key: cord-0780451-nb8xvv1b authors: Kichula, Elizabeth A.; Proud, Crystal M.; Farrar, Michelle A.; Kwon, Jennifer M.; Saito, Kayoko; Desguerre, Isabelle; McMillan, Hugh J. title: Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy date: 2021-07-20 journal: Muscle Nerve DOI: 10.1002/mus.27363 sha: 730ff4cdb2cee8eaa6efc84b9cc9619e414a0f10 doc_id: 780451 cord_uid: nb8xvv1b Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease‐modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently. Only 8% survived beyond 20 months of age without permanent ventilator support. One such therapy, onasemnogene abeparvovec, an adeno‐associated virus–based gene replacement therapy, delivers functional human SMN through a one‐time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient‐centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patient‐centered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti–adeno‐associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day‐to‐day care at time of treatment and patient‐ and family‐centered discussions on realistic expectations are also recommended. We detail the importance of following standard‐of‐care guidance and long‐term monitoring of all children with SMA who have received one or more disease‐modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder. disease-modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder. in progressive muscle atrophy and weakness. 1 SMA occurs in 1 in 11 000 live births in the United States. 2 The severity of SMA is largely dependent on the number of copies of survival motor neuron 2 (SMN2) gene, a back-up gene to SMN1. Each SMN2 copy produces approximately 10% of the functional SMN protein produced by a single functional SMN1 copy, 1 partially compensating for the disrupted SMN1 genes as SMN protein is essential for life. 3 Patients lacking functional SMN1 and SMN2 genes do not survive. Children with two or fewer copies of SMN2 will typically exhibit the most severe SMA phenotype. 4, 5 Historically, SMA was classified into three major phenotypes (SMA types 1, 2, and 3), differentiated by the child's age at symptom onset and maximum motor milestone achieved. 6, 7 SMA types 0 and 4 were added to describe rare congenital and adult-onset forms of SMA, respectively. 8, 9 Presymptomatic infants are described by SMN2 copy number, as type remains a clinical diagnosis. Despite this traditional categorization, SMA patients are on a continuum rather than fitting neatly into distinct types. Moreover, with disease-modifying therapies, this classification system is less relevant, with less predictive value. Experts increasingly recommend that patients with SMA be reclassified as non-sitters, sitters, and walkers. 10, 11 SMA's clinical course is changing. Patients with genotypes historically predictive of SMA type 1 are receiving disease-modifying treatments and achieving independent sitting or walking, particularly if treated early. 12 Onasemnogene abeparvovec is a gene replacement therapy that delivers functional human SMN through a one-time intravenous (IV) infusion. 14 As of June 2021, more than 1200 patients had been treated with onasemnogene abeparvovec globally. As more countries and regions approve IV onasemnogene abeparvovec, questions have arisen regarding its implementation in practice that are not covered in the prescribing information or a review describing the clinical trial experience. 15 This expert opinion provides recommendations in key areas by an expert panel of neuromuscular specialists who have treated SMA patients with onasemnogene abeparvovec. Onasemnogene abeparvovec is an in vivo adeno-associated virus serotype 9 (AAV9) gene replacement therapy that delivers the SMN transgene under a ubiquitous promoter into target cells, through a one-time IV infusion. 14 Indications for onasemnogene abeparvovec are presented in Table 1 for each jurisdiction where it is currently approved. AAV gene therapy platforms offer several advantages over other viral vectors. For example, AAVs are not known to cause human disease. Compared with adenovirus vectors, activation of innate immunity is lower with AAVs. 16 In addition, AAVs have a low risk of genomic integration because the transgene is maintained as an episome. 17 However, with limited reports of AAV integration, [18] [19] [20] [21] there is a theoretical risk of malignancy should the insertion occur near a proto-oncogene. Recent deaths of patients with X-linked myotubular myopathy related to progressive liver dysfunction after AAV8-based gene therapy highlight potential safety concerns. 22 All three patients treated with the high dose (3 Â 10 14 vector genomes/kg) had evidence of pre-existing liver disease, underscoring importance of dose selection and identifying patients with underlying hepatic disease. AAV9 can cross the blood-brain barrier ( Figure 1 ). 23, 24 The selfcomplementary feature of onasemnogene abeparvovec allows for rapid transgene expression. 25 The hybrid cytomegalovirus enhancerchicken beta-actin promoter drives sustained SMN protein expression, 26 which may enable lifelong transgene expression. Analysis of two human case studies confirmed that IV administration of onasemnogene abeparvovec results in generalized cell transduction and expression of SMN protein in spinal motor neurons, neurons, glial cells, heart, liver, skeletal muscles, and other tissues. 14 In the phase I START study, treatment of SMA patients less than 8 months of age with onasemnogene abeparvovec demonstrated improvements in survival, as well as achievement of motor milestones not observed in natural history, without the need for permanent ventilation. 27, 28 The phase III STR1VE-US study demonstrated the favorable benefit-risk profile observed in the phase I study for a larger group. 29 Long-term evaluation for up to 5.6 years has indicated the maintenance of motor milestones without any new safety signals in patients who received the targeted therapeutic dose in START. 30 Onasemnogene abeparvovec has not been studied for children with profound weakness, including those requiring invasive ventilator support, and the potential benefit of treatment in this subgroup of patients may be low because of irreversible loss of motor neurons as the disease progresses. Treatment of patients, including those with the most severe form of SMA who required invasive mechanical ventilation and tracheostomy before receiving onasemnogene abeparvovec, has also been reported. 31 Figure 2 ). [34] [35] [36] [37] [38] [39] Current guidelines recommend immediate treatment for all infants with two, three, or four copies of SMN2. [40] [41] [42] Recommendation: Treating physicians should discuss timing of therapeutic initiation with families, highlighting treatment urgency given that motor neuron degeneration largely occurs in the first few months and rapid decreases in motor unit number estimation and maximum compound motor action potential amplitude occur within 2 postnatal months, demonstrating irreversible loss of motor units. 43 Physicians should also highlight the benefits of early treatment 12, 13 to prevent treatment delays in newly diagnosed patients. 44 Treatment decisions for presymptomatic patients may be guided by clinical context, in addition to SMN2 copy number. 40 Recommendation: Widespread adoption of newborn screening will facilitate early SMA diagnosis and treatment initiation, which holds the potential to improve outcomes. Discussions on factors that predict treatment response are important to provide realistic expectations and goals. Although gene therapy may stabilize SMA, parents should be counseled that ongoing disability may be expected, and possibly become clinically evident for presymptomatic children. Although outcomes are improved with treatment, complications, particularly for patients with long disease duration, may arise. Discussions of potential benefits and risks or burdens of treatment are needed to manage expectations, especially for those patients with severe motor weakness, respiratory insufficiency, and bulbar dysfunction. 45 Discussions should emphasize need for continual multidisciplinary coordinated care throughout the patient's life Counseling on possible adverse events is also required before dosing, and close clinical and laboratory monitoring is required in the weeks to months after treatment. Although gene therapy only requires a single administration, close follow-up and safety monitoring are essential. Recommendation: The interpretation of anti-AAV9 antibody titers is based on assay and laboratory cutoffs. Repeat testing can be considered for those who initially have elevated titers depending on the specific clinical scenario. Repeat testing should also be considered if there is a prolonged period between original testing and onasemnogene abeparvovec dosing, given the risk of a new exposure. In waiting for titers to decrease, consideration of treatment with other agents, such as nusinersen, is reasonable. It should be noted that pretreatment with nusinersen leads to the dilemma of whether to continue with nusinersen after onasemnogene abeparvovec dosing. Criteria for doing so are not firmly established and pretreatment may be best considered if there are concerns about imminent deterioration of clinical status. Breastfeeding offers many advantages to infants, including nourishment, protective immunity, and enhanced mother-infant bonding. 55 Breast milk contains cytokines, secretory immunoglobulins, and immune cells that are transferred from the mother to the infant's gastrointestinal lumen. 56 Secretory immunoglobulin A comprises approximately 90% of total antibodies in human breast milk. 57 In humans, breast milk antibodies do not enter an infant's circulation in any substantial amount because humans lack the intestinal Fc receptor, which other mammals possess, that actively transports IgG subtypes to their circulation. 50 Immunoglobulins contained within breast milk instead remain within the intestinal lumen of human infants, acting as an important line of mucosal defense along with bactericidal lactoferrin. 58 Recommendation: The potential benefits of breastfeeding are many. With no known risk of active transfer of immunoglobulins from the infants' intestinal lumen to circulation, we recommend infants continue breastfeeding before and after administration of onasemnogene abeparvovec, unless other contraindications exist. The importance of evaluating baseline liver function has been highlighted in the recent tragic deaths of three patients in the phase I/II ASPIRO clinical trial, who experienced serious liver problems that appeared related to high-dose IV AT132 (AAV8-based gene therapy) for X-linked myotubular myopathy. 22 All three patients had preexisting hepatobiliary disease. 22 Liver transaminase elevations are a known risk factor with AAV vectors. 28 For patients with significant increases in transaminase concentrations, hepatic fibrosis may occur and pose a risk of liver-related complications later in life. Assessment of liver function is particularly important given that SMA patients may have a greater risk of impaired fatty acid metabolism and/or hepatic dysfunction. 59 In identifying patients with elevated baseline concentrations of alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), and bilirubin, one should note that reference ranges differ between neonates and older children. 60 The troponin complex consists of three subunits, troponin I, T, and C, and is required for contraction of skeletal and cardiac muscle regulated by calcium. Both cardiac troponin I and T are increasingly used as diagnostic indicators of myocardial infarction. 62 In clinical trials, minor transient increases in troponin I along with changes in heart rate were observed after onasemnogene abeparvovec. 65 However, they were without clinical sequelae, and the clinical significance of these elevations is not known. 14 Recommendation: Troponin T concentration may increase in patients with skeletal muscle diseases, including those with SMA, 68, 69 further increasing with disease severity. 70 As with troponin I, its use for monitoring cardiac function in SMA patients is unknown. Consultation with a cardiologist is recommended for patients with persistently abnormal troponins. Because infection before or after infusion could lead to more serious complications, physicians should advise caregivers of possible viral infection signs. 14 To avoid potential illness, the authors recommend families limit potential contacts and practice good hand hygiene both pre-and post-infusion. In clinical trials, transient decreases in platelet counts were observed, and some met the criteria for thrombocytopenia (<75 000/μL), 14, 76 often within 10 days of infusion. Those that were not attributable to other causes resolved without intervention and were without associated bleeding events. 76 Thrombocytopenia is frequently short-lived. Nevertheless, monitoring platelet counts weekly for the first month and every other week for the second and third months until platelet counts return to baseline is important ( Assess liver function (clinical examination, AST, ALT, total bilirubin, prothrombin time) at baseline, weekly for the first month, and every other week for the second and third months, until results are unremarkable. Japan 83 Assess liver function (clinical symptoms, AST, ALT, total bilirubin, prothrombin time) at baseline, and 3 months following (once a week for 1 month and once every 2 weeks thereafter). Assess liver function (clinical examination, AST, ALT, total bilirubin) at baseline, weekly for 30 days, and every 2 weeks for next 60 days. Brazil 85 Assess liver function (clinical examination, AST, ALT, total bilirubin) at baseline, weekly for the first month, and every other week for second and third months until results are unremarkable. Given cardiac toxicity observed in animal studies, troponin I concentrations should be regularly monitored for at least 3 months after onasemnogene abeparvovec (weekly for the first month, and then monthly for the second and third months until troponin I concentrations return to baseline) ( Measure platelet counts at baseline, weekly for the first month, then every other week for the second and third months, until return to baseline. Japan 83 Platelet count should be measured at baseline and for 3 months thereafter (once a week for 1 month and once every 2 weeks thereafter). Measure platelet counts weekly for the first month and then every other week for second and third months until platelet counts return to baseline. Brazil 85 Measure platelet counts at baseline, weekly for the first month and then every other week for second and third months until platelet counts return to baseline. Australia 86 Measure platelet counts weekly for the first month, and then every other week for the second and third months, until platelet counts return to baseline. Measure platelet count before infusion and monitor weekly for the first month and then every other week for the second and third months until platelet count results are unremarkable. Note: Surveillance recommendations from each country are shown as described in the respective prescribing information. T A B L E 4 Surveillance troponin I blood tests recommended postdosing for troponin I United States 14 Measure troponin I at baseline, weekly for the first month, then monthly until return to baseline. Japan 83 Cardiac troponin I should be measured at baseline and for 3 months thereafter (once a week for 1 month and once a month thereafter); keep measuring until abnormalities resolve. Assess troponin I at baseline and for at least 3 months or until concentrations return to within normal reference range for SMA. Brazil 85 Troponin I concentrations should be monitored at baseline and then for at least 3 months or until concentrations return to normal reference range for SMA. Australia 86 Assess troponin I weekly for the first month, and then monthly for the second and third months, until troponin I concentrations return to baseline. Assess troponin I concentrations infusion and monitor for at least 3 months after until concentrations are unremarkable. Note: Surveillance recommendations from each country are shown as described in the respective prescribing information. Abbreviation: SMA, spinal muscular atrophy. month 18 (stool) visit. Analysis of vector DNA by droplet digital polymerase chain reaction revealed shedding in saliva, urine, and stool after infusion, with much greater concentrations found in stool. Vector shedding decreased rapidly and was undetectable in samples after 60 days ( Figure 3) . Specifically, the vector DNA could be detected in saliva and urine samples through day 7, with the majority of concentrations below the limit of quantitation on day 14 (1.1 Â 10 6 genome copies/mL) ( Figures 3A and 3B , and Tables S1 and S2.). In stool, vector DNA could be detected through day 30, with the majority of concentrations below the limit of quantitation on day 60 (1.1 Â 10 7 genome copies/mL) ( Figure 3C and Table S3 ). Theoretical risks of vector shedding after onasemnogene abeparvovec are extremely low, including for immunocompromised sib- Onasemnogene abeparvovec requires thawing before use either at room temperature or in a refrigerator. It is a clear to slightly opaque, colorless to faint white liquid, and free of particles once thawed. Once Older patients, many of whom were previously treated with nusinersen, were more likely to have had transaminase elevations and require a prolonged prednisolone course. 72 Three of these patients experienced drops in platelet counts. None had thrombocytopenia that required treatment. 72 In another case series, the clinical courses were described for two patients, one with a delayed diagnosis and the other diagnosed through newborn screening, who were initially treated with nusinersen and later treated with onasemnogene abeparvovec. 80 Improvements in both children were observed. 80 Three of four patients initially treated with nusinersen continued nusinersen after onasemnogene abeparvovec in another case series of patients treated with both nusinersen and onasemnogene abeparvovec. 31 The authors highlighted the importance of monitoring liver function. Thrombocytopenia was the main overlapping potential adverse effect, which caused more issues with potential lumbar puncture than with IV infusion. Although improvement with combination therapy was observed in these individual cases, the effect relative to monotherapy was not established. The impact of combination therapy on patient outcomes and safety is unknown and is being evaluated in clinical tri- Recommendation: Patients may also have acute viral reactions, including fever, with onasemnogene abeparvovec. Fever can be controlled using age-appropriate dosing of antipyretics. Ibuprofen is preferred if platelets are normal. If there is concern for thrombocytopenia, or the patient is less than 6 months of age, then acetaminophen is preferred. Despite recent advancements in SMA management, patients continue to require multidisciplinary care directed by a neurologist or other specialist with expertise in neuromuscular disease, facilitating multidisciplinary interventions. Specifically, respiratory care must be established to monitor cough, airway clearance, and potential hypoventilation. Rehabilitative therapies are recommended to improve motor skills, and may include physical, occupational, and speech therapy. Orthopedic management should also be in place to monitor contractures and scoliosis; nutrition evaluations are also required to ensure adequate feeding, growth, and swallow function. 10, 82 Recommendation: The treating physician should counsel families on the importance of multidisciplinary and long-term care after treatment, even in those who may appear to be only minimally symptomatic. Recommendation: Long-term monitoring of treated patients through registries is important for collaboration and dissemination of outcome and safety data. Physicians should discuss the importance of participation in long-term registries with their patients' parents or guardians. Onasemnogene abeparvovec provides a novel, effective, single-dose treatment for SMA patients and has the potential to significantly alter the course of the disease. As more patients receive this innovative therapy, treatment centers must be prepared to handle and administer the drug. Given the progressive nature of SMA and the need to initiate treatment before irreversible motor neuron loss, physicians must be able to identify those patients eligible to receive onasemnogene abeparvovec through newborn screening whenever possible, make careful baseline assessments, conduct follow-up assessments, and educate caregivers. Long-term registry studies will be necessary to understand the durability and safety of this therapy both alone and in combination with other therapies. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2 Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy Chaos in the classification of SMA: a possible resolution International SMA consortium meeting Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype Genetic basis of adult-onset spinal muscular atrophy Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy Package insert. AveXis, Inc, 2021 From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1 Immune responses to adenovirus and adeno-associated virus in humans Episomal persistence of recombinant adenoviral vector genomes during the cell cycle in vivo Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas Helper-independent and AAV-ITRindependent chromosomal integration of double-stranded linear DNA vectors in mice Recombinant adeno-associated viral integration and genotoxicity: insights from animal models Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction Audentes therapeutics provides update on the ASPIRO clinical trial evaluating AT132 in patients with X-linked myotubular myopathy Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes Adeno-associated virus (AAV) as a vector for gene therapy Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis CMV-beta-Actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort Single-dose gene-replacement therapy for spinal muscular atrophy Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy with two copies of SMN2 (STR1VE): an open-label, single-arm, phase 3 study Five-year extension results of the phase I START trial of onasemnogene abeparvovec in spinal muscular atrophy Combination molecular therapies for type 1 spinal muscular atrophy Clinical course in a patient with spinal muscular atrophy type 0 treated with nusinersen and onasemnogene abeparvovec Delay in diagnosis of spinal muscular atrophy: a systematic literature review The implementation of newborn screening for spinal muscular atrophy: the Australian experience A novel system for spinal muscular atrophy screening in newborns: Japanese pilot study 244th ENMC international workshop: newborn screening in spinal muscular atrophy One year of newborn screening for SMA: results of a German pilot project Presymptomatic diagnosis of spinal muscular atrophy through newborn screening Newborn screening for spinal muscular atrophy: Ontario testing & follow-up recommendations Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2 Natural history of denervation in SMA: relation to age, SMN2 copy number, and function Time is motor neuron: therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy The whole game is changing and you've got hope": Australian perspectives on treatment decision making in spinal muscular atrophy Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: a case series Onasemnogene abeparvovoec gene therapy for spinal muscular atrophy type 1: phase III study update (STR1VE-EU). Virtual poster session. Presented at the 2020 International Annual Congress of the World Muscle Society Adeno-associated virus antibody profiles in newborns, children, and adolescents Differential prevalence of antibodies against adeno-associated virus in healthy children and patients with mucopolysaccharidosis III: perspective for AAV-mediated gene therapy Transfer of antibody via mother's milk Transplacental transport of IgG antibodies to preterm infants: a review of the literature Adeno-associated virus serotype 9 antibodies in patients with spinal muscular atrophy screened for treatment with gene-replacement therapy onasemnogene abeparvovec-xioi or AVXS-101 IT Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec Transfer of measles, mumps, and rubella antibodies from mother to infant. Its effect on measles, mumps, and rubella immunization Human milk composition. Nutrients and bioactive factors Immune markers in breast milk and fetal and maternal body fluids: a systemic review of perinatal concerns The mucosal immune system and its integration with the mammary glands Breastfeeding provides passive and likely long lasting active immunity Abnormal fatty acid metabolism is a core component of spinal muscular atrophy American College of Clinical Pharmacy. Reference values for common laboratory tests. Pediatric Self-Assessment Program (PedSAP) Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy Troponin: the biomarker of choice for the detection of cardiac injury Cardiac pathology in spinal muscular atrophy: a systematic review Type 0 spinal muscular atrophy: further delineation of prenatal and postnatal features in 16 patients Committee for Medicinal Products for Human Use and Committee for Advanced Therapies High-sensitivity generation 5 cardiac troponin T sex-and age-specific 99th percentiles in the CALIPER cohort of healthy children and adolescents Cardiac troponin I serum concentrations in newborns: a study and review of the literature Elevated cardiac troponin T in patients with skeletal myopathies Childhood spinal muscular atrophy induces alterations in contractile and regulatory protein isoform expressions 275 cardiac troponin T (cTnT) as a highly sensitive parameter for spinal muscular atrophy (SMA) in a floppy infant Clinical experience with gene therapy in older patients with spinal muscular atrophy Gene therapy for spinal muscular atrophy: safety and early outcomes Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1 Long-term corticosteroid use, adrenal insufficiency, and the need for steroid-sparing treatment in adult severe asthma Pediatric adrenal insufficiency: diagnosis, management, and new therapies Intravenous onasemnogene abeparvovec for spinal muscular atrophy: cumulative safety report. Virtual presentation at the Cure SMA Annual Conference Thrombotic microangiopathy (TMA): a potential adverse reaction post Zolgensma (onasemnogene abeparvovec-xioi) therapy for spinal muscular atrophy (SMA) (5483) National Institutes of Health. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). Bethesda, MD: NIH Office of Science Policy US Centers for Disease Control and Prevention. National Institutes of Health Spinal muscular atrophy in the treatment era Clinical development on the frontier: gene therapy for Duchenne muscular dystrophy Diagnosis and management of spinal muscular atrophy: Part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics Medical Device Evaluation Division. Pharmaceutical Safety and Environmental Health Bureau. Ministry of Health, Labour and Welfare Annex I: Summary of product characteristics Australian Product Information-Zolgensma ® (onasemnogene abeparvovec) for single-dose intravenous infusion only Product Monograph Including Patient Medical Information-Zolgensma™ (onasemnogene abeparvovec) solution for intravenous infusion, 2 Â 10 13 vector genomes/mL Additional supporting information may be found online in the Supporting Information section at the end of this article.