Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes

Waldrop, Megan A.; Karingada, Cassandra; Storey, Mike A.; Powers, B.; Iammarino, M.; Miller, N.; Alfano, Lindsay; Noritz, Garey; Rossman, Ian; Ginsberg, Matthew L.; Mosher, Kathryn; Broomall, Eileen; Goldstein, Jessica; Bass, Nancy; Lowes, Linda; Tsao, Chang-Yong; Mendell, Jerry R.; Connolly, Anne M.

doi:10.1542/peds.2020-0729

Cited by 104 publications

(104 citation statements)

References 13 publications

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“…Clinical experience with onasemnogene in 21 children across three tertiary centers in Ohio was recently published 37 . Eight children were on nocturnal NIV before gene transfer, and currently, seven remain on NIV (one child uses intermittently when ill or after a particularly tiring day, and one child no longer requires NIV).…”

Section: Onasemnogene Abeparvovec‐xioimentioning

confidence: 99%

The respiratory impact of novel therapies for spinal muscular atrophy

Paul

Gushue

Kotha

et al. 2020

Pediatric Pulmonology

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The phenotype of spinal muscular atrophy (SMA) has been changing with the recent availability of three FDA‐approved treatments: intrathecal nusinersen, intravenous onasemnogene abeparvovec‐xioi, and enteral risdiplam. The degree of improvement in muscle strength and respiratory health varies with SMA genotype, severity of baseline neuromuscular and pulmonary impairment, medication used, and timing of the first dose. A spectrum of pulmonary outcomes has been reported with these novel medications when used early and in conjunction with proactive multidisciplinary management of comorbidities. In this review, we summarize the reported impact of these novel therapies on pulmonary well‐being and the improving trajectory of pulmonary morbidity, compared to the natural history of SMA. The importance of ongoing clinical monitoring albeit the improved phenotype is reiterated. We also discuss the limitations of the current SMA‐therapy trials and offer suggestions for future clinical‐outcome studies and long‐term monitoring.

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Section: Onasemnogene Abeparvovec‐xioimentioning

confidence: 99%

The respiratory impact of novel therapies for spinal muscular atrophy

Paul

Gushue

Kotha

et al. 2020

Pediatric Pulmonology

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“…viral titers and increased likelihood of immune response) and the fact that this drug has only been tested for this age group. (17,21,22) The most recent treatment approved by the FDA is Evrysdi® (risdiplam), an orally administered, SMN2 splicing modi er for patients 2 months of age and older with SMA. (23,24) The drug increases exon 7…”

Section: Introductionmentioning

confidence: 99%

Treatment Preference among Patients with Spinal Muscular Atrophy (SMA): A Discrete Choice Experiment

Monnette

Hong

et al. 2020

Preprint

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OBJECTIVE: To examine patient/caregiver preference for key attributes of treatments for spinal muscular atrophy (SMA). BACKGROUND: In the rapidly evolving SMA treatment landscape, it is critically important to understand how attributes of potential treatments may impact patient/caregiver choices.DESIGN/METHODS: A discrete choice experiment survey was developed based on qualitative interviews. Patients with SMA (³18 years) and caregivers of patients were recruited through a U.S. patient organization. Respondents made choices in each of 12 sets of hypothetical treatments. The relative importance of five treatment characteristics was compared (measured by regression coefficients [RC] of conditional logit models): (1) improvement or stabilization of motor function, (2) improvement or stabilization of breathing function, (3) indication for all ages or pediatric patients only, (4) route of administration (repeated intrathecal [IT] injections, one-time intravenous [IV] infusion, daily oral delivery) and (5) potential harm (mild, moderate, serious/life threatening).RESULTS: Patient ages ranged from less than 1 to 67 years (n=101, 65 self-reported and 36 caregiver-reported) and 64 were female. Total SMA subtypes included: type 1 (n=21), type 2 (n=48), type 3 (n=29), other (n=3). Prior spinal surgery was reported in 47 patients. Nusinersen and onasemnogene abeparvovec-xioi use were reported in 59 and 10 patients, respectively. Improvement in motor and breathing function was highly valued (RC: 0.65, 95% confidence interval [CI]: 0.47–0.83 and RC: 0.79, 95% CI: 0.60–0.98, respectively). Oral medication and one-time infusion were strongly preferred over repeated IT injections (RC: 0.80, 95% CI: 0.60–0.98 and RC: 0.51, 95% CI: 0.30–0.73, respectively). Patients least preferred an age-restricted label/approved use (£ 2 years of age) (RC: -1.28, 95% CI: -1.47 to -1.09). Cross-attributes trade-off decision suggested a lower willingness for a high-risk therapy despite additional efficacy gain. For some patients, there may be willingness to trade off additional gains in efficacy for a change in route of administration from repeated intrathecal administration to oral medication.CONCLUSIONS: Improvements in motor/breathing function, broad indication, oral or one-time infusion, and minimal risk were preferred treatment attributes. Treatment decisions should be made in clinical context and be tailored to patient needs.

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“…In addition, the majority (11/12) of children tolerated at least partial oral feeding safely and spoke by the end of long‐term follow‐up. Dosing infants at 6 months of age or earlier with minimal to no symptoms may be associated with greater improvements in motor outcomes and more modest elevations in aminotransferases 40,41 …”

Section: Gene Therapy In Smamentioning

confidence: 99%

Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy

Abreu

Waldrop

2020

Pediatric Pulmonology

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Both 5q‐linked spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by loss‐of‐function mutations. SMA is an autosomal recessive disorder affecting motor neurons that is typically caused by homozygous whole‐gene deletions of SMN1. DMD is an X‐linked recessive muscle disease most often due to exon deletions, but also duplications and smaller sized variants within the DMD gene. Gene replacement therapy offers the opportunity to correct the underlying genetic defect by the introduction of a functional gene. We review the transformative work from clinical trials to United States Food and Drug Administration approval of onasemnogene abeparvovec‐xioi in SMA and its application in clinical practice and the early results of microdystrophin delivery in DMD. We also review the introduction of antisense oligonucleotides to alter pre‐messenger RNA splicing to promote exon inclusion (as in nusinersen in SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular therapeutics. There are multiple promising novel genetically mediated therapies on the horizon, which in aggregate point towards a hopeful future for individuals with SMA and DMD.

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Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes

Cited by 104 publications

References 13 publications

The respiratory impact of novel therapies for spinal muscular atrophy

The respiratory impact of novel therapies for spinal muscular atrophy

Treatment Preference among Patients with Spinal Muscular Atrophy (SMA): A Discrete Choice Experiment

Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy

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