from peripheral blood, amplified the full-length SMN1 and SMN2 genes together with their downstream regions using long-range PCR, and ligated the amplicons into dumbbell-shaped SMRTbell libraries. These libraries were sequenced on a Sequel II CNDx platform in circular consensus sequencing mode for thirty hours, generating high-fidelity reads that span the entire locus. Because each read covers the whole gene, the c.840 site unambiguously labels each molecule as SMN1 or SMN2, allowing the software to count copies of each gene separately and scan for point mutations at the same time. The technology carries no GC bias and handles the highly repetitive sequence architecture of this region that defeats shorter reads.

The clinical validation was striking. Among the 771 screened individuals, SMRT sequencing and qPCR produced fully concordant results in one hundred percent of samples. The most common genotype was two copies each of SMN1 and SMN2, found in 55.25 percent of participants, followed by a 2:1 ratio in 29.44 percent. Two SMN1 copies were present in 91.18 percent of the cohort, but the distribution revealed important outliers: 2.33 percent of individuals carried only one SMN1 copy and were classified as deletion carriers, yielding a carrier frequency of 2.33 percent, consistent with previously reported rates of 1.2 to 2.2 percent in Chinese populations. More provocatively, 6.36 percent carried three SMN1 copies and one individual carried four, indicating that at least two SMN1 genes sit on a single chromosome in these people, a configuration that standard qPCR cannot distinguish from the benign two-copies-on-two-chromosomes arrangement.

That finding carries direct reproductive consequences. Individuals with elevated SMN1 copy numbers may be silent carriers whose risk is invisible to conventional screening, since qPCR reports only total copy number without allele distribution. The study authors note that definitive assignment of 2+0 status still requires family-based haplotype phasing and pedigree analysis, which lay beyond the scope of the current work. Even so, the results underscore a hidden reservoir of reproductive risk in the general population. With roughly one in fifty people in many populations carrying an SMN1 deletion, and couples who are both carriers facing a one-in-four chance of an affected child in each pregnancy, carrier screening has become a public health priority, and the accuracy of that screening depends entirely on the resolution of the underlying technology.

The study also catalogued the distribution of SMN2, the modifier gene that shapes disease severity. Two copies of SMN2 were the most common configuration at 57.59 percent, one copy accounted for 33.07 percent, and small fractions of individuals carried three or four copies. Notably, 6.10 percent of the screened population carried homozygous SMN2 deletions, a genotype that is not itself disease-causing but eliminates the compensatory buffer that SMN2 provides. Because SMN2 copy number is inversely related to clinical severity in SMA patients, knowing a patient’s SMN2 count helps predict disease course and informs treatment decisions, particularly now that disease-modifying therapies exist for a condition that was, until recently, essentially untreatable.

Four qPCR-confirmed SMA patients served as independent validation cases, and their stories illustrate both the technology’s power and the disease’s variability. Patient 1, a 16-year-old female with severe scoliosis who first showed hand tremors at twelve months, had zero copies of SMN1 and three copies of SMN2 confirmed by all three methods, consistent with SMA type II. Patient 2, a 12-year-old male unable to walk independently at seventeen months, showed the same molecular profile with profound proximal weakness and absent reflexes, also diagnosed as type II. Patient 3, a 17-year-old male with flexion contractures, generalized hypotonia, and complete lower limb paralysis, carried zero SMN1 copies and three SMN2 copies but was classified as type I. Patient 4, a three-month-old male with hypotonia since birth, had zero SMN1 copies and two SMN2 copies, with electromyography revealing nerve fiber damage across multiple limbs, confirming type I disease. No pathogenic point mutations were detected in any patient.

The discordance among patients sharing three SMN2 copies is scientifically telling. Three of the four patients carried the same SMN2 count yet spanned two clinical types, echoing a large analysis of 1,627 SMA patients with three SMN2 copies in which fifteen percent had type I disease, fifty-four percent type II, and thirty-one percent type III. The relationship between copy number and severity is clearly not a simple inverse correlation; even among patients with four or five SMN2 copies, one and five percent respectively still develop type I disease. Whether different SMN2 variants possess distinct functional properties, or whether modifying mutations within SMN2 influence its compensatory capacity, remains an open question that the authors flag for future investigation.

The study’s limitations are candidly acknowledged. Point mutations in SMN1 account for roughly two percent of SMA carrier alleles, yet none were detected in this cohort, a result that may reflect their genuine rarity or a sample size insufficient to capture such infrequent events. Larger-scale studies will be needed to validate the technology’s performance on rare genotypes. Nevertheless, the trajectory is clear: SMA genetic testing has evolved from single-site detection toward whole-gene, haplotype-level analysis, and long-read sequencing has already matured into clinical practice for other monogenic disorders such as thalassemia and congenital adrenal hyperplasia. With its ability to resolve copy numbers, haplotypes, and point mutations in a single assay across one of the human genome’s most treacherous paralogous regions, single-molecule real-time sequencing appears poised to become a cornerstone of SMA diagnosis, carrier screening, and genetic counseling, potentially catching silent carriers that today’s methods routinely miss.

Subject of Research: Clinical application of single-molecule real-time long-read sequencing for spinal muscular atrophy diagnosis and carrier screening

Article Title: Clinical Practice of Single‐Molecule Real‐Time Sequencing in the Diagnosis of Spinal Muscular Atrophy

Article References: Wei, H., Zheng, Y.-W., Zhang, N.-K., Gao, T.-L., Zheng, J.-X., Li, T.-Y., & Hong, S.-R. (2026). Clinical Practice of Single‐Molecule Real‐Time Sequencing in the Diagnosis of Spinal Muscular Atrophy. Molecular Genetics & Genomic Medicine, 14(10), Article e70314. https://doi.org/10.1002/mgg3.70314

Image Credits: AI Generated

DOI: 10.1002/mgg3.70314

Keywords: spinal muscular atrophy, SMRT sequencing, SMN1, SMN2, long-read sequencing, carrier screening, genetic diagnosis, copy number variation, qPCR, MLPA, motor neuron disease, genetic counseling

The study, published in the journal Advances in Therapy, drew on the Komodo Health Research Database, one of the largest longitudinal healthcare claims datasets in the country, covering approximately 330 million individuals across commercial insurance, Medicare, and Medicaid programs. Researchers led by Walter Toro Jimenez of Novartis Pharmaceuticals Corporation, together with colleagues at Analysis Group, examined claims recorded between January 2016 and October 2024 to reconstruct how patients with spinal muscular atrophy actually move through the therapeutic landscape. Because the data capture routine clinical care rather than the carefully controlled conditions of a clinical trial, the findings offer a rare window into how the promise of these therapies is being translated into everyday practice.

The biology underlying the disease explains why treatment has evolved so rapidly. Spinal muscular atrophy results from homozygous deletions or mutations in the SMN1 gene, which deprives the body of survival motor neuron protein and triggers the progressive degeneration of motor neurons in the spinal cord. A second gene, SMN2, produces small amounts of the same protein, and the severity of disease generally tracks with how much functional protein the SMN2 copies can generate. All three approved therapies work by increasing the output of that backup gene, but they do so through strikingly different mechanisms. Nusinersen, approved in 2016, is an antisense oligonucleotide injected into the spinal canal that corrects the splicing of SMN2 transcripts. Risdiplam, approved in 2020, is an oral small molecule that achieves the same splicing modulation through daily dosing. Onasemnogene abeparvovec, approved in 2019 as an intravenous infusion for children under two, delivers a functional copy of the SMN1 gene directly into cells using a viral vector, effectively replacing the missing genetic instructions in a single administration.

The clearest signal in the new analysis comes from the youngest patients. Among 257 children who initiated their first disease-modifying therapy at age two or younger during 2022 through 2024, a period after newborn screening had become widely available across most of the United States, 64.6 percent began with onasemnogene abeparvovec, 24.9 percent with risdiplam, and only 10.5 percent with nusinersen. The contrast with the immediate post-approval era is stark. An earlier study using a different claims database covering January 2017 through March 2021 found that just 16.2 percent of children under two received the gene therapy, while 83.8 percent received nusinersen. The researchers attribute the reversal largely to newborn screening, which was introduced in the US in 2018 and now identifies affected infants before symptoms appear, allowing treatment to begin at the stage when clinical trials have shown the greatest benefit.

Equally revealing is what happens after the first treatment. Children who started with the gene therapy were the least likely to add a second therapy type: only 12.0 percent of them did so, compared with 20.3 percent of those who began with risdiplam and 55.6 percent of those who began with nusinersen. Among the subset of 209 children with the most severe, type 1 form of the disease, the pattern held, with 8.3 percent of gene therapy recipients adding a second therapy versus 60.9 percent of nusinersen recipients and 18.5 percent of risdiplam recipients. The implication is that a single gene replacement appears to satisfy treatment needs for most infants, whereas patients on the chronic, repeat-dosing therapies more often end up adding or switching to another modality, most frequently the gene therapy itself.

To understand sequencing across the full age spectrum, the researchers assembled a second cohort of 341 patients with types 1 through 3 of the disease who received at least two different therapy types between May 2019, when at least two options became available, and October 2024. This group was markedly older, with a mean age of 15.4 years at the start of their first recorded therapy, and reflected an era when nusinersen was the only option: 75.4 percent of them began with the antisense oligonucleotide, 15.2 percent with risdiplam, and 9.4 percent with the gene therapy. Within this cohort, risdiplam was the most common second treatment, received by 76.2 percent of patients, followed by nusinersen at 13.2 percent and the gene therapy at 10.6 percent. Only five patients, or 1.5 percent, progressed to a third therapy type. The median interval between the first and second treatments was 18.9 months, though the timing varied by starting therapy, from 21.7 months for nusinersen starters to 13.2 months for those who began with risdiplam.

The picture changes again when the analysis is restricted to the 44 children who received multiple therapies and began treatment at age two or younger during 2022 through 2024, the true newborn screening generation. In this group, first treatments were distributed far more evenly, with 36.4 percent starting on the gene therapy, 34.1 percent on nusinersen, and 29.5 percent on risdiplam. When these children did move to a second therapy, the gene therapy dominated: 52.3 percent received onasemnogene abeparvovec as their second treatment, 45.5 percent received risdiplam, and just 2.3 percent received nusinersen. All of the children who had started on risdiplam, and most of those who had started on nusinersen, went on to receive the gene therapy. The median time from first to second treatment in this young cohort was 13.4 months, and the researchers suggest that some patients may have received the oral or injectable therapies as a bridge while awaiting gene therapy, while others switched because of the demonstrated value of gene replacement in previously treated patients.

The data also expose the growing complexity of managing a disease that now has multiple viable treatment pathways. A 2023 community survey cited in the study reported that 47.4 percent of children with spinal muscular atrophy had received more than one therapy type, with families and physicians citing reasons that included wanting a different treatment, physician recommendation, the desire to pursue every available option, and loss of motor function. The claims analysis adds a further wrinkle: among young children treated with multiple therapies, 20.0 percent of those who started on nusinersen and 38.5 percent of those who started on risdiplam later received the same therapy again after initiating a second one. Whether this reflects concurrent use, re-initiation after a gap, or something else cannot be determined from claims data alone, but the authors note that it points to increasing treatment complexity and burden for patients and caregivers alike.

The study has important caveats, which the authors acknowledge candidly. Claims databases lack the clinical measures, such as motor function scores, disease severity, and genetic modifiers like SMN2 copy number, that would allow researchers to connect treatment sequencing to outcomes. The specific reasons behind any switch, whether efficacy concerns, adverse effects, or issues of access and insurance coverage, are invisible in billing records. Disease type itself had to be inferred from an established algorithm based on age at diagnosis and patterns of clinical activity, raising the possibility of misclassification, particularly among pre-symptomatic infants identified by screening in whom distinguishing clinical features have not yet emerged. Birth-year service dates are masked for privacy, which forced the exclusion of the small fraction of patients, 5.2 percent, who received multiple therapy types in their first year of life, and small subgroup sizes limit the precision of some estimates.

Even with those limitations, the analysis stands as the first large-scale, real-world description of how patients with spinal muscular atrophy navigate an era of multiple disease-modifying options, and its message is unambiguous: newborn screening has reshaped the field, gene replacement therapy now anchors early treatment, and sequential multi-therapy strategies have become an ordinary feature of care rather than an exception. The landscape is still shifting. In 2025, regulators approved an intrathecal formulation of onasemnogene abeparvovec for patients aged two and older, meaning that for the first time all three therapeutic modalities are available across the full age range. Future studies, the authors write, will need to examine treatment sequencing across that broader population, control for the confounding factors that claims data cannot capture, and, most critically, link sequencing strategies to long-term clinical outcomes as the therapeutic story of this once untreatable disease continues to unfold.

Subject of Research: Real-world treatment sequencing patterns among patients with spinal muscular atrophy receiving multiple disease-modifying therapies

Article Title: Real-World Treatment Patterns in Patients with Spinal Muscular Atrophy Receiving Multiple Disease-Modifying Therapies

Article References: Toro Jimenez, W., Yang, M., Song, W., Ye, D., Lemus Wirtz, E., Meehan, J., & Reyna, S. (2026). Real-World Treatment Patterns in Patients with Spinal Muscular Atrophy Receiving Multiple Disease-Modifying Therapies. Advances in Therapy. https://doi.org/10.1007/s12325-026-03710-4

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03710-4

Keywords: spinal muscular atrophy, onasemnogene abeparvovec, nusinersen, risdiplam, gene therapy, newborn screening, disease-modifying therapy, treatment patterns, SMN1, SMN2, motor neuron disease, real-world evidence

Spinal muscular atrophy is caused by mutations in the SMN1 gene, which deprives spinal motor neurons of functional survival motor neuron (SMN) protein. The resulting degeneration produces progressive weakness of skeletal muscles and, in the most severe form, compromises breathing and swallowing. Before disease-modifying therapies existed, children with SMA type I — defined by symptom onset within the first six months of life and an inability to sit unsupported — almost invariably died or required permanent mechanical ventilation by 20 months of age. The introduction of onasemnogene abeparvovec, which delivers a functional copy of SMN1 directly to motor neurons via an AAV9 vector, fundamentally changed this trajectory. In pivotal trials such as STR1VE and SMART, which enrolled carefully selected infants under six months without bulbar or respiratory complications, survival rates climbed to between 90 and 100 percent and most infants gained the ability to sit.

Real-world experience, however, has always been more complicated. Once the therapy became commercially available, its approved label expanded well beyond the narrow trial population, allowing treatment of older and heavier infants, children with bulbar and respiratory impairment, and patients who had already been exposed to other disease-modifying therapies such as nusinersen or risdiplam. These broader cohorts have shown greater variability in outcome: while survival and motor gains remain the norm, not every child achieves independent sitting within the first year, and older, heavier children tend to respond less robustly. Recognizing that some milestones may simply take longer to emerge, the Italian research consortium set out to determine whether extended follow-up would reveal continued functional progress that shorter studies had missed.

The new analysis draws on the Italian SMA Consortium (ITASMAC) registry and includes all consecutive symptomatic type I patients treated with onasemnogene abeparvovec who completed at least 24 months of follow-up, regardless of SMN2 copy number, age or weight at treatment, prior therapy, or sex. The cohort of 64 children was divided into three groups based on treatment history: 27 received the gene therapy as monotherapy, 9 received a short bridging course of nusinersen or risdiplam for less than three months before switching, and 28 had been treated with another disease-modifying drug for a median of nearly two years before transitioning to the gene therapy. Motor function was assessed with the validated CHOP-INTEND scale, and milestone acquisition, nutritional status, and respiratory support were documented prospectively at each clinical visit across the two-year observation window.

The baseline characteristics of the three treatment groups differed markedly, reflecting the realities of sequential therapy in clinical practice. Children treated with the gene therapy alone were the youngest, with a mean age at infusion of just 0.33 years, while those who switched from prior therapy were significantly older at a mean of 2.92 years. Switch patients also entered with the highest baseline CHOP-INTEND scores — a mean of 47.8 compared with 30.6 among monotherapy patients — because their earlier treatment had already partially stabilized their motor function. To disentangle these overlapping variables, the researchers built two separate multivariable linear mixed-effects models, one anchored to pretreatment status and one to chronological age at infusion, both adjusting for baseline motor score and SMN2 copy number.

Across the entire cohort, motor scores improved dramatically, rising on average by roughly 20 CHOP-INTEND points per year of follow-up. Yet the pace of improvement was not uniform. Children who switched to the gene therapy after prolonged prior treatment improved significantly more slowly than those treated without prior exposure, a difference that persisted even after accounting for their higher starting scores. Similarly, in the age model, each additional month of age at infusion was associated with a measurable slowing of the rate of motor gain. The researchers caution that age and pretreatment status are so strongly intertwined in this observational dataset that the independent contribution of each factor cannot be definitively separated — older children were, almost by definition, the ones who had spent more time on prior therapies. Both patterns may simply reflect that children who received early prior treatment had already captured much of their achievable therapeutic benefit before the gene therapy was administered.

The milestone data paint a striking picture of how timing shapes outcome. Of the 49 children who could not sit at the time of infusion, 40 — or 80 percent — achieved independent sitting during the two years of follow-up, and 5 achieved independent walking. Crucially, 12.5 percent of those who gained sitting did so only after the 18-month mark, well beyond the window captured by earlier trials, confirming that meaningful motor gains continue into the second year and that premature judgments about treatment failure may be unwarranted. Every child treated before six months of age who carried three copies of the SMN2 modifier gene achieved sitting within the age-appropriate physiological window. In contrast, among infants with two SMN2 copies, outcomes ranged from on-time sitting to never achieving the milestone, with low baseline CHOP-INTEND scores and the presence of bulbar or respiratory impairment most consistently associated with less favorable trajectories, though not invariably so for every individual child.

Bulbar and respiratory function also evolved favorably for many children. Of the 54 children fed orally at the time of treatment, only 3 required a feeding tube during follow-up, while 2 of the 10 who already had tubes successfully transitioned back to oral feeding. On the respiratory front, none of the 43 children already requiring ventilatory support at baseline progressed to tracheostomy, and 3 were ultimately weaned off ventilation altogether. Among infants who entered treatment with no evident respiratory or bulbar impairment, fewer than 5 percent needed a gastrostomy and only 12 percent required non-invasive ventilation over the two-year period. Safety surveillance throughout the second year after treatment identified no adverse events, and the authors note that no new safety signal emerged between the first and second years, consistent with prior international reports.

Set against the natural history of the disease, the results are transformative. Untreated children with SMA type I never achieve independent sitting, and more than 90 percent die or require permanent ventilation by age two. In this cohort, fewer than 20 percent of the children who could not sit at treatment failed to gain that milestone within two years. The authors acknowledge the interpretive limits of their observational design — confounding by indication, selection bias, and the entanglement of age with treatment history all complicate attribution, and larger cohorts with methods such as propensity score matching would be needed to fully resolve them. Even so, the findings carry a clear clinical message: two years after a single infusion, children with the most severe form of spinal muscular atrophy continue to gain function, milestones once considered unattainable are achieved, and the duration of follow-up matters when judging the true efficacy of this therapy. Future studies, the researchers suggest, should extend to cognitive, behavioral, and language outcomes to fully characterize the long-term neurodevelopmental trajectory of these gene therapy-treated children.

Subject of Research: Long-term efficacy of onasemnogene abeparvovec gene therapy in type I spinal muscular atrophy

Article Title: Onasemnogene Abeparvovec in Type I Spinal Muscular Atrophy: 24‐Month Follow‐Up From the Italian Registry

Article References: Pane, M., Coratti, G., Cutrì, C., Varone, A., Masson, R., D'Amico, A., Sansone, V., Messina, S., Ricci, F., Ticci, C., Bruno, C., Agosto, C., Benedetti, F., Pini, A., Siliquini, S., Filosto, M., Zambon, A., Bitetti, I., Manna, M. R., … the ITASMAC working group (2026). Onasemnogene Abeparvovec in Type I Spinal Muscular Atrophy: 24‐Month Follow‐Up From the Italian Registry. Annals of Clinical and Translational Neurology, 13(9), 1866-1877. https://doi.org/10.1002/acn3.70356

Image Credits: AI Generated

DOI: 10.1002/acn3.70356

Keywords: spinal muscular atrophy, gene therapy, onasemnogene abeparvovec, SMN1, AAV9 vector, CHOP-INTEND, motor milestones, Italian registry, nusinersen, risdiplam, real-world data, pediatric neurology