Received: 11 December 2020 Revised: 22 June 2021 Accepted: 27 June 2021

DOI: 10.1002/mus.27363

ISSUES & OPINIONS

Expert recommendations and clinical considerations in the use

of onasemnogene abeparvovec gene therapy for spinal
muscular atrophy

Elizabeth A. Kichula MD, PhD1 | Crystal M. Proud MD2 |

Michelle A. Farrar PhD, MBBS | Jennifer M. Kwon MD | Kayoko Saito MD, PhD5 |
3 4

Isabelle Desguerre MD, PhD6 | Hugh J. McMillan MD, MSc7

1
Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania, USA Abstract
2
Children's Hospital of the King's Daughters, Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease
Norfolk, Virginia, USA
caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is
3
School of Women's and Children's Health,
UNSW Medicine, University of New South characterized by motor neuron degeneration, resulting in progressive muscle atrophy
Wales Sydney and Sydney Children's Hospital and weakness. Before the emergence of disease-modifying therapies, children with
Network, Sydney, New South Wales, Australia
4
the most severe form of SMA would never achieve the ability to sit independently.
School of Medicine and Public Health,
University of Wisconsin, Madison, Only 8% survived beyond 20 months of age without permanent ventilator support.
Wisconsin, USA
One such therapy, onasemnogene abeparvovec, an adeno-associated virus–based
5
Institute of Medical Genetics, Tokyo
Women's Medical University, Tokyo, Japan
gene replacement therapy, delivers functional human SMN through a one-time intra-
6
Necker-Enfants Malades Hospital, University venous infusion. In addition to substantially improving survival, onasemnogene abe-
of Paris, AP-HP, Paris, France parvovec was found to increase motor milestone attainment and reduce the need for
7
Children's Hospital of Eastern Ontario,
respiratory or nutritional support in many patients. This expert opinion provides rec-
University of Ottawa, Ottawa, Ontario,
Canada ommendations and practical considerations on the patient-centered decisions to use
onasemnogene abeparvovec. Recommendations include the need for patient-
Correspondence
Hugh J. McMillan, Children's Hospital of centered multidisciplinary care and patient selection to identify those with underlying
Eastern Ontario, University of Ottawa,
medical conditions or active infections to reduce risks. We also describe the impor-
401 Smyth Road, Ottawa,
ON K1H 8L1, Canada. tance of retesting patients with elevated anti–adeno-associated virus serotype 9 anti-
Email: [email protected]
bodies. Recommendations for prednisolone tapering and monitoring for potential
Funding information adverse events, including hepatotoxicity and thrombotic microangiopathy, are
Novartis Gene Therapies, Inc.
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

Abbreviations: AAV, adeno-associated virus; AAV9, adeno-associated virus serotype 9; ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; AST, aspartate transaminase; BSL1,
biosafety level 1; dsDNA, double-stranded DNA; GGT, gamma-glutamyltransferase; IgG, immunoglobulin G; IV, intravenous; MAP, managed access program; NGT, Novartis Gene Therapies Inc;
RG1, National Institutes of Health Risk Group 1; SARS-CoV-2, severe acute respiratory–syndrome coronavirus-2; ssAAV, single-stranded AAV; scAAV, self-complementary AAV; SMA, spinal
muscular atrophy; SMN, survival motor neuron; SMN1, survival motor neuron 1 gene; SMN2, survival motor neuron 2 gene; TMA, thrombotic microangiopathy; ULN, upper limit of normal.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Muscle & Nerve. 2021;64:413–427. wileyonlinelibrary.com/journal/mus 413

414 KICHULA ET AL.

disease-modifying therapy using registries. We also highlight the need for

presymptomatic or early symptomatic treatment of this disorder.

KEYWORDS
efficacy, gene therapy, onasemnogene abeparvovec, safety, spinal muscular atrophy

1 | I N T RO DU CT I O N 2 | METHODS

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegener- To address questions encountered with the use of onasemnogene
ative disease caused by biallelic mutations in the survival motor neuron abeparvovec, Novartis Gene Therapies, Inc. (NGT) invited the coau-
1 (SMN1) gene. Biallelic SMN1 mutations lead to survival-motor-neuron thors to develop this expert opinion. Coauthors, representing five
(SMN) protein deficiency and degeneration of motor neurons, resulting countries and four continents, included seven pediatric neurologists
1
in progressive muscle atrophy and weakness. SMA occurs in 1 in and neuromuscular specialists who have experience treating children
11 000 live births in the United States.2 The severity of SMA is largely with SMA, six of whom were site investigators for onasemnogene
dependent on the number of copies of survival motor neuron 2 (SMN2) abeparvovec clinical trials. They have each treated approximately 5 to
gene, a back-up gene to SMN1. Each SMN2 copy produces approxi- 21 patients in both clinical trials and post-approval clinical treatment
mately 10% of the functional SMN protein produced by a single func- as of January 2021. Each coauthor demonstrated a leadership role in
tional SMN1 copy,1 partially compensating for the disrupted SMN1 clinical trials with onasemnogene abeparvovec and/or early introduc-
genes as SMN protein is essential for life.3 Patients lacking functional tion of gene replacement therapy in their respective countries.
SMN1 and SMN2 genes do not survive. Children with two or fewer cop- Experts established key areas for these recommendations through a
4,5
ies of SMN2 will typically exhibit the most severe SMA phenotype. series of virtual meetings from September 2020 to November 2020,
Historically, SMA was classified into three major phenotypes where knowledge was exchanged and experiences were shared. For
(SMA types 1, 2, and 3), differentiated by the child's age at symptom example, intrathecal administration of onasemnogene abeparvovec
onset and maximum motor milestone achieved.6,7 SMA types 0 and was outside the scope of these recommendations because this would
4 were added to describe rare congenital and adult-onset forms of be evaluated in future clinical trials. Because vector shedding was
SMA, respectively.8,9 Presymptomatic infants are described by SMN2 considered an area of interest, NGT agreed to share these data with
copy number, as type remains a clinical diagnosis. Despite this tradi- the coauthors. After review of the relevant medical literature, the
tional categorization, SMA patients are on a continuum rather than authors worked collaboratively to carefully construct recommenda-
fitting neatly into distinct types. Moreover, with disease-modifying tions to provide their expert consensus after the discussion. The
therapies, this classification system is less relevant, with less predic- authors agreed with the recommendations made within this article,
tive value. Experts increasingly recommend that patients with SMA be and also identified areas of uncertainty and gaps.
reclassified as non-sitters, sitters, and walkers.10,11
SMA's clinical course is changing. Patients with genotypes histori-
cally predictive of SMA type 1 are receiving disease-modifying treat- 3 | WHAT IS ONASEMNOGENE
ments and achieving independent sitting or walking, particularly if ABEPARVOVEC?
treated early.12,13 Disease-modifying therapies and supportive care have
improved SMA patient prognoses and functional status, and have Onasemnogene abeparvovec is an in vivo adeno-associated virus sero-
decreased the likelihood and severity of comorbidities. Three treatments type 9 (AAV9) gene replacement therapy that delivers the SMN trans-
have demonstrated clinical efficacy in SMA by increasing SMN protein gene under a ubiquitous promoter into target cells, through a one-time
expression. Nusinersen and risdiplam alter SMN2 splicing, resulting in a IV infusion.14 Indications for onasemnogene abeparvovec are presented
greater inclusion of exon 7 and increase in full-length SMN protein. in Table 1 for each jurisdiction where it is currently approved.
Onasemnogene abeparvovec is a gene replacement therapy that delivers AAV gene therapy platforms offer several advantages over other
functional human SMN through a one-time intravenous (IV) infusion.14 viral vectors. For example, AAVs are not known to cause human disease.
As of June 2021, more than 1200 patients had been treated with Compared with adenovirus vectors, activation of innate immunity is
onasemnogene abeparvovec globally. As more countries and regions lower with AAVs.16 In addition, AAVs have a low risk of genomic inte-
approve IV onasemnogene abeparvovec, questions have arisen gration because the transgene is maintained as an episome.17 However,
regarding its implementation in practice that are not covered in the with limited reports of AAV integration,18-21 there is a theoretical risk of
prescribing information or a review describing the clinical trial experi- malignancy should the insertion occur near a proto-oncogene. Recent
15
ence. This expert opinion provides recommendations in key areas deaths of patients with X-linked myotubular myopathy related to pro-
by an expert panel of neuromuscular specialists who have treated gressive liver dysfunction after AAV8-based gene therapy highlight
SMA patients with onasemnogene abeparvovec. potential safety concerns.22 All three patients treated with the high dose
KICHULA ET AL. 415

TABLE 1 Key indications for onasemnogene abeparvovec by country

United States14 Japan83 European Union84 Brazil85 Australia86 Canada87

Age <2 years <2 years No upper age limit <2 years <9 months No upper
age limit
Weight — — Explicitly states there Explicitly states there — —
is limited is limited
experience in experience in
patients with body patients with body
weight >13.5 kg weight >13.5 kg
SMN2 copy number No restrictions No restrictions ≤3 SMN2 copies ≤3 SMN2 copies ≤3 SMN2 ≤3 SMN2
copies copies
Anti-AAV9 — Explicitly excludes patients with — — — —
antibody titers seropositive anti-AAV9 antibody
titers

Abbreviations: AAV9, adeno-associated virus serotype 9; SMN2, survival motor neuron gene 2.

(3  1014 vector genomes/kg) had evidence of pre-existing liver disease, presymptomatic phase are known, diagnostic delays occur. A system-
underscoring importance of dose selection and identifying patients with atic literature review revealed that lags between symptom onset to
underlying hepatic disease. diagnosis were 3.6, 14.3, and 43.6 months for SMA types 1, 2, and 3,
AAV9 can cross the blood-brain barrier (Figure 1).23,24 The self- respectively.33 To expedite treatment initiation, the United States,
complementary feature of onasemnogene abeparvovec allows for Europe, Taiwan, Japan, and Australia, among other countries and
rapid transgene expression.25 The hybrid cytomegalovirus enhancer– regions, have introduced newborn screening programs or pilot studies
chicken beta-actin promoter drives sustained SMN protein (Figure 2).34-39 Current guidelines recommend immediate treatment
26
expression, which may enable lifelong transgene expression. Analy- for all infants with two, three, or four copies of SMN2.40-42
sis of two human case studies confirmed that IV administration of Recommendation: Treating physicians should discuss timing of
onasemnogene abeparvovec results in generalized cell transduction therapeutic initiation with families, highlighting treatment urgency
and expression of SMN protein in spinal motor neurons, neurons, glial given that motor neuron degeneration largely occurs in the first few
cells, heart, liver, skeletal muscles, and other tissues.14 months and rapid decreases in motor unit number estimation and
In the phase I START study, treatment of SMA patients less than maximum compound motor action potential amplitude occur within
8 months of age with onasemnogene abeparvovec demonstrated 2 postnatal months, demonstrating irreversible loss of motor units.43
improvements in survival, as well as achievement of motor milestones Physicians should also highlight the benefits of early treatment12,13 to
not observed in natural history, without the need for permanent ven- prevent treatment delays in newly diagnosed patients.44 Treatment
27,28
tilation. The phase III STR1VE-US study demonstrated the favor- decisions for presymptomatic patients may be guided by clinical
able benefit-risk profile observed in the phase I study for a larger context, in addition to SMN2 copy number.40
29
group. Long-term evaluation for up to 5.6 years has indicated the Recommendation: Widespread adoption of newborn screening will
maintenance of motor milestones without any new safety signals in facilitate early SMA diagnosis and treatment initiation, which holds
patients who received the targeted therapeutic dose in START.30 the potential to improve outcomes.
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 5 | PATIENT- AND
patients may be low because of irreversible loss of motor neurons as FA M I LY - C EN T E RE D CA R E
the disease progresses. Treatment of patients, including those with
the most severe form of SMA who required invasive mechanical Discussions on factors that predict treatment response are important
ventilation and tracheostomy before receiving onasemnogene to provide realistic expectations and goals. Although gene therapy
abeparvovec, has also been reported.31,32 may stabilize SMA, parents should be counseled that ongoing disabil-
ity may be expected, and possibly become clinically evident for pres-
ymptomatic children. Although outcomes are improved with
4 | NEED FOR PRESYMPTOMATIC treatment, complications, particularly for patients with long disease
O R E A R L Y SY M P T O M A T I C T R E A T M E N T duration, may arise. Discussions of potential benefits and risks or bur-
dens of treatment are needed to manage expectations, especially for
Clinical studies have consistently demonstrated the benefits of early those patients with severe motor weakness, respiratory insufficiency,
treatment initiation in SMA, before irreversible loss of motor neu- and bulbar dysfunction.45 Discussions should emphasize need for con-
12,13
rons. Although the clinical benefits of early treatment in the tinual multidisciplinary coordinated care throughout the patient's life
416 KICHULA ET AL.

FIGURE 1 Legend on next page.

KICHULA ET AL. 417

F I G U R E 2 Newborn screening programs for SMA implemented globally; this includes all countries conducting newborn screening for SMA as
of November 2020

and that, in agreeing to treatment, the family is also agreeing to all (TMA).46 In the STR1VE-EU study, respiratory infection was observed
recommended safety monitoring. In some countries (eg, France), in a patient who died after treatment with onasemnogene abe-
expert committees are used to guide treatment decisions. parvovec. This patient's death indicates that viral illness can cause
Recommendation: Patient-centered multidisciplinary care should severe illness, even in individuals with treated SMA. This may be exac-
continue after treatment to optimize outcomes for patients and erbated for those who have recently received gene therapy, because
families. of corticosteroid treatment and potential adrenal insufficiency.47
Although age and weight limits for onasemnogene abeparvovec
treatment differ by jurisdiction (Table 1), limited evidence exists on
6 | P A T I E NT SE L EC T I O N safety and efficacy in older, heavier patients, and those with advanced
AND PREPARATION disease. Further research is needed to evaluate onasemnogene abe-
parvovec for these patients. Risk-benefit has to be carefully assessed
Before AAV9 administration, children should be evaluated for under- before treatment.
lying medical conditions, including severe or symptomatic liver dis- Counseling on possible adverse events is also required before dos-
ease, thrombocytopenia, or any other serious underlying medical ing, and close clinical and laboratory monitoring is required in the weeks
conditions, that may heighten the risk of AAV9 therapy. Active infec- to months after treatment. Although gene therapy only requires a single
tion may be a risk factor for developing thrombotic microangiopathy administration, close follow-up and safety monitoring are essential.

F I G U R E 1 After intravenous administration of onasemnogene abeparvovec, the SMN transgene is maintained as a non-integrating episome in
the nuclei of target cells. A, Attachment and entry. Cell-surface attachment of rAAV is mediated by primary glycan receptors and stabilized by
proteinaceous secondary receptors. B, Internalization. AAV-based vectors utilize multiple endocytic routes during their journey towards the
nucleus. C, Sorting steps. The rAAV capsid undergoes substantial conformational changes in the sorting compartments (endosomes and the
Golgi). D, Cytoplasmic escape and nuclear import. After escaping the sorting compartments, vector particles accumulate around the perinuclear
space and enter the nucleus via nuclear pore complexes. E, Genome release and transgene expression. Inside the nucleus, the vector genome is
released and transcribed, resulting in the expression of the transgene. Abbreviations: dsDNA, double-stranded DNA; GEEC,
glycosylphosphatidylinositol-anchored protein (GPI-AP)-enriched compartment; scAAV, self-complementary AAV; ssAAV, single-stranded AAV;
TGN, trans-Golgi network. Reprinted from Trends in Molecular Medicine, Dhungel BP, Bailey CG, and Rasko JEJ, Journey to the center of the cell:
tracing the path of AAV transduction, p4, 2020, with permission from Elsevier
418 KICHULA ET AL.

7 | ANTI-AAV9 ANTIBODY TITERS Recommendation: The interpretation of anti-AAV9 antibody titers

is based on assay and laboratory cutoffs. Repeat testing can be con-
To be eligible to receive onasemnogene abeparvovec, SMA patients sidered for those who initially have elevated titers depending on the
must be tested for the presence of pre-existing anti-AAV9 specific clinical scenario. Repeat testing should also be considered if
antibodies,14 which can, in theory, increase the risk of immune there is a prolonged period between original testing and
responses, resulting in reduced transduction and limited therapeutic onasemnogene abeparvovec dosing, given the risk of a new exposure.
efficacy. SMA patients must have anti-AAV9 antibody titers of no In waiting for titers to decrease, consideration of treatment with other
greater than 1:50, as measured by enzyme-linked immunosorbent agents, such as nusinersen, is reasonable. It should be noted that pre-
assay.14 treatment with nusinersen leads to the dilemma of whether to con-
Prevalence of antibodies against AAVs is relatively low, particu- tinue with nusinersen after onasemnogene abeparvovec dosing.
48,49
larly in infants. In infants, particularly neonates, anti-AAV9 Criteria for doing so are not firmly established and pretreatment may
antibodies may result from maternal transplacental transfer. Exposure be best considered if there are concerns about imminent deterioration
to maternal neutralizing antibodies to AAV serotypes during of clinical status.
breastfeeding may occur. However, the risk of entering the infant cir-
culation through the intestinal mucosa is low.50 More commonly in
older children, anti-AAV9 antibodies may arise also from environmen- 8 | BREASTFEEDING
tal exposure to naturally occurring AAV9.51 Screening results from the
onasemnogene abeparvovec clinical trials and the managed access Breastfeeding offers many advantages to infants, including nourish-
program through December 31, 2019, yielded 15 of 196 patients ment, protective immunity, and enhanced mother-infant bonding.55
52,53
(7.7%) with exclusionary titers (>1:50). Breast milk contains cytokines, secretory immunoglobulins, and
When onasemnogene abeparvovec treatment is within the immune cells that are transferred from the mother to the infant's gas-
goals of the family and treating physician, retesting titers for trointestinal lumen.56 Secretory immunoglobulin A comprises approxi-
patients with elevated baseline anti-AAV9 antibody titers may also mately 90% of total antibodies in human breast milk.57 In humans,
be considered. Although the half-life of passively acquired immuno- breast milk antibodies do not enter an infant's circulation in any sub-
globulin G (IgG) antibodies ranges from 35 to 40 days,54 the time stantial amount because humans lack the intestinal Fc receptor, which
course of the clearance of anti-AAV9 antibodies has not been other mammals possess, that actively transports IgG subtypes to their
established. Retesting frequency is at the discretion of the treating circulation.50 Immunoglobulins contained within breast milk instead
physician. The extent to which baseline titers are elevated and remain within the intestinal lumen of human infants, acting as an
patient age may be useful in predicting whether titers will fall, as important line of mucosal defense along with bactericidal lactoferrin.58
younger patients likely have elevations because of maternal trans- Recommendation: The potential benefits of breastfeeding are
placental transfer vs environmental exposure. Some authors have many. With no known risk of active transfer of immunoglobulins from
repeated testing as frequently as weekly, typically every 2 weeks, the infants' intestinal lumen to circulation, we recommend infants con-
in settings in which they anticipated titers to decrease. For young tinue breastfeeding before and after administration of onasemnogene
patients with baseline anti-AAV9 antibody titers of at least 1:50, abeparvovec, unless other contraindications exist.
titers may fall enough to permit dosing within 1 week. In the
interim, other treatments may be considered. Two of three patients
in START, one of six patients in STR1VE-EU, one patient in the 9 | S C R E E N I N G F O R U N D E RL Y I N G L I V E R
managed access programs (MAPs), and one patient in the US com- OR CARDIAC DISEASE
mercial program (personal correspondence from Dr Proud) who ini-
tially had exclusionary anti-AAV9 antibody titers were subsequently The importance of evaluating baseline liver function has been
enrolled after antibody titers had declined to 1:50 with repeat highlighted in the recent tragic deaths of three patients in the phase
testing.52,53 I/II ASPIRO clinical trial, who experienced serious liver problems that
Samples used for anti-AAV9 antibody testing (serum vs whole appeared related to high-dose IV AT132 (AAV8-based gene therapy)
blood) and reference ranges differ between laboratories, which are of for X-linked myotubular myopathy.22 All three patients had pre-
relevance in interpreting the results. Furthermore, differences in sam- existing hepatobiliary disease.22 Liver transaminase elevations are a
ple collection, processing, storage, and shipment make it difficult to known risk factor with AAV vectors.28 For patients with significant
easily compare results across studies. To reduce assay variability, all increases in transaminase concentrations, hepatic fibrosis may occur
AAV9 antibody tests performed for eligibility of onasemnogene abe- and pose a risk of liver-related complications later in life.
parvovec were centralized in four laboratories: two in the United Assessment of liver function is particularly important given that
States, one in Japan, and one in Europe. One US and one European SMA patients may have a greater risk of impaired fatty acid metabo-
laboratory defined samples less than or equal to 1:50 titers as sero- lism and/or hepatic dysfunction.59 In identifying patients with ele-
negative. The other US laboratory defined samples with less than vated baseline concentrations of alanine aminotransferase (ALT),
1:25 titers as seronegative.53 aspartate transaminase (AST), gamma-glutamyltransferase (GGT), and
KICHULA ET AL. 419

bilirubin, one should note that reference ranges differ between neo- Recommendation: In the event of an infection (eg, rhinovirus infec-
nates and older children.60 Of the patients treated with onasemno- tion), patients should wait at least 2 weeks after illness resolves
gene abeparvovec in clinical trials, 61% had baseline elevations in ALT before initiating treatment with onasemnogene abeparvovec.
and/or AST and/or bilirubin, but these elevations were less
than threshold values for study exclusion before dosing (greater than
two- or three times the upper limit of normal [ULN]).61 11 | POTENTIAL ADVERSE EVENTS
Recommendation: Baseline ALT and AST concentrations should be
evaluated to foster appropriate discussions between families and Adverse events have been reported after administration of
treating physicians within a reasonable time frame to dosing. When a onasemnogene abeparvovec. For example, treatment may result in ami-
delay in dosing is necessary, retesting baseline safety assessments notransferase elevations, particularly in older, heavier patients.71,72 In
should be strongly considered. clinical trials, 90% of children had elevations in ALT and/or AST, often
Because cardiac toxicity was observed in neonatal mice after IV occurring at week 1 as well as month 1 after therapy.61 Two of
14
onasemnogene abeparvovec infusion, patients are evaluated for 44 patients in clinical trials had increased AST and ALT concentrations of
baseline cardiac function, including clinical examination and analysis up to 48-times the ULN after onasemnogene abeparvovec infusion.
62
of cardiac troponin I, a sensitive biomarker of myocardial injury, These patients, who were otherwise asymptomatic with normal total bil-
before dosing. Patients with the severe phenotype may have irubin, were managed with systemic corticosteroids, and the abnormali-
coincident structural cardiac abnormalities.63,64 ties resolved without clinical sequelae. In addition, two cases of
The troponin complex consists of three subunits, troponin I, T, subacute liver failure after treatment with onasemnogene abeparvovec
and C, and is required for contraction of skeletal and cardiac muscle have been reported.73
regulated by calcium. Both cardiac troponin I and T are increasingly Current prescribing information recommends liver function
used as diagnostic indicators of myocardial infarction.62 In clinical trials, should be monitored for at least 3 months after onasemnogene abe-
minor transient increases in troponin I along with changes in heart rate parvovec infusion (weekly for the first month, and then at a minimum
65
were observed after onasemnogene abeparvovec. However, they every other week for the second and third months, until results have
were without clinical sequelae, and the clinical significance of these normalized).
elevations is not known.14 In addition, normative data on troponin I in
infants and young children are limited,66,67 and the clinical importance
of mild elevations is unknown. Although baseline values are important 12 | R O L E O F P R O P H Y L A C T I C
for subsequent comparison after dosing, elevations at baseline typi- P RE D N I S O LO N E
cally do not delay dosing, and clinicians should react when appropriate.
Recommendation: Evaluation of troponin I concentration should SMA patients are treated with prophylactic prednisolone with the goal
include a comparison of results with those of age-appropriate normal of attenuating serum aminotransferase elevations.28 Starting 1 day
ranges, as infants less than 6 months of age have greater troponin before onasemnogene abeparvovec infusion, systemic corticosteroids
concentrations compared with older children.66,67 Although the signif- equivalent to oral prednisolone at 1 mg/kg of body weight/day should
icance of mild elevations in baseline troponin I is unknown, consulta- be administered for a total of 30 days.14 For patients with
tion with a cardiologist is recommended for thorough evaluation and unremarkable findings (normal clinical examination, total bilirubin, and
multidisciplinary care of those patients with abnormal baseline prothrombin time, and ALT and AST concentrations below two-times
cardiology assessments. ULN), the corticosteroid dose should be tapered over the next
Recommendation: Troponin T concentration may increase in 28 days (eg, 2 weeks at 0.5 mg/kg/day and then 2 weeks at 0.25 mg/
68,69
patients with skeletal muscle diseases, including those with SMA, kg/day). Steroid taper should not proceed faster than this rec-
further increasing with disease severity.70 As with troponin I, its use ommended approach and may need to be longer and slower if more
for monitoring cardiac function in SMA patients is unknown. Consul- persistent abnormalities occur (discussed later).
tation with a cardiologist is recommended for patients with
persistently abnormal troponins.
13 | P O S T - D O SA G E M O N I T O R I N G A N D
MANAGEMENT OF CORTICOSTEROIDS
1 0 | R E S P I R A T O RY I N F E C T I O N S A N D
O T H E R C O N D I T I O NS 13.1 | Serum transaminase elevations

Because infection before or after infusion could lead to more serious Some patients, particularly older (≥8 months) patients,72 may experi-
complications, physicians should advise caregivers of possible viral ence serum transaminase elevations, occurring as early as 1 to 2
14
infection signs. To avoid potential illness, the authors recommend weeks after infusion, with a second occurrence often observed later
families limit potential contacts and practice good hand hygiene both at 1 to 2 months post-dosing.61 Transaminase elevations may persist
pre- and post-infusion. for as long as 6 months in some patients, requiring a prolonged course
420 KICHULA ET AL.

of prednisolone. For these patients, systemic corticosteroids (equiva- monitoring. Treating physicians may also consider pulsing with IV
lent to oral prednisolone at 1 mg/kg/day) should be continued until methylprednisolone (30-mg/kg infusion) in those patients who con-
AST and ALT values are both below two-times the ULN and all other tinue to have further increases in transaminases despite increasing
assessments return to normal range. Taper of corticosteroid dosage their daily steroid dosages. Insufficient data exist regarding the opti-
over the next 28 days should follow (Table 2). mal scenario on when to pulse IV methylprednisolone. We suggest
Serum transaminase elevations may be successfully managed using that the rate of rise and height of rise should be considered on a case-
different assessments and treatment regimens. In France, where 18 SMA by-case basis.
type 1 patients (3–10 months of age) were treated, some patients experi- Recommendation: In the presence of AST and ALT elevations, we
enced elevated transaminases that persisted over 8 weeks after infusion recommend analyzing synthetic liver function (international normal-
without severe hepatic failure (personal correspondence from Professor ized ratio, prothrombin time, albumin, bilirubin, and GGT tests), as it is
I. Desguerre). A hepatologist was consulted and echography was per- more indicative of liver injury. For patients with abnormalities in syn-
formed to exclude other potential causes for the elevated serum transam- thetic liver function and/or elevated bilirubin, consultation with a
inase concentrations. Echography was normal in all cases, and serum gastroenterologist may be required.
transaminase concentrations were monitored. Prednisolone dosing did Recommendation: Treating physicians should counsel families on
not need to be increased for these patients. the importance of monitoring laboratory results after onasemnogene
Recommendation: Patients with marked or persistent transami- abeparvovec, and the need for potentially longer steroid dosing
nase elevation (eg, three- or four-times ULN) may require an increased schedules in response to abnormal laboratory values.
prednisolone dosage (up to 1.5 or 2 mg/kg/day), followed by close Recommendation: Given the long duration of steroid treatment
that may be required for some patients, consultation with an endocri-
nologist may be considered when pursuing treatment, given the risk
T A B L E 2 Surveillance blood tests recommended post-dosing for of adrenal insufficiency.74 This is important to ensure adrenal function
liver function
is normal in treated patients, especially in context of a respiratory
United Assess liver function (clinical examination, AST, ALT, infection or other physiological stress. Examinations in older children
States14 total bilirubin, prothrombin time) at baseline,
may include a morning (8:00 AM) cortisol test and adrenocorticotropic
weekly for the first month, and every other week
for the second and third months, until results are hormone (ACTH) stimulation tests to ensure patients have recovered
unremarkable. normal adrenal function after steroid exposure. Newborns may
Japan 83
Assess liver function (clinical symptoms, AST, ALT, require additional testing to detect adrenal insufficiency because of
total bilirubin, prothrombin time) at baseline, and residual adrenal reserve that can respond to synthetic ACTH75 and
3 months following (once a week for 1 month and lack of normal circadian rhythm in morning cortisol concentration.
once every 2 weeks thereafter).
Recommendation: For patients receiving prolonged corticoste-
European Assess liver function (clinical examination, AST, ALT,
roids, physicians should consider using injectable stress dosing hydro-
Union84 total bilirubin) at baseline, weekly for 30 days, and
every 2 weeks for next 60 days. cortisone if evidence of acute illness presents in the post-dosage
period. Physicians may also consider consultation with an endocrinol-
Brazil85 Assess liver function (clinical examination, AST, ALT,
total bilirubin) at baseline, weekly for the first ogist in the context of acute illness of a hospitalized child receiving
month, and every other week for second and third post-dose corticosteroids. After prednisolone is stopped, a sick-day
months until results are unremarkable. plan for adrenal insufficiency should be provided to families according
Australia86 Assess liver function (clinical examination, AST, ALT, to institutional guidelines.
total bilirubin, prothrombin time) weekly for the
first month, and every other week for the second
and third months, until results are unremarkable
(normal clinical examination, total bilirubin, and 13.2 | Thrombocytopenia
prothrombin results, and ALT and AST
concentrations are <2 ULN). In clinical trials, transient decreases in platelet counts were observed,
Canada87 Assess liver function (clinical examination, AST, ALT, and some met the criteria for thrombocytopenia (<75 000/μL),14,76
total bilirubin, prothrombin time) weekly for
often within 10 days of infusion. Those that were not attributable to
30 days, and every 2 weeks for at least an
additional 60 days through the end of other causes resolved without intervention and were without associ-
corticosteroid taper. A longer duration or increased ated bleeding events.76 Thrombocytopenia is frequently short-lived.
dose of corticosteroid treatment may be required. Nevertheless, monitoring platelet counts weekly for the first month
Tapering of corticosteroid should not be
and every other week for the second and third months until platelet
considered until AST and ALT concentrations are
<2 ULN. counts return to baseline is important (Table 3).14 In cases of throm-
bocytopenia, particularly in the immediate week post-infusion, imma-
Note: Surveillance recommendations from each country are shown as
ture platelet profile can be used to monitor whether the body is
described in the respective prescribing information.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate appropriately making new platelets. In these cases, no treatment
transaminase; ULN, upper limit of normal. escalation is needed.
KICHULA ET AL. 421

T A B L E 3 Surveillance blood tests recommended post-dosing for T A B L E 4 Surveillance troponin I blood tests recommended post-
platelet counts dosing for troponin I

United Measure platelet counts at baseline, weekly for the United Measure troponin I at baseline, weekly for the first
States14 first month, then every other week for the second States14 month, then monthly until return to baseline.
and third months, until return to baseline. Japan83 Cardiac troponin I should be measured at baseline
83
Japan Platelet count should be measured at baseline and for and for 3 months thereafter (once a week for
3 months thereafter (once a week for 1 month and 1 month and once a month thereafter); keep
once every 2 weeks thereafter). measuring until abnormalities resolve.
European Measure platelet counts weekly for the first month European Assess troponin I at baseline and for at least
Union84 and then every other week for second and third Union84 3 months or until concentrations return to within
months until platelet counts return to baseline. normal reference range for SMA.
Brazil85 Measure platelet counts at baseline, weekly for the Brazil85 Troponin I concentrations should be monitored at
first month and then every other week for second baseline and then for at least 3 months or until
and third months until platelet counts return to concentrations return to normal reference range
baseline. for SMA.
Australia86 Measure platelet counts weekly for the first month, Australia86 Assess troponin I weekly for the first month, and then
and then every other week for the second and monthly for the second and third months, until
third months, until platelet counts return to troponin I concentrations return to baseline.
baseline. Canada87 Assess troponin I concentrations infusion and
87
Canada Measure platelet count before infusion and monitor monitor for at least 3 months after until
weekly for the first month and then every other concentrations are unremarkable.
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.
Note: Surveillance recommendations from each country are shown as Abbreviation: SMA, spinal muscular atrophy.
described in the respective prescribing information.

normal for all patients. No clinically significant electrocardiogram find-

Thrombocytopenia can also be one of the first signs of TMA, ings were obtained.76
along with hemolytic anemia and acute renal impairment, which has Given cardiac toxicity observed in animal studies, troponin I con-
been reported in some patients receiving onasemnogene abe- centrations should be regularly monitored for at least 3 months after
parvovec.46,77 In some cases, TMA may have been precipitated by onasemnogene abeparvovec (weekly for the first month, and then
infections, triggering complement activation or dysregulation and monthly for the second and third months until troponin I concentra-
coagulation abnormalities and underpinning recommendations to wait tions return to baseline) (Table 4).14 Clear clinical significance of tro-
at least 2 weeks after illnesses have resolved before initiating treat- ponin I elevations in the absence of other signs of cardiac disease is
ment with onasemnogene abeparvovec. If thrombocytopenia is lacking.
detected, analysis of hemoglobin, hemolysis, and renal dysfunction There remains no consensus on increases that are significant.
(including urinalysis) should be undertaken, as early identification of Repeating troponin I tests may be useful. All individuals with eleva-
TMA is critical in initiating timely therapeutic intervention.46 If clinical tions should have history and examination reviewed for potential new
signs, symptoms, or laboratory findings consistent with TMA occur, symptoms. If elevations persist or are associated with accompanying
physicians should manage as clinically indicated. concerns, consultation with a cardiologist should be strongly
Recommendation: Along with clinical assessment for bruising, we considered.
recommend conducting broader laboratory analyses, such as complete The clinical utility of measuring other cardiac biomarkers in place
blood counts, at each time point, as permitted by patient age and size, of troponin I is unknown. Original protocols for phase III studies
to detect thrombocytopenia and coincident hematologic abnormalities included analyses of creatine kinase-MB. All study protocols were
that may indicate inflammation/infection. subsequently amended to accommodate additional cardiac safety
monitoring, including troponin I measurements, in response to the
findings from mouse toxicology studies.
13.3 | Troponin I

Transient increases in troponin I and changes in heart rate without 14 | T E M P O R A R Y V E C T O R SH E D D I N G

clinical sequelae were observed after onasemnogene abe- A N D WA S T E H A N D L I N G
parvovec.14,65 In clinical studies, echocardiogram revealed no abnor-
mality of cardiac contractility, as indicated by left ventricle ejection Onasemnogene abeparvovec vector DNA shedding post-infusion was
fraction and no thrombus formation in any patients with elevated tro- analyzed in samples of saliva, urine, and stool from five patients in the
ponin I concentrations. Baseline to final cardiac function remained phase I START study through the month 21 (saliva and urine) or
422 KICHULA ET AL.

month 18 (stool) visit. Analysis of vector DNA by droplet digital poly-

merase chain reaction revealed shedding in saliva, urine, and stool after
infusion, with much greater concentrations found in stool. Vector shed-
ding 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  106 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  107 genome copies/mL)
(Figure 3C and Table S3).
Theoretical risks of vector shedding after onasemnogene abe-
parvovec are extremely low, including for immunocompromised sib-
lings. Because AAVs are not associated with disease in healthy adult
humans, they are classified as a National Institutes of Health Risk
Group 1 (RG1) agent,78 with US Centers for Disease Control and Pre-
vention biosafety level 1 (BSL1) designation.79 Although these desig-
nations are specific to the United States and may have region-specific
differences, AAVs are generally considered low risk. Onasemnogene
abeparvovec is non-replicating, further adding to the drug's safety
profile. Although risks of exposure to onasemnogene abeparvovec are
low, the treatment may expose siblings who also have SMA to AAV9,
potentially precluding them from receiving AAV9-based therapies.
Recommendation: Given that temporary vector shedding of
onasemnogene abeparvovec occurs primarily through body waste,
caregivers should be advised on proper handling of patient feces and
contact with urine. To avoid the potential for causing a sibling to sero-
convert, we recommend patients and siblings avoid bathing together
during the period immediately after dosing.

14.1 | Pharmacy considerations

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
IV access is confirmed, onasemnogene abeparvovec can be drawn up
in a syringe at the appropriate dose volume, and all transfers should
be performed using polypropylene materials only. Onasemnogene
abeparvovec is then delivered at room temperature to the infusion
location and used within 8 hours. Onasemnogene abeparvovec should
be administered as a single-dose IV infusion through a venous
catheter over 60 minutes.
F I G U R E 3 Onasemnogene abeparvovec shedding in START study
Recommendation: The recommended dose of onasemnogene abe-
patient samples over time. Viral particle titers in saliva (A), urine (B),
parvovec is 1.1  1014 vector genomes per kilogram of body weight.14 and stool (C) samples were examined by droplet digital polymerase
Because patients' weights can change in a short period, we recommend chain reaction. The lower limit of quantification (LLOQ) for the assay
obtaining the most up-to-date weight before ordering the medication. is indicated by the hatched line. Samples were taken at visit days 1, 2,
Recommendation: Given onasemnogene abeparvovec's relative 7, 14, 21, 30, 60, and 90 (shown) and monthly until month 21 post-
dose (Table S1). Only those values above the LLOQ are presented
safety (RG1 requiring BSL1 safety equipment), personal protective
equipment should be used according to institutional guidelines.
Recommendation: Vascular access can be challenging in SMA type Note: There are certain circumstances in which a single line may
1. Having the best possible team to obtain access is important. Before be chosen as a result of venous access challenges. In France, 90% of
dosing, placement of two IV lines is preferred (in case one line fails).15 SMA type 1 patients (n = 18; 3–10 months old) required a transient
KICHULA ET AL. 423

central line (jugular or femoral) with local anesthesia because of diffi- were described for two patients, one with a delayed diagnosis and the
culties with peripheral venous access. other diagnosed through newborn screening, who were initially
Recommendation: All transfers must be performed using polypro- treated with nusinersen and later treated with onasemnogene abe-
pylene syringes and tubing, as stability studies have been conducted parvovec.80 Improvements in both children were observed.80 Three of
to confirm drug product compatibility with those materials. Compati- four patients initially treated with nusinersen continued nusinersen
bility of onasemnogene abeparvovec has not been analyzed when after onasemnogene abeparvovec in another case series of patients
stored in polystyrene or polycarbonate syringes. 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,
15 | P O T E N T I A L DR U G I N T E R A C T I O N S which caused more issues with potential lumbar puncture than with
IV infusion. Although improvement with combination therapy was
15.1 | Vaccinations observed in these individual cases, the effect relative to monotherapy
was not established. The impact of combination therapy on patient
Scheduled and seasonal vaccination of patients should be adjusted to outcomes and safety is unknown and is being evaluated in clinical tri-
accommodate concomitant prednisolone administration (ideally a min- als. Currently, there are no published data on combination treatment
imum of 2 weeks before infusion). Vaccines such as measles, mumps, with risdiplam and onasemnogene abeparvovec, although some
rubella, and varicella are contraindicated for patients receiving sub- patients have received both treatments.
stantially immunosuppressive steroids. Oral rotavirus vaccines are also Recommendation: There is no evidence that combination therapy
live attenuated viruses and should be adjusted to accommodate improves efficacy. Until evaluated in a clinical trial, no recommenda-
dosing and prednisolone tapering. tions can be made regarding combination therapy. It could be consid-
Recommendation: Children should be current on all rec- ered for patients who demonstrate suboptimal responses to initial
ommended vaccinations before administration of onasemnogene therapy. Consideration should be given to timing between treatments.
abeparvovec. Vaccinations should be avoided within 2 weeks before Given thrombocytopenia can be an adverse effect of both
or after administration to avoid systemic inflammatory events and onasemnogene abeparvovec and nusinersen, we recommend an inter-
potential issues with thrombocytopenia. Live virus vaccines, such as val of at least 2 weeks before and 1 month after onasemnogene abe-
vaccination against rotavirus, are contraindicated during higher-dos- parvovec before nusinersen is administered. Platelets should be
age prednisolone. monitored in between treatments with potential for increasing the
Recommendation: Seasonal respiratory syncytial virus prophylaxis interval of dosing if thrombocytopenia occurs. Risdiplam should not
(palivizumab) is recommended for symptomatic SMA infants. Vaccina- be administered until serum transaminases have normalized after
tion against seasonal influenza is also recommended. onasemnogene abeparvovec.
Recommendation: We recommend family members and caregivers Recommendation: Long-term registry studies will be necessary to
be current on vaccines and avoid live attenuated vaccines after understand the durability and safety of this treatment both alone and
onasemnogene abeparvovec. We also recommend all eligible family in combination with other therapies.
members be vaccinated against SARS-CoV-2.

16 | I S O L A T I O N B E F O R E A N D A F T E R
15.2 | Combination treatment DO SIN G

Some SMA patients have been treated with both nusinersen and Given the potential for treatment postponement for respiratory or
onasemnogene abeparvovec. This includes patients who transitioned other systemic infections, or the immunosuppressive effects of pred-
from nusinersen to onasemnogene abeparvovec and those who nisolone, it may be beneficial for patients to be isolated to limit poten-
received nusinersen after gene therapy.31,72,80 In a retrospective tial contact with other viruses (eg, flu season). This is particularly
review of the first 21 children with SMA treated with onasemnogene critical immediately before scheduled infusions and immediately after-
abeparvovec in Ohio, 11 had been previously treated with ward, when coinfection with another virus may increase inflammatory
nusinersen.72 A 3-month gap between last nusinersen dose and responses. Contact with anyone exhibiting any symptoms should be
onasemnogene abeparvovec infusions was implemented after one avoided, and family members should practice appropriate
patient developed thrombocytopenia after nusinersen, followed with handwashing hygiene.
onasemnogene abeparvovec 1 month later.72 Recommendation: We recommend limiting contact with others for
Older patients, many of whom were previously treated with 2 weeks before dosing to avoid infection that would delay the dosing.
nusinersen, were more likely to have had transaminase elevations and Recommendation: Although patients are immunosuppressed with
72
require a prolonged prednisolone course. Three of these patients steroids, especially during the first 4 to 6 weeks, we advise families to
experienced drops in platelet counts. None had thrombocytopenia minimize exposure to other viruses that may increase risk and severity
that required treatment.72 In another case series, the clinical courses of adverse events.
424 KICHULA ET AL.

1 7 | P O S T - I N F U S I ON V O M I T I N G A N D the course of the disease. As more patients receive this innovative

ACUTE VIRAL REACTIONS therapy, treatment centers must be prepared to handle and administer
the drug. Given the progressive nature of SMA and the need to initi-
Vomiting is one of the most frequently observed adverse events with ate treatment before irreversible motor neuron loss, physicians must
onasemnogene abeparvovec,27,28 similar to other AAV gene therapy be able to identify those patients eligible to receive onasemnogene
platforms. Although the exact etiology for this specific adverse event abeparvovec through newborn screening whenever possible, make
is not known, acid reflux resulting from the prednisolone may be careful baseline assessments, conduct follow-up assessments, and
involved, as well as an acute viral response.81 Important clinical fac- educate caregivers. Long-term registry studies will be necessary to
tors include maintaining hydration, sustaining urine output, and understand the durability and safety of this therapy both alone and in
absorbing prednisolone. combination with other therapies.
Recommendation: Treating physicians should educate parents
about the potential for vomiting after infusion, fluid management, and ACKNOWLEDG MENTS
red flags for dehydration, and should plan around this adverse event. Medical writing assistance was provided by Marjet D. Heitzer, PhD, of
Parents should also be counseled on the importance of oral predniso- 360 Medical Writing. This support was fully funded by Novartis Gene
lone. If the patient vomits within 30 minutes of prednisolone, the Therapies, Inc. (Bannockburn, IL).
dose should be readministered when vomiting has ceased. Consider-
ation may be given to use of famotidine for gastric protection and CONFLIC T OF INT ER E ST
ondansetron as needed for vomiting. Hospitalization should be rec- This expert opinion was derived from a series of telephone meetings
ommended if concerns for adequate hydration or an inability to keep and multiple rounds of electronic communication by the coauthors.
down corticosteroids are observed. The authors received no financial remuneration for establishing these
Recommendation: Patients may also have acute viral reactions, includ- recommendations or for their work in the preparation of this manu-
ing fever, with onasemnogene abeparvovec. Fever can be controlled using script. Novartis Gene Therapies, Inc., had no input or influence on the
age-appropriate dosing of antipyretics. Ibuprofen is preferred if platelets opinions of the coauthors, and the contents of this work were devel-
are normal. If there is concern for thrombocytopenia, or the patient is less oped based on the meetings and communications by the coauthors.
than 6 months of age, then acetaminophen is preferred. E.A.K. has received honoraria for advisory board participation from
Biogen, Novartis, and Roche, and speaker's fees from Roche. She is a
site principal and subinvestigator for Novartis Gene Therapies clinical
1 8 | S T A ND A R D - O F - C A R E G U I D E L I N E S trials. C.M.P. is a site principal investigator for Biogen and Novartis
A N D N EE D F OR LO N G- T ER M F OL L OW- U P Gene Therapies clinical trials, and has received honoraria for advisory
board participation from Biogen, Novartis, and Roche, and speaker's
Despite recent advancements in SMA management, patients continue fees from Biogen and Novartis. M.A.F. is a site principal investigator
to require multidisciplinary care directed by a neurologist or other for Novartis Gene Therapies clinical trials and has received honoraria
specialist with expertise in neuromuscular disease, facilitating multi- for advisory board participation from Biogen, Novartis, and Roche and
disciplinary interventions. Specifically, respiratory care must be speaker's fees from Biogen. In addition, she has received grant sup-
established to monitor cough, airway clearance, and potential hypo- port from the National Health and Medical Research Council of
ventilation. Rehabilitative therapies are recommended to improve Australia (Investigator Grant APP1194940). J.M.K. is a site principal
motor skills, and may include physical, occupational, and speech ther- investigator for Novartis Gene Therapies clinical trials. K.S. is a site
apy. Orthopedic management should also be in place to monitor con- principal investigator for Biogen and Novartis Gene Therapies clinical
tractures and scoliosis; nutrition evaluations are also required to trials, has received honoraria for advisory board participation from
ensure adequate feeding, growth, and swallow function.10,82 Biogen, Novartis, and Roche/Chugai, and speaker's fees from Biogen
Recommendation: The treating physician should counsel families on and Novartis. I.D. is a site principal investigator for Roche and PTC
the importance of multidisciplinary and long-term care after treatment, Inc., clinical trials, and has received honoraria for advisory board par-
even in those who may appear to be only minimally symptomatic. ticipation from Biogen, Novartis Gene Therapies, Inc., PTC Inc., Roche,
Recommendation: Long-term monitoring of treated patients through and Sarepta Therapeutics. She is also a member of the RESTORE reg-
registries is important for collaboration and dissemination of outcome and istry steering committee for Novartis Gene Therapies, Inc. H.J.M. is a
safety data. Physicians should discuss the importance of participation in site principal investigator for Novartis Gene Therapies, Inc and has
long-term registries with their patients' parents or guardians. received honoraria for advisory board participation and speaker's fees
from Novartis, and research support from Roche.

19 | CO NC LUSIO NS ET HICAL PU BLICAT ION ST AT E ME NT

We confirm that we have read the Journal's position on issues
Onasemnogene abeparvovec provides a novel, effective, single-dose involved in ethical publication and affirm that this report is consistent
treatment for SMA patients and has the potential to significantly alter with those guidelines.
KICHULA ET AL. 425

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