Onasemnogene abeparvovec gene therapy for treatment of patients with spinal muscular atrophy: Updated real-world practical considerations

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease resulting from biallelic pathogenic variants of the survival motor neuron 1 (SMN1) gene that leads to motor neuron degeneration, progressive muscle atrophy, and weakness. In its most severe form and without timely initiation of treatment, SMA can be fatal or lead to a requirement for permanent ventilation by 2 years of age. Approved treatments for SMA target an increase in SMN protein production. These include nusinersen and risdiplam, which modify splicing of the SMN2 pre-mRNA, and onasemnogene abeparvovec, a viral-mediated gene therapy. In 2020, an expert panel provided recommendations and practical considerations regarding onasemnogene abeparvovec administration. As more countries have approved onasemnogene abeparvovec and new data have emerged from clinical trials and real-world use, a similar expert panel provides updated recommendations along with additional guidance. Specific recommendations are centered around family preparation prior to and immediately following dosing to minimize risk of infectious illness, timing of anti–adeno-associated virus serotype 9 antibody titer testing for those patients with exclusionary titers, modifying immunization schedules, avoiding potential complications with long-term corticosteroid administration, safety monitoring, considerations for combination therapy, implementing newborn screening, and emphasizing the need for ongoing multidisciplinary care and adherence to standard-of-care guidelines.

Introduction

Spinal muscular atrophy (SMA) is a progressive autosomal recessive neuromuscular disease resulting from biallelic pathogenic variants, typically deletions of the survival motor neuron 1 (SMN1) gene. ¹ Patients with SMA have an insufficient amount of functional SMN protein, leading to degeneration of motor neurons. ¹ The SMN2 gene, an SMN1 paralog, produces a low concentration of functional SMN protein. Patients demonstrate variability in SMN2 copy number, with fewer copies typically correlating with earlier onset and more severe phenotype.^2,3 Untreated patients with two or fewer SMN2 copies are predicted to not achieve independent sitting, while those with three or more SMN2 copies may achieve independent sitting or independent ambulation.^4,5 Individuals with SMA with more than four SMN2 copies may also develop symptoms, albeit often with a milder phenotype. ⁶

All currently approved disease-modifying treatments increase SMN protein production. Nusinersen is an SMN2 splicing modifier administered via repeated intrathecal injections (three times per year after four loading doses). ⁷ Risdiplam, also an SMN2 splicing modifier, requires daily oral dosing. ⁸ Onasemnogene abeparvovec is a gene therapy that uses an adeno-associated virus serotype 9 (AAV9) vector to deliver an SMN transgene via a one-time intravenous infusion. ⁹

Compared with natural history, patients treated with intravenous onasemnogene abeparvovec in clinical studies achieved increased survival, improved motor function and motor milestone achievements, and reduced respiratory and feeding support requirements.^10–16 Sustained efficacy has been demonstrated up to 10.1 years post-dosing. ¹⁷

Since its initial approval by the US Food and Drug Administration in May 2019 and the European Medicines Agency (EMA) in May 2020, onasemnogene abeparvovec is now approved in over 40 countries, and more than 4000 patients have been treated worldwide. With increasing regulatory approvals, use, and experience with onasemnogene abeparvovec, clinicians require updated guidance pertaining to patient-related issues and questions that may arise. In 2020, a global expert panel comprised of pediatric neurologists and neuromuscular specialists with expertise in treating patients with SMA with onasemnogene abeparvovec met to provide recommendations regarding the management of children receiving this therapy. ¹⁸ The present expert opinion update reflects new data that have emerged since the original report along with further real-world expertise from coauthors treating patients around the world.

Methods

All authors were invited to develop this updated expert opinion by Novartis Pharma AG. Coauthors represent seven countries and four continents. Coauthors have each treated 24 to 152 patients with onasemnogene abeparvovec in clinical trials and/or post-approval as of May 2025. Coauthors from the prior publication ¹⁸ identified the need to meet and revise the expert recommendations. Additional colleagues with clinical and clinical research expertise were invited to participate with the goal of representing different geographic regions and health care systems. The coauthors developed a list of key areas for recommendations based on those in the previous publication ¹⁸ as well as real-world experience, and these recommendations were developed through a series of virtual meetings from September 2024 to May 2025. The coauthors identified topics and formulated and attained consensuses for all recommendations made in this manuscript. Such recommendations were made independently from and without influence by Novartis Pharma AG. Additional knowledge gaps were also identified as considerations for future studies.

Topic 1: Preparation prior to dosing

Discussions with families prior to dosing are crucial not only for setting realistic clinical expectations but also for describing the benefit-risk profile for each patient. For parents of infants diagnosed in a presymptomatic state through newborn screening (NBS), it is necessary to convey a sense of urgency to treat early while balancing a new family's understandable psychosocial support needs that come along with an unexpected life changing diagnosis.

Requirements for pursuing treatment include (1) commitment of the treating physician and team to be available for potentially urgent issues that could arise post-dosing; (2) commitment from the family to continue prophylactic corticosteroid treatment and carry out regular long-term follow-up, including surveillance bloodwork; and (3) assurance that SMA standard of care (SoC)^19,20 is met in the short and long term to optimize outcomes and manage and mitigate other potential disease-related sequelae. Ongoing, comprehensive, multidisciplinary care is integral for continued care of the patient regardless of treatment choice.

Obtaining a neonatal history, including vitamin K administration and completion of hepatitis B virus vaccinations (where indicated), is an important component of assessment, alongside interpretation of baseline laboratory investigations and the benefit-risk profile. Of note, newborns who have not received vitamin K may be at greater risk of hemorrhagic disease of the newborn.

Adverse event (AE) counseling prior to treatment is also important for families to make informed decisions. Families should be informed that all patients must be monitored for potential adverse effects of AAV treatments. Recently published data suggest that some older and heavier patients, who receive a greater total vector genome dose intravenously, may experience greater or more prolonged serum transaminase elevations post-dosing, necessitating longer-term steroid use (discussed in depth in Topic 5: Corticosteroid Use and Post-Dosing Monitoring)^16,21 and monitoring of serum transaminases. An assessment of the benefit-risk profile for older and heavier children needs to be considered based on the individual family and child.

Like other disease-modifying treatments, onasemnogene abeparvovec aims to prevent the continued loss of lower motor neurons, but, in consideration of the biology of this post-mitotic cell line, cannot reverse any loss that has already occurred. Clinical trials have demonstrated that SMA disease-modifying treatments, including onasemnogene abeparvovec, offer the greatest potential benefit when administered earlier in the course of disease, particularly to presymptomatic infants.^14,15 The role of SMN protein is particularly important in late fetal life to early childhood when the structural connections of the neuromuscular system are developing. ²² SMN protein continues to be important in older children and adults, with progressive decline in motor function documented for patients with untreated SMA types 2 and 3. ²⁰

Recommendation: Precautions that warrant discussion with families prior to treatment include mechanisms for keeping the patient healthy, such as limiting exposure to communicable diseases (e.g., viral respiratory illnesses) that may delay gene therapy or potentially add to the risk of heightened immunogenic responses that occur following gene therapy. In this context, it is imperative to review the importance of handwashing, avoiding unnecessary exposures, and encouraging family members to keep up to date on their own immunizations (discussed further in Topic 4: Immunizations).

Families should also reduce unnecessary social contact, including consideration for avoiding or delaying interactions with extended family members and friends immediately prior to and after dosing. The length and extent of isolation must also be balanced with the needs and socioeconomic considerations of individual families, and can be influenced by factors such as the demands of having a young infant, employment status of the parents, requirement for childcare, and sibling exposures including but not limited to school participation. As with healthy newborns, avoiding individuals who are symptomatic of acute infective illness is important.

Recommendation: Families should be advised to notify the prescribing clinical team of any illnesses within the days prior to gene therapy and should have a direct point of contact or method of contact within the dosing team for ease of communication pre- and post-dosing. The patient should be assessed prior to dosing to ascertain that the patient is clinically appropriate for infusion. If a patient has an active or recent illness beyond SMA on the day of dosing (e.g., acute febrile infection), consideration should be given to delaying onasemnogene abeparvovec infusion as its administration in close proximity to an intercurrent illness may potentially increase the risk of complications, including transaminitis and thrombotic microangiopathy (TMA). ²³ The severity of the illness along with the availability of bridging therapy should be considered when weighing whether to postpone onasemnogene abeparvovec infusion. Ideally, onasemnogene abeparvovec infusion should be delayed until the patient is clinically recovered and healthy (e.g., > 2 weeks of wellness after an acute infectious illness). During this period, an alternate SMN-augmenting treatment may be considered as a bridge, if available. In certain clinical situations, such as mild illness or lack of bridging therapy availability, discussions regarding the advantages and disadvantages of delaying therapy should be undertaken, and earlier administration of onasemnogene abeparvovec may be considered.

Recommendation: Families should be advised that the most important factor determining better overall outcomes is the prompt initiation of an SMN-augmenting therapy, especially for infants with two or three copies of SMN2. At present, there is no international consensus for presymptomatic treatment of patients with four or more SMN2 copies. In a consensus statement, neuromuscular experts in the United States have strongly advocated the need for immediate treatment of presymptomatic four-copy patients on the grounds that the adoption of a watch and wait approach amid irreversible loss of motor neurons is unethical and cannot be medically justified.^24,25 This approach is increasingly advocated in other jurisdictions where approval and reimbursement of onasemnogene abeparvovec for four-copy patients is currently not available. ²⁶

For those individuals with four SMN2 copies for whom treatment is deferred, it is important that families understand that these individuals do have SMA, with potential for progression to symptomatic disease. For this reason, close monitoring is important to enable treatment initiation as soon as clinical signs of SMA are identified.

Topic 2: Anti-AAV9 antibodies

Prior to treatment, all patients must be tested to determine anti-AAV9 antibody titers ⁹ because the immune response associated with the presence of elevated titers may pose greater safety concerns and reduce treatment efficacy through opsonization. Anti-AAV9 antibodies can occur from either passive, vertical transmission from a mother to a newborn infant (expected to decline over time) or develop as part of the adaptive immune response in an older child after exposure to a community-acquired infection (unlikely to decline over time). Regardless, patients with persistently elevated anti-AAV9 antibody titers (using enzyme-linked immunosorbent assays, > 1:50) are not eligible for treatment with onasemnogene abeparvovec.

Published studies suggest that the percentage of patients who might have anti-AAV9 antibody titers >1:50 that would exclude them from treatment is low. For patients with SMA screened for preexisting anti-AAV9 antibodies prior to treatment with onasemnogene abeparvovec, 7.7% of patients had titers >1:50 at their initial screening, decreasing to 5.6% on final screening. ²⁷ In a separate retrospective analysis of patients in the United States, 13% had elevated anti-AAV9 antibody titers, with a greater prevalence in younger versus older patients (18.2% of those ≤3 months old vs 1.1% of those ≥21 months old), suggesting transplacental transfer of antibodies to the fetus as the likely mechanism of elevated titers. ²⁸ In Japan, 6% of patients had high titers, which decreased after 6 months. ²⁹

Recommendation: For newborns, transient, placental transfer of maternal antibodies (both immunoglobulin G [IgG] and immunoglobulin A [IgA]) is the most common mechanism for antibody positivity in the infant as transplacental transfer yields systemic transmission of immunoglobulins in the newborn. This mode of transmission is in contrast to the transfer of IgA antibodies via breast milk into the gastrointestinal tract of newborns, which does not enter the infant's circulation. ³⁰ Given that the benefits of breastfeeding (e.g., passive immunity and maternal-infant bonding ³¹ ) outweigh the risks of further increasing or prolonging elevated anti-AAV9 titers in a patient, breastfeeding should be continued particularly as it does not influence serum anti-AAV9 concentrations. ³²

Recommendation: Once eligibility testing is complete and demonstrates appropriate anti-AAV9 antibody titers to permit therapy, treatment with onasemnogene abeparvovec may proceed. Repeat anti-AAV9 antibody testing is encouraged if >30 days has elapsed since the most recent titer analysis.

Recommendation: The most important factor determining a better overall outcome is the prompt initiation of an SMN-augmenting therapy. For those patients with elevated anti-AAV9 antibody titers (>1:50), alternative therapy should be considered or continued while repeat anti-AAV9 antibody testing is undertaken (additional detail below and in Topic 1: Preparation Prior to Dosing).

Recommendation: Maternally derived anti-AAV9 antibodies decline over time (half-life of anti-AAV9 IgG is approximately 41 days ³³ ), and neonates and young infants with exclusionary anti-AAV9 antibody titers at initial screening are generally expected to become eligible for treatment at retesting. ²⁷ Individual case reports of patients initially ineligible for treatment but eventually becoming eligible have been reported.^34,35

The period between the initial screening and retesting may differ based on titers. For example, patients with titers between 1:50 and 1:100 could be retested more quickly (e.g., within 1–2 weeks). For titers >1:200, it is likely that this will take at least two half-lives to fall to <1:50. Repeat testing may be undertaken to assess the trend of decline, with practices varying from every 1 to 4 weeks. Retesting is recommended as clinically determined until titers are <1:50 if the plan is to pursue treatment with onasemnogene abeparvovec. If baseline anti-AAV9 titers remain >1:400 after three adequately spaced repeat tests, then it is predicted that the patient has developed adaptive immunity (not passive maternal antibody transfer). In this case, no further antibody testing is indicated, and treatment with onasemnogene abeparvovec is not feasible.

Topic 3: Screening for underlying liver disease

Prior to dosing, patients are screened for transaminase elevations. In cases in which initial values may be elevated, it is important that age-appropriate reference ranges are used, as the upper limit of normal (ULN) is greater in newborns. For example, reference ranges for aspartate aminotransferase (AST) in newborns <15 days of age can range from 32 to 162 U/L, falling to 20 to 67 U/L at 15 days to <1 year of age. ³⁶ Similarly, gamma-glutamyltransferase (GGT) concentrations can range from 23 to 219 U/L at <15 days of age, decreasing to 8 to 127 U/L from 15 days to <1 year of age. ³⁶

The identification of persistently elevated serum transaminase concentrations prior to onasemnogene abeparvovec treatment warrants further investigation to determine etiology. This includes investigations for active infectious etiologies that may place the patient at greater risk post-gene therapy. For example, testing for underlying cytomegalovirus and Epstein-Barr virus is performed before administration of onasemnogene abeparvovec at some centers, although there is regional variability. Testing may include IgG, IgM, or PCR quantitative assessments to guide insight regarding infectious phase.

Topic 4: Immunizations

Vaccination schedules may require modification prior to and after treatment with onasemnogene abeparvovec. This is to avoid potential risk for vaccine-related immunogenic responses contemporaneous with onasemnogene abeparvovec administration. Live virus vaccinations pose a potential heightened risk for patients on immune-modulating doses of corticosteroids, which are required beginning on the day prior to dosing and continued for a specified time after gene therapy (discussed in detail in Topic 5: Corticosteroid Use and Post-Dosing Monitoring). However, even attenuated vaccines should be deferred for the period immediately preceding and following gene therapy. In addition to risk for adverse effects, there is potential for reduced vaccine efficacy due to the requirement for a typical immune response in order to induce appropriate immunogenicity, which may be blunted in the context of corticosteroid administration.

For neonates with SMA identified through NBS or prenatal testing, no changes to the hepatitis B vaccination at birth are necessary. There may be a short period in which administration of subsequent vaccines are delayed (discussed above). Consequently, it is important to review the immunization history and provide catch-up vaccinations. In some countries, mothers may have received respiratory syncytial virus (RSV) immunization during pregnancy, which can influence considerations for RSV prophylaxis in infants with SMA. While the timing of live vaccines for individuals taking corticosteroids varies with duration and dose, a general and straightforward guide for children taking any dose of corticosteroids >28 days is that live, attenuated vaccinations are administered at least 4 weeks after stopping corticosteroids. ³⁷ The live, attenuated rotavirus vaccine has age limits and, therefore, may not be recommended in a catch-up schedule. For example, for children older than 3 months of age, the “window” for administration of the live-attenuated rotavirus vaccine may have passed (e.g., ages 6–15 weeks per Health Canada guidance ³⁸ and first dose administered before 15 weeks old per CDC guidance ³⁹ ). Consultation with an infectious disease specialist may also be considered on a case-by-case basis for additional information or guidance. Online resources to specific local practices may also be referenced. ⁴⁰

Regional variability exists regarding specific vaccine recommendations and scheduling for those at risk of severe respiratory infections. Therefore, guidance should be sought from the country or local jurisdiction. Many countries or jurisdictions recommend additional, augmented vaccines for patients with SMA, such as palivizumab or nirsevimab for young infants or pneumococcal 20-valent conjugate vaccine for older children who may manifest more disease-related symptoms, depending upon their age. Vaccine considerations for family members should include seasonal vaccines, such as COVID-19 and influenza, as well as dTaP boosters for individuals who may have extensive contact with infants, such as grandparents. Clinicians should ensure that children with SMA are offered current and comprehensive recommendations pertaining to vaccinations that are aligned with their public health authority.

Recommendation: Patients should avoid vaccines in the 2 weeks prior to onasemnogene abeparvovec treatment, following an adjusted catch-up vaccination schedule, if necessary, after corticosteroids are discontinued post-treatment.

Recommendation: Because patients may have alterations in vaccine scheduling/administration while they are receiving corticosteroid treatment, it is recommended that infants and their families avoid contact with individuals with symptoms attributable to an infectious illness and larger social gatherings as much as possible until a vaccination catch-up schedule is initiated.

Recommendation: In most clinical scenarios, waiting 4 weeks after the discontinuation of corticosteroids is recommended prior to catching up on any vaccinations that have been delayed. However, in certain clinical scenarios, vaccination may be considered once a patient's prednisolone dose is <1 mg/kg/day, noting that an age limit exists for some immunizations (e.g., live-attenuated rotavirus vaccine). In these cases, consultation with an infectious disease specialist may be considered.

Recommendation: High-dose systemic corticosteroids can interfere with vaccine-induced immune responses. ⁴⁰ For patients receiving a greater dosage of prednisolone (≥2 mg/kg/day or ≥20 mg/day) or longer duration (≥14 days) of corticosteroid therapy, ⁴⁰ expert advice from an immunization specialist may assist in determining the appropriateness and safety of administering vaccines.

For patients on a prolonged course or those receiving low-dose corticosteroids during the tapering period (<1 mg/kg/day), vaccination may be considered, especially if the window for rotavirus immunization is closing. In addition, seasonal RSV prophylaxis (palivizumab or nirsevimab) may be considered at clinician discretion if it is in the child's best interest given the scenario. ⁹

Recommendation: For older patients, the intranasal live-attenuated influenza virus is not recommended if on high-dose corticosteroids (≥2 mg/kg or ≥20 mg/day prednisone equivalents). For these patients, the intramuscular inactivated influenza vaccine may be considered, if available.

Recommendation: Vaccinating family members for whooping cough, chicken pox, COVID-19, and influenza is highly recommended to protect the unvaccinated newborn.

Topic 5: Corticosteroid use and post-dosing monitoring

Patients treated with onasemnogene abeparvovec receive oral corticosteroid therapy starting the day before dosing and extending into the post-dosing period (systemic corticosteroids equivalent to oral prednisolone at 1 mg/kg of body weight/day for a minimum of 30 days followed by an additional, minimum 30-day tapering period in the absence of transaminase elevations. The length of corticosteroid exposure varies from individual to individual. However, some patients, particularly those who are older and/or heavier, may require prolonged corticosteroid treatment (>180 days) or dosage increases because of transaminase elevations. ¹⁶

For cases in which corticosteroid treatment is anticipated to be prolonged (>6 months), consideration should be given to mitigate potential adverse effects. Corticosteroids can lead to weight gain, changes in mood, reduced bone health, gastrointestinal AEs, and changes in growth. Consultation with a dietician may be helpful to address nutritional strategies. Supplementation may be appropriate, particularly regarding vitamin D, which is typically a standard recommendation for infants who are breastfeeding but may require ongoing supplementation in the context of chronic corticosteroids and a neuromuscular diagnosis due to risk for impacts on bone health. Patients may require prophylactic antacid medication or augmented dosing if gastroesophageal reflux is encountered. Collectively, adverse effects of corticosteroids accumulate with prolonged administration.

Strategies to minimize corticosteroid adverse effects due to the need for ongoing immune-modulation have been pursued. Pulse methylprednisolone up to 30 mg/kg/dose has been administered either on one occasion, at weekly intervals, or as consecutive doses given daily for 3 to 5 days (followed by return to oral prednisone) in efforts to more rapidly influence a transaminitis that is prompting prolonged corticosteroid administration and permit a more timely wean once a downtrend in laboratory values is noticed. Some corticosteroid sparing regimens have been implemented as well, including T-cell targeted therapies or medications such as tacrolimus, as well as sirolimus, which targets T and B cells. However, this is an area of limited experience, and further research is needed.

Post-dosing serum transaminase evaluation

Following treatment with onasemnogene abeparvovec, cases of acute liver failure with fatal outcomes have been reported along with acute serious liver injury and elevated aminotransferases. ⁹ Thus, patients’ liver function is monitored for at least 3 months post-dosing and at other times as clinically indicated. ⁹

Recommendation: The risk of adrenal insufficiency must be considered for all children receiving corticosteroid therapy for at least 14 days or more. ⁴¹ Parents should be educated and provided with a plan for stress doses in emergency situations, with an alert placed in the patient's medical records. Neuromuscular clinicians should be aware of the risk of adrenal insufficiency, develop center- or clinic-specific guidelines for stress dose steroids and sick plans, and counsel patient families on these risks. Referral to an endocrinologist may be considered, particularly for patients on prolonged steroids, to ensure they pursue a steroid wean and eventual discontinuation plan that is appropriate and safe. For patients who have required greater dosages or longer durations of prednisone, it may be appropriate to consider confirmation of return of endogenous adrenal function. This can be accomplished by evaluating morning (8:00 am–8:30 am) cortisol concentrations or by means of an adrenocorticotropic hormone stimulation test in young infants where diurnal hormonal patterns have not been established. Transition from prednisone to hydrocortisone and then subsequent weaning may be required for some patients if they demonstrate delay in return of endogenous adrenal function.

Recommendation: If children become acutely ill or require surgical intervention while on corticosteroids, stress dose hydrocortisone administration should be pursued given the risk for impacts from adrenal insufficiency during these heightened physiologic stressors. Pre-treatment counseling with families should address this topic.

Recommendation: Consider consultation with a hepatologist if serum transaminitis is marked (>20× ULN), more prolonged (>6 months), or if higher doses of oral prednisone equivalents (>2 mg/kg/d) or intravenous corticosteroids are required. Potential use of steroid-sparing immunosuppressants may be considered in some cases of prolonged transaminitis. Unexpected or prolonged hepatic laboratory abnormalities may also warrant additional investigations with hepatology, including liver imaging and broadened workup for other contributing viral triggers or hepatic steatosis, which has been reported in some children with SMA.^42,43

Recommendation: Once corticosteroids are weaned and serum transaminase concentrations are consistently normal, serum transaminase concentrations should continue to be monitored because of the theoretical risk of rebound reflective of liver pathology. In such cases, increasing or restarting corticosteroids may be necessary. Long-term laboratory monitoring is variable between the expert sites. Many clinicians opt for an annual laboratory monitoring schedule to evaluate for the theoretical risk of liver neoplasm. A more frequent laboratory monitoring schedule may be pursued by individual clinicians based on clinical practice, especially for patients treated while symptomatic. Clinicians include some or all of the following in these evaluations: complete blood count (CBC), serum ALT, AST, GGT, and bilirubin, and alpha fetoprotein.

Troponin and cardiac symptoms

Post-dosing increases in concentrations of cardiac troponin-I (up to 0.176 µg/L  ⁹ ), a biomarker that may indicate myocardial injury, ⁴⁴ have been observed in clinical trials. ⁴⁵ Transient troponin I elevations (≥0.04 ng/mL) were also noted for patients enrolled in the RESTORE registry; all resolved and were not associated with cardiac AEs. ⁴⁶

Troponin-I and troponin-T are required for cardiac muscle contraction and are markers of myocardial injury. However, in several diseases with skeletal muscle pathology, including SMA, troponin-T expression was detected in skeletal muscle^47,48; therefore, this assay may detect both cardiac and skeletal muscle injury for these patients. Care should be taken to use age-appropriate reference ranges, particularly for newborns, in which normal ranges of troponin concentrations are much greater than that observed in older children. ³⁶ For newborns with SMA, median high-sensitivity cardiac troponin-I concentrations were 39.5 (range, 4–1205) ng/L, with some children having concentrations greater than the upper reference limit. ⁴⁹ Troponin-T elevations have also been reported for patients with SMA, particularly in infants with more severe phenotypes. ⁵⁰

The clinical significance of these troponin elevations both pre- and post-gene therapy, however, is unclear. While a small subset of patients with SMA may have cardiac pathology, overt cardiac dysfunction is atypical. Cardiac pathology for patients with SMA can include structural abnormalities typically observed in those with more severe SMA, and rhythm disturbances, which are reported more in those patients with milder SMA. ⁵¹ However, troponin elevations prior to onasemnogene abeparvovec treatment have been noted but not linked to cardiac pathology. ⁴⁶ Likewise, after onasemnogene abeparvovec treatment, troponin elevations have also been reported but have not to date been associated with cardiac dysfunction, although cardiac disorders following treatment have been reported. ⁵² In fact, one author notes that, at their center, the cardiologists reported that adequate rationale to continue troponin testing did not exist and recommended cardiology referral only if there were other clinical symptoms suggestive of cardiac disease.

Tremendous variability exists in troponin concentrations during the first 3 months of life for healthy newborns, with concentrations ranging from 2.97 to 936 ng/L for children 5 to <15 days of age, 4.61 to 165 ng/L for those 15 days to <3 months of age, and 0 to <9 ng/L for children 3 months to <19 years of age. ³⁶ Similar variability and age-dependent decreases in concentrations are also observed for troponin-T. Thus, it is important to place this variability into context and consider clinical symptomatology or the absence thereof to alleviate parental anxiety and develop consistent approaches among clinicians.

As more institutes move to using high-sensitivity troponin-I assays, detecting elevations will likely become more common. Although the clinical significance of post-dosing troponin-I elevations is unknown, these elevations, coupled with cardiac findings (thrombi, myocardial inflammation, and degeneration/regeneration) in preclinical murine studies, ⁴⁵ led to the recommendation to monitor cardiac function through both clinical examination and evaluation of troponin-I before and after onasemnogene abeparvovec treatment in some jurisdictions. Of note, pre- and post-dosing troponin assessments are no longer required per recently updated US FDA and EMA prescribing information.^9,23 Some authors have questioned whether this recommendation could be modified in consideration of the confusion that exists about how best to follow generally healthy infants with elevated troponins.

Recommendation: Clinicians may consider assessing patients for elevated troponin concentrations before and after onasemnogene abeparvovec administration. Physicians should also perform a general examination to assess for any cardiac abnormalities that may influence treatment management decisions. In the event of post-dosing troponin elevations, response will vary based on both the condition of the infant and clinical judgement of the treating physician. In a well-appearing infant with incidental post-dosing troponin elevation, various approaches to follow-up may include no additional follow-up, electrocardiogram (EKG) only, brief review with cardiology team, or cardiac consultation. If EKG results are normal and the patient appears well and is feeding normally, no further workup may be needed. In cases of persistent tachycardia or elevated serum troponin concentrations (>5–10× ULN for age), consideration should be given to an EKG, pediatric cardiology consultation, and echocardiogram.

Thrombotic microangiopathy

TMA is characterized by a combination of hemolytic anemia, thrombocytopenia, and acute kidney injury. TMA results from an overactivation and dysregulation of the complement cascade and has been linked to adverse drug reactions as well as active infection. Out of >4000 children treated with onasemnogene abeparvovec, there have been 25–30 cases of TMA (0.5% to 1%) reported.^52–57 In some cases, simultaneous activation of the immune system from either concurrent infections or vaccinations occurred.^9,23

Recommendation: Despite the rarity of TMA, clinicians must keep a high index of suspicion. The initial clinical signs of TMA are vomiting and reduced oral intake and urine output 5–8 days after administration of onasemnogene abeparvovec. ⁵⁵ Isolated, transient thrombocytopenia following onasemnogene abeparvovec treatment must be differentiated from other hematological and biochemical evidence of emerging TMA. Such signs could include: (1) reduced hemoglobin concentrations compared with the prior result, (2) presence of schistocytes on blood smear, (3) elevated bilirubin (particularly unconjugated or indirect concentrations), and (4) more prominent rise in AST compared with ALT (since AST but not ALT is contained within erythrocytes). The constellation of thrombocytopenia, anemia, and red blood cell fragmentation (schistocytes) on blood film is sufficient to make the diagnosis of TMA. Urinalysis may demonstrate hematuria and proteinuria. Clinical symptoms may not be initially apparent but can evolve to include fatigue, confusion, edema, or pallor. These findings must prompt an emergency consultation with a nephrologist and hematologist with consideration for hospitalization and evaluation for potential need for dialysis or other immunomodulatory treatment intervention. Clinical assessment of fluid balance and hemodynamic status are important. Further blood tests that should be considered include analysis of complement levels, coagulation testing (international normalized ratio, partial thromboplastin time, fibrin levels), lactate dehydrogenase, electrolyte panel (Na, K, Cl, HCO₃, Ca), and renal function (urine protein, blood urea nitrogen, creatinine, cystatin C, and estimated glomerular filtration rate). TMA can be complicated by hypercreatinemia, electrolyte disturbances (hyponatremia or hyperkalemia), oliguria/anuria, and hypertension.

Although soluble C5b9 may be one of the best markers, this test does not have a quick turnaround at most sites but may be confirmatory of improvement.

Recommendation: Patients with suspected TMA require emergency evaluation and hospitalization (possible intensive care unit admission) with appropriate medical monitoring by a multidisciplinary team (that may include hematology, nephrology, and immunology) with close monitoring of electrolytes and blood counts, as well as hemodynamic and fluid states. It is important to consider and monitor other organs, including the brain, heart, and lungs, which may also be sites of microangiopathy and be affected by hypertension and fluid overload.

Recommendation: Management will differ from patient to patient and require communication between neurology, nephrology, hematology, and other specialists. While no obvious standardized approach exists, immune therapy with high-dosage corticosteroids or other agents (e.g., complement inhibitor, such as eculizumab) and close attention to renal function and electrolyte management have been useful.

Topic 6: Post-infusion symptoms

Of the AEs reported following onasemnogene abeparvovec administration in both clinical trials and real-world studies, some of the most common include pyrexia, vomiting, and nausea.^12–16,51 Specifically, in a retrospective observational study of 661 individual case safety reports of patients treated with onasemnogene abeparvovec in Europe, suspected AEs related to onasemnogene abeparvovec treatment included pyrexia (6.3%), vomiting (5.1%), and nausea (0.8%). ⁵¹ Rare reports of necrotizing enterocolitis in term infants have been reported post-treatment with onasemnogene abeparvovec. ⁵⁸ Therefore, more prominent vomiting or feeding intolerance should prompt further investigation for rare complications in infants post-treatment.

Recommendation: Parental education should be undertaken regarding the management of vomiting to ensure corticosteroid absorption and avoid dehydration. This includes small, frequent feeds, administration of antiemetics, administration of gastrointestinal protective medications, and monitoring of frequency of use and the heaviness of diapers. Instructions include knowledge of red flags, such as wet diapers <50% of expected and persistent vomiting.

Recommendation: Infants with a post-dosing fever should be evaluated appropriately by a physician that day. An emergency department evaluation may be necessary if the patient is within an age whereby infantile fever would typically require comprehensive assessments, regardless of intervention with gene therapy. The specific type of antipyretic selected should be based on factors including blood counts, liver function tests, and age of the patient.

Recommendation: Because corticosteroids are known to cause gastrointestinal AEs, anti-nausea medication (selective serotonin 5-HT3 antagonists, ondansetron) can be used to address vomiting, and proton pump inhibitors (e.g., lansoprazole) and histamine H2 antagonist (e.g., famotidine) can be used to provide gastric protection. Because it is imperative for daily corticosteroids to be administered, patients who are vomiting may require administration of corticosteroids via a nasogastric tube, intravenous infusion, or via other administration routes.

Recommendation: Parents should be counseled about and provided with written information on the signs and symptoms to look for as related to the body's immune reaction(s) to viral capsids that can occur within the first 3 to 10 days post-dosing, and instructions on when and who to call from the dosing or hospital team. Symptoms that would warrant timely reassessment would include any or all of the following: persistent or high-grade fever, frequent vomiting that would increase risk of dehydration, or potential signals of other intestinal pathology, ⁵⁸ bruising, bleeding, petechiae, lethargy (suggestive of hypoglycemia), pigmenturia, hematuria, or oliguria. This information is critical for monitoring purposes as well as alerting emergency personnel.

Topic 7: Importance of ongoing, long-term, multidisciplinary care for optimal outcomes and at-home monitoring

Following treatment with any SMN-augmenting therapy, ongoing multidisciplinary care, along with adherence to SoC, is crucial. Follow-up visits are also important for safety monitoring, evaluation of the overall developmental profile of each patient, and provision of allied health therapy and equipment to optimize functioning. Frequency of follow-up visits may vary by site and by child. For example, older children will often be treated with corticosteroids for longer periods of time and therefore need more follow-up visits over a longer duration. Some coauthors evaluate patients more frequently while they are receiving corticosteroids and during the weaning period (e.g., weekly), with subsequent visits more spread out (e.g., monthly or every 3 months). Other clinicians evaluate patients at monthly visits for the first year (also includes functional motor scoring during these visits) with subsequent visits occurring at longer intervals, and some clinicians can closely monitor laboratory assessments and communicate with families via telephone or telehealth without frequent in-person visits. In the setting of abnormal laboratory values or other concerns, more frequent visits may be considered. If available, use of complex care pediatricians or team coordinators/nursing support within the dosing team may help coordinate the initial frequent visits and laboratory monitoring.

Longer term laboratory monitoring (discussed in detail in Topic 5: Corticosteroid Use and Post-Dosing Monitoring) along with monitoring of neurodevelopmental progress and motor outcomes, may be undertaken at intervals deemed appropriate by the clinician.

Recommendation: During long-term follow-up, parents and doctors should inform patients that they have been treated, explaining in an age-appropriate language they can understand. Clinicians should also explain to the patient and their families about the importance of continued medical check-ups and adherence to SoC even if patients have a paucity of symptoms attributable to SMA.^19,20,59

Recommendation: After the first year following onasemnogene abeparvovec treatment, visit intervals of at least once or twice per year are recommended indefinitely, depending upon the patient's individual needs, and in keeping with general SoC guidelines for SMA.

Rare AEs following onasemnogene abeparvovec treatment have been described in single cases. Some of these AEs may represent immune-driven events, including cases of necrotizing enterocolitis in two infants with two SMN2 copies identified by NBS ⁵⁸ and a case of hemophagocytic lymphohistiocytosis in a 3-year-old patient ⁶⁰ following treatment with onasemnogene abeparvovec. In addition, individual cardiac and liver AEs have also been reported. ⁵¹ Although it is difficult to determine causality in single case reports, it is important that physicians report these AEs to the appropriate authority, ideally a registry, to enable assessment and collation. ⁶¹

While the genetic payload of AAV-based gene therapies is primarily maintained as a non-integrating episome following transduction, rare integration events have been linked to tumor formation in animal models, and a theoretical risk of insertional mutagenesis and tumorigenicity in humans remains. One case report of a child who developed an epithelioid tumor ⁶² and another of a child who developed pilocytic astrocytoma ⁶³ following onasemnogene abeparvovec treatment were reported, although integration site analysis suggested causal independence from onasemnogene abeparvovec administration in both instances. While no causally related tumorigenesis has been observed in humans post-AAV gene therapy, determining if there is or is not an integration event is important to identify any causal association or lack thereof. ⁶³

Recommendation: Families occupy an important role in monitoring the occurrence of long-term AEs. Caregivers are encouraged to maintain regular communication with health care providers to discuss any concerning signs and symptoms or complications. In addition to multidisciplinary care, academic collaboration around potentially rare long-term events is important.

Topic 8: Combination therapy

In some cases, patients are treated with multiple disease-modifying therapies at the same time or sequentially. This can be referred to as “bridging therapy” or “switching therapy” if risdiplam or nusinersen is administered prior to onasemnogene abeparvovec and then discontinued at or shortly after onasemnogene abeparvovec treatment. In contrast, “combination therapy” is defined as continuing or initiating risdiplam or nusinersen treatment after onasemnogene abeparvovec. Bridging therapy is an important consideration for patients with elevated anti-AAV9 antibody titers, believed to be due to passive transfer of maternal antibodies, until the titers fall below the cutoff threshold for dosing, as well as for other patients requiring a delay in onasemnogene abeparvovec treatment (e.g., in cases of acute illness) to prevent disease progression. ⁶⁴ In some situations, patients treated initially with onasemnogene abeparvovec may receive an additional disease-modifying treatment after SMN gene therapy, referred to as “combination” or “add-on” therapy). ⁶⁴ The potential use of combination therapy is an area of active interest,^65–69 with some clinical trials (RESPOND and JEWELFISH) demonstrating safety and tolerability.^70–72 Comparison of outcomes for patients treated with onasemnogene abeparvovec monotherapy or dual therapy (onasemnogene abeparvovec plus nusinersen or risdiplam) indicated that dual therapy was well-tolerated. ⁷⁰ At this time, the potential role of combination therapy is being studied in regulated clinical trials.

Geographic variability related to regional availability, affordability, and insurance coverage also exists for access to bridging and combination therapies for SMA. For those regions where approval and/or reimbursement is available for combination therapy, the decision is based on an individual patient and their signs and symptoms and is made in collaboration between the parents and treating clinician in specific clinical circumstances.

Recommendation: For instances in which a delay in onasemnogene abeparvovec treatment exists (e.g., active infection, elevated anti-AAV9 antibody titers, or delay in the insurance approval or shipping), it is important to relay to families the need for timely treatment with a disease-modifying therapy (i.e., consideration of bridging therapy), for optimal outcomes (discussed in Topic 1: Preparation Prior to Dosing). Considerations when choosing between risdiplam and nusinersen include regional availability, affordability, insurance coverage, ease of administration, and considerations for AEs and efficacy. For example, even when the family is opting for onasemnogene abeparvovec treatment, some coauthors initiate alternate SMN-augmenting therapy immediately after diagnosis (with some terminating that treatment the day prior to receiving gene therapy).

Recommendation: In jurisdictions where combination therapy is available, there is no evidence that a washout period for either risdiplam or nusinersen is necessary prior to dosing with onasemnogene abeparvovec. When initiating nusinersen following onasemnogene abeparvovec, some coauthors waited until the post-dosing steroid course was completed and laboratory evaluations were back to baseline to ensure AEs from onasemnogene abeparvovec (e.g., thrombocytopenia) were adequately addressed prior to initiating an additional therapy.

Topic 9: Newborn screening

The clinical benefits of initiating SMN-augmenting treatment as early as possible are well-recognized irrespective of the specific treatment.^{14,15,73–77} In the phase 3 SPR1NT trial, all patients with two SMN2 gene copies (n = 14) who were expected to develop SMA type 1 and were treated presymptomatically with onasemnogene abeparvovec achieved independent sitting at age 18 months, ¹⁴ and 14 of 15 patients with three SMN2 copies (expected to develop SMA type 2) achieved independent walking at age 24 months. ¹⁵ Many of these patients achieved these milestones within the World Health Organization developmental windows. ⁷⁸ Long-term follow-up of these patients indicated that all SPR1NT patients, who had either two or three SMN2 gene copies, eventually walked. ⁷⁹

To identify patients at risk for SMA earlier in life, many countries have implemented NBS initiatives. At the time of the earlier expert opinion publication, NBS programs were underway in 11 countries. ¹⁸ Since then, more countries have implemented programs (33 at the beginning of 2024 ⁸⁰ ) such that 72% of children are screened at birth in Europe (including Russia and Turkey), ⁸¹ 100% of children born in the United States are screened as of 2024, ⁸² and 18% of the world's newborns are projected to be screened for SMA by 2028. ⁸⁰

Some countries (e.g., Turkey) have opted to cover NBS program testing as a national expense. In Japan, a pilot project has been started in which the national government will cover half the cost, and the local government will cover the remaining half.

In the real-world setting, most patients identified by NBS programs in the United States received treatment with onasemnogene abeparvovec within the first 2 to 4 weeks of life. ⁸³ Challenges included delays in obtaining prior authorization or insurance approval and AAV testing, ⁸⁴ reinforcing the need for bridging therapy in these instances (described in detail in Topic 8: Combination Therapy). As previously mentioned, the paucity of clinical trial data in neonates with SMA and four copies of SMN2 has precluded the approval and reimbursement of onasemnogene abeparvovec for these patients in certain jurisdictions, highlighting the importance of further research. ⁸⁵ In addition, some parents of children with four SMN2 copies may choose not to start treatment immediately following diagnosis, instead choosing the alternative of very close clinical observation.

Some laboratories only report results as four or more copies of SMN2 without distinguishing an exact copy number. ²⁴ In these cases, it is important to pursue testing to discern exact copy number (multiplex ligation dependent probe assay, MLPA) for patients with four or more copies to help guide treatment decisions for those with five or six copies of SMN2.

Between 30% to 40% of newborns with SMA and two SMN2 copies identified through NBS may have clinical manifestations of SMA at their first assessment. ⁸⁶ A careful neurological examination is critical as this can guide therapeutic decision-making and timing of treatment. ⁸⁷

For NBS, clinicians must understand what is screened in their country or jurisdiction. For example, some countries report screening solely for biallelic deletions in SMN1 and will not detect pathogenic missense or nonsense variants in SMN1. If NBS is positive, the nature of SMN2 reporting, whether reflexively tested or specifically ordered, needs to be understood for each country. Knowing the range of SMN2 copies reported for each positive NBS test is crucial since it helps predict phenotype. Furthermore, some countries do not report patients with four SMN2 copies as a screen positive despite the likelihood of eventual progression to symptomatic SMA. ⁸⁸ In addition, approximately 5% of SMA cases will be missed if NBS only screens for biallelic deletions in SMN1 because this testing does not detect SMA due to deletions or point mutations on one allele combined with SMN1 deletion on the other allele. When SMA is clinically suspected, and biallelic SMN1 deletions are not present, consideration should be given to performing Sanger sequencing of the SMN1 gene. Short-read exome sequencing, the backbone of most neuromuscular gene panels, cannot differentiate SMN1 from SMN2 due to the highly homologous nature of these genes. Relying upon an exome in such cases could result in a false negative result and delay diagnosis of SMA.

Recommendation: NBS for SMA can greatly improve outcomes. It is imperative that the laboratory and clinicians charged with treating these infants develop clear workflows to ensure early treatment. For example, determine the designated first point of contact after a positive SMA NBS test relative to the treating SMA physician with the goal of minimizing delays and enhancing rapid communication with key personnel. ⁸⁷

Recommendation: Based on what is tested through the NBS program (which varies between countries), some cases of SMA may not be detected and therefore should be considered in the differential diagnosis of any infant with hypotonia or child with motor delay or motor weakness that requires further confirmatory testing if a clinical suspicion exists. Physicians should be aware of where or if NBS was completed, as time of initiation varies considerably, and this could impact older children born before NBS initiation in their jurisdiction.

Recommendation: In addition to a system of NBS implementation, development of a family-centered model of care that facilitates rapid diagnosis and initiation of treatment when appropriate is also critical. This necessitates collaboration and coordination of care between clinicians, families, diagnostic laboratories, insurers, and pharmaceutical companies. Cure SMA, a US-based patient organization, has advocated that collaboration between these groups ideally should occur within 14 days of birth for those patients with two copies of SMN2 with immediate treatment thereafter. ²⁵

Future directions

As discussed earlier, patients with neutralizing anti-AAV antibodies may be ineligible for treatment with AAV-based gene therapies, including onasemnogene abeparvovec. Thus, environmentally derived adaptive immunity prevents some patients who could benefit from onasemnogene abeparvovec from receiving treatment. In addition, for patients who have already received an AAV-based gene therapy, the neutralizing antibodies produced in response to that therapy also preclude the possibility of subsequent treatment with this modality, ⁸⁹ although the persistence of detectable total and neutralizing antibodies produced against the vector is not known. Efforts are currently underway to prevent or block the humoral response to AAV vectors. ⁸⁹

Additional efforts are underway to broaden the eligible patient population for onasemnogene abeparvovec by evaluating the safety and efficacy of intrathecal (IT) administration. This approach would enable fixed dosing, reducing the viral load (by approximately ten-fold compared with the intravenous route) and potentially reducing risks of treating older or heavier patients with high-dose systemic delivery. In the phase 1/2 STRONG study (NCT03381729), OAV101 IT was demonstrated to be safe and well-tolerated in treatment-naïve patients aged 6 to <60 months who could sit but not stand/walk independently. It also resulted in significant increases in motor function as measured by Hammersmith Functional Motor Scale – Expanded scores. ⁹⁰ Two additional phase 3 studies have been conducted to further evaluate IT administration: (1) STEER (NCT05089656), a phase 3, multicenter, randomized, sham-controlled, double-blind clinical trial to investigate the efficacy and safety of OAV101 IT for patients with SMA who were 2 to <18 years of age, treatment-naive, and were able to sit, but have never walked ⁹¹ and (2) STRENGTH (NCT05386680), a phase 3b, open-label, multicenter study to evaluate safety, tolerability, and efficacy of OAV101 IT for patients with SMA who discontinued treatment with nusinersen or risdiplam. ⁹²

Conclusions

Initiation of disease-modifying treatments immediately following a SMA diagnosis is crucial irrespective of the treatment selected, and NBS programs are essential for facilitating early and ideally, presymptomatic diagnosis of SMA. A single intravenous administration of onasemnogene abeparvovec provides long-lasting benefits for patients with SMA. Long-term safety monitoring, careful evaluation of developmental progression, multidisciplinary monitoring and care, adherence to SoC guidelines, and caregiver education continue to be important factors impacting the safety profile of this innovative therapy.