Translational and Regulatory Challenges for Exon Skipping Therapies

Aartsma‐Rus, Annemieke; Ferlini, Alessandra; Goemans, Nathalie; Pasmooij, Anna M. G.; Wells, Dominic J.; Bushby, K.; Vroom, Elizabeth; Balabanov, Pavel

doi:10.1089/hum.2014.086

Cited by 39 publications

(36 citation statements)

References 37 publications

(53 reference statements)

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“…Large scale clinical trials have been conducted to test therapeutic benefits of exon-skipping [34, 35]. Systemic AAV micro-dystrophin therapy is slotted to start in the next couple of years [7, 8].…”

Section: Discussionmentioning

confidence: 99%

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Wasala

Yue

Vance

et al. 2017

Journal of Molecular and Cellular Cardiology

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Dystrophin deficiency results in Duchenne cardiomyopathy, a primary cause of death in Duchenne muscular dystrophy (DMD). Gene therapy has shown great promise in ameliorating the cardiac phenotype in mouse models of DMD. However, it is not completely clear how much dystrophin is required to treat dystrophic heart disease. We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophin-null mdx mice. Many gene therapy strategies will unlikely restore dystrophin to the wild-type level in a cardiomyocyte. To determine whether low-level dystrophin expression can reduce the cardiac manifestations in DMD, we examined heart histology, ECG and hemodynamics in 21-mold normal BL6 and two strains of BL6-background dystrophin-deficient mice. Mdx3cv mice show uniform low-level expression of a near full-length dystrophin protein in every myofiber while mdx4cv mice have no dystrophin expression. Immunostaining and western blot confirmed marginal level dystrophin expression in the heart of mdx3cv mice. Although low-level expression did not reduce myocardial histopathology, it significantly ameliorated QRS prolongation and normalized diastolic hemodynamic deficiencies. Our study demonstrates for the first time that low-level dystrophin can partially preserve heart function.

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Section: Discussionmentioning

confidence: 99%

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Wasala

Yue

Vance

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…This test has been adopted from the cardiovascular field and was successfully used for the development of enzyme replacement therapy for another neuromuscular disorder (Pompe's disease). To obtain marketing authorization for a medication from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the primary end point must be clinically meaningful (2). Because DMD is a progressive disease, over time the distance patients walk in 6 min levels off around the age of eight years and then declines (180).…”

Section: Infrastructurementioning

confidence: 99%

“…Jointly, these would benefit ∼38% of DMD patients (26). Hopefully a faster trajectory for clinical development can be adopted should marketing authorization be obtained for initial AONs (2).…”

Section: Myoblasts (Muscle Stem Cells) Can Be Cultured Ex Vivo To Obtmentioning

confidence: 99%

The Pathogenesis and Therapy of Muscular Dystrophies

Guiraud

Aartsma‐Rus

Vieira

et al. 2015

Annu. Rev. Genom. Hum. Genet.

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286

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Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics.

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“…As we move into the era of precise molecular correction, there are considerable limitations in moving these therapies into humans (21). In many instances, ASOmediated exon skipping is only able to target subgroups of individuals with rare diseases, often requiring precise sequences designed to treat personalized diseases.…”

Section: The Splice Agementioning

confidence: 99%

Welcome to the splice age: antisense oligonucleotide–mediated exon skipping gains wider applicability

McNally¹,

Wyatt²

2016

Journal of Clinical Investigation

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C o m m e n t a r y Exon skipping and neuromuscular diseaseThere has been considerable progress toward using exon skipping for therapeutic intent for inherited muscle diseases in humans. Significant efforts have focused on such strategies for treating Duchenne muscular dystrophy (DMD), a lethal X-linked recessive disorder caused by mutations in the gene encoding dystrophin (reviewed in ref. 1). In the case of DMD, exon skipping is applied to convert out-of-frame mutations that ablate protein expression to those mutations that restore the open reading frame, thereby converting severe disease to milder disease. A primary antisense oligonucleotide (ASO) strategy in clinical development targets exon 51 of the dystrophin gene, as exon deletions proximal to this region are a relatively common cause of DMD. In the setting of these specific exon deletions, ASO-mediated exclusion of exon 51 generates in-frame mature RNA transcripts and rescues protein expression. The protein encoded by the ASO-modified transcript results in a relatively small internal deletion of the dystrophin protein (2). Moving ASOs beyond DMDWith progress, ASO exon skipping approaches are now moving beyond the original DMD paradigm. Strategies for exon skipping have been developed for a number of neuromuscular conditions, including limb girdle muscular dystrophy (3), Pompe disease (4), cardiomyopathies (5, 6), and cystic fibrosis (7). Other approaches toward treating laminopathies have also been tested (8). For DMD, approaches extend beyond correction of the dystrophin gene and include combining ASO exon skipping with targeted reduction of myostatin (9, 10). ASO-induced exon skipping may be useful beyond rare genetic diseases, extending to disorders like rheumatoid arthritis (11) and cancer (12). A strategy to treat laminopathiesIn this issue, Lee and colleagues piloted an ASO-directed approach to treat Hutchinson Gilford progeria syndrome (HGPS) (13), a rare disorder that is often associated with a de novo dominant mutation in the lamin A/C (LMNA) gene that disrupts the processing of lamin A (14). Lamin A and lamin C are produced from a single gene through alternative splicing and together form the core filamentous structure that lines the inner nuclear membrane ( Figure 1). Lamin A is initially produced as prelamin A, which includes an additional 98 amino acids at the carboxy terminus. Embedded in the last four amino acids of prelamin A are signals that direct farnesylation, which is linked to cleavage and processing to help localize mature lamin A at the inner nuclear membrane. Lamin C is encoded by an alternative splice form that terminates in exon 10 and does not undergo this maturation process. The de novo HGPScausing mutation (c.1824 C>T) disrupts splicing and leads to excess accumulation of prelamin A, also called progerin. Lee et al. designed and tested ASOs to shift the balance of splicing to encode less lamin A and more lamin C (13). The rationale for this shift was justified by previous observations in lamin C-only mice, which, by geneti...

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Translational and Regulatory Challenges for Exon Skipping Therapies

Cited by 39 publications

References 37 publications

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

The Pathogenesis and Therapy of Muscular Dystrophies

Welcome to the splice age: antisense oligonucleotide–mediated exon skipping gains wider applicability

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