Transitioning From Nusinersen to Risdiplam for Spinal Muscular Atrophy in Clinical Practice: A Single-Center Experience.

Background: Nusinersen and risdiplam are U.S. Food and Drug Administration (FDA)-approved treatments for spinal muscular atrophy (SMA).

Clinical decision making around commercial use of gene and genetic therapies for spinal muscular atrophy.

Spinal muscular atrophy is no longer a leading cause of inherited infant death in the United States. Since 2016, three genetic therapies have been approved for the treatment of spinal muscular atrophy. Each therapy has been well studied with robust data for both safety and efficacy.

Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication.

Parental Experiences with Newborn Screening and Gene Replacement Therapy for Spinal Muscular Atrophy.

Background: Spinal muscular atrophy (SMA) is a genetic neurodegenerative disorder with onset predominantly in infants and children. In recent years, newborn screening and three treatments, including gene replacement therapy (Onasemnogene abeparvovec-xioi), have become available in the United States, aiding in the diagnosis and treatment of children with SMA.

Objective: To evaluate parents' experiences with newborn screening and gene replacement therapy and to explore best practices for positive newborn screen disclosure and counseling of families.

Continued safety and long-term effectiveness of onasemnogene abeparvovec in Ohio.

5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023.

Exome sequencing in the pediatric neuromuscular clinic leads to more frequent diagnosis of both neuromuscular and neurodevelopmental conditions.

Introduction/aims: Exome sequencing (ES) has proven to be a valuable diagnostic tool for neuromuscular disorders, which often pose a diagnostic challenge. The aims of this study were to investigate the clinical outcomes associated with utilization of ES in the pediatric neuromuscular clinic and to determine if specific phenotypic features or abnormal neurodiagnostic tests were predictive of a diagnostic result.

Methods: This was a retrospective medical record review of 76 pediatric neuromuscular clinic patients who underwent ES.

A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity.

The major determinant of disease severity in Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether the dystrophin gene (DMD) mutation truncates the mRNA reading frame or allows expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, and candidate gene studies have implicated several genes as modifiers. Here we present the largest genome-wide search to date for loci influencing severity in N = 419 DMD patients.

A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK..

In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK. (also ) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion.

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis.

Phenotypic Spectrum of Dystrophinopathy Due to Duchenne Muscular Dystrophy Exon 2 Duplications.

Background And Objectives: To describe the phenotypic spectrum of dystrophinopathy in a large cohort of individuals with exon 2 duplications (Dup2), who may be particularly amenable to therapies directed at restoring expression of either full-length dystrophin or nearly full-length dystrophin through utilization of the exon 5 internal ribosome entry site (IRES).

Methods: In this retrospective observational study, we analyzed data from large genotype-phenotype databases (the United Dystrophinopathy Project [UDP] and the Italian DMD network) and classified participants into Duchenne muscular dystrophy (DMD), intermediate muscular dystrophy (IMD), or Becker muscular dystrophy (BMD) phenotypes. Log-rank tests for time-to-event variables were used to compare age at loss of ambulation (LOA) in participants with Dup2 vs controls without Dup2 in the UDP database and for comparisons between steroid-treated vs steroid-naive participants with Dup2.

Validity and Reliability of the Neuromuscular Gross Motor Outcome.

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities.

Absence of Significant Off-Target Splicing Variation with a U7snRNA Vector Targeting Exon 2 Duplications.

Exon skipping therapies for Duchenne muscular dystrophy that restore an open reading frame can be induced by the use of noncoding U7 small nuclear RNA (U7snRNA) modified by an antisense exon-targeting sequence delivered by an adeno-associated virus (AAV) vector. We have developed an AAV vector (AAV9.U7-ACCA) containing four U7snRNAs targeting the splice donor and acceptor sites of dystrophin exon 2, resulting in highly efficient exclusion of exon 2.

Time is muscle: A recommendation for early treatment for preterm infants with spinal muscular atrophy.

Implementation of newborn screening for spinal muscular atrophy (SMA) in 33 US states and increased genetic carrier screening have led to an increase in early, presymptomatic diagnosis of SMA. Early treatment is critically important and is recommended for presymptomatic infants with two to four copies of survival motor neuron 2. Currently, no specific treatment recommendations exist for preterm infants with SMA.

Spinal Muscular Atrophy.

Spinal muscular atrophy is one of the most common neuromuscular disorders of childhood and has high morbidity and mortality. Three different disease-modifying treatments were introduced in the last 4 years: nusinersen, onasemnogene abeparvovec, and risdiplam. These agents have demonstrated safety and efficacy, but their long-term benefits require further study.

Lack of Toxicity in Nonhuman Primates Receiving Clinically Relevant Doses of an AAV9.U7snRNA Vector Designed to Induce Exon 2 Skipping.

Therapeutic exon skipping as a treatment for Duchenne muscular dystrophy (DMD) has largely concentrated on the delivery of antisense oligomers to treat out-of-frame exon deletions. Here we report on the preclinical development of an adeno-associated virus (AAV)-encapsidated viral vector containing four copies of the noncoding U7 small nuclear RNA (U7snRNA), each targeted to either the splice donor or the splice acceptor sites of exon 2. We have previously shown that delivery of this vector (scAAV9.

Natural History of Steroid-Treated Young Boys With Duchenne Muscular Dystrophy Using the NSAA, 100m, and Timed Functional Tests.

Introduction: Clinical trials targeting younger cohorts of boys with Duchenne muscular dystrophy are necessary as earlier intervention may maximize treatment effect. Boys with Duchenne muscular dystrophy often have gross motor delays very early in life, and although they gain skills, they are on a lower trajectory than typical peers. Quantifying the natural rate of motor maturation in Duchenne muscular dystrophy from an early age permits identification of deviations from the expected trajectory related to treatment effects.

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

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.

Spinal Muscular Atrophy in the Treatment Era.

Spinal muscular atrophy is an autosomal-recessive degenerative neuromuscular disease that has historically been categorized into 5 types based on the individual's best functional ability. Two rather remarkable treatments have recently been approved for commercial use, and both have markedly changed the natural history of this disease. Here the authors report several cases of individuals, ranging from infants to adults, to highlight diagnostic considerations, along with initial and long-term treatment considerations in these individuals who now have the potential for stabilization to significant improvement in functional outcomes.

Clinical Phenotypes of DMD Exon 51 Skip Equivalent Deletions: A Systematic Review.

Background: Eteplirsen, the first FDA-approved RNA-modifying therapy for DMD, is applicable to ∼13% of patients with DMD. Because multiple exonic deletions are amenable to exon 51 skipping, the isoforms resulting from the various exon 51-skipped transcripts may vary in stability, function, and phenotype.

Objective/methods: We conducted a detailed review of dystrophinopathy published literature and unpublished databases to compile phenotypic features of patients with exon 51 "skip-equivalent" deletions.

The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy.

The bicaudal D cargo adaptor 2 (BICD2) gene encodes a conserved cargo adaptor protein required for dynein-mediated transport. Inherited and de novo variants in BICD2 cause SMALED2 (spinal muscular atrophy lower extremity dominant 2), and a subset have recently been reported to cause severe, often lethal disease. However, a true genotype-phenotype correlation for BICD2 has not been performed, and cases described to date are scattered among at least 14 publications.