Antisense-mediated exon skipping: Taking advantage of a trick from Mother Nature to treat rare genetic diseases

Veltrop, Marcel H. A. M.; Aartsma‐Rus, Annemieke

doi:10.1016/j.yexcr.2014.01.026

Cited by 34 publications

(28 citation statements)

References 43 publications

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“…Given the recent promising results of using AONs to alter splicing in diseases (for reviews, see refs. [18][19][20], and their success in clinical trials for Duchenne muscular dystrophy (21,22), we propose that our results warrant further study to develop this approach as a potential mast cell-specific treatment for allergic diseases.…”

Section: Significancementioning

confidence: 70%

“…Exon skipping has been effectively used for rare genetic defects where frameshift mutations in genomic DNA lead to loss of protein function (for reviews, see refs. [18][19][20]. Indeed, two new drug applications for the AON drugs Drisapersen (BioMarin Pharmaceutical) and Eteplirsen (Sarepta Therapeutics) to treat Duchenne muscular dystrophy have been filed with the Food and Drug Administration.…”

Section: Discussionmentioning

confidence: 99%

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Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Cruse

Yin

Fukuyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high-affinity IgE receptor (FceRIβ) to eliminate surface high-affinity IgE receptor (FceRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FceRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of FceRIβ is a potential approach for mast cell-specific treatment of allergic diseases.A sthma and related allergic diseases affect up to 1 in 10 people in developed countries, and about 10% of patients with asthma cannot be controlled with current therapeutic approaches. The most widely used therapies for asthma rely upon dampening the inflammatory response with either oral or inhaled glucocorticosteroids and relaxing the constricted airway smooth muscle cells with β-adrenoreceptor agonists. However, high doses of steroids when needed for severe asthma are associated with undesirable side effects and inhaled β-adrenoreceptor agonists can increase the risk of death from asthma if not used in combination with glucocorticosteroids. It is suggested that β-adrenoreceptor agonists may promote underlying inflammation that could contribute to the airway wall remodeling seen in asthma (1). Other clinical approaches that aim for more long-term alleviation of symptoms, including desensitization with incremental increases in dose of allergen or hyposensitization to induce immune tolerance, have proven beneficial for some, but not all, patients, and serious adverse effects can occur (2).In addition to asthma, other allergic diseases have similar treatment strategies and also have an unmet clinical need. An example is atopic dermatitis (AD), which like asthma, is also a multifactorial disease with complex pathophysiology, remains incurable, and affects 10-20% of children in the United States (3). The two major symptoms of AD are inflammatory lesions and severe pruritus. Both the prevalence and the economic burden of AD are increasing worldwide. Symptomatic treatment with topical and/or systemic glucocorticosteroids or calcineurin inhibitors are still considered the gold standard. However, due to the known adverse effects of these drugs, prescription rates are low and patient compliance is often poor (3). Thus, there is still a need for new therapeutic approaches with a better safety profile.An approach for intervention in allergic inflammation that we have pursued is based on the finding that the gene loci 11q12-q13 are strongly linked to allergy and asthma suscepti...

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Section: Significancementioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Cruse

Yin

Fukuyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Genetic “bypass” methods are also being developed, and these methods manipulate RNA using anti-sense sequences to induce alternative splicing to avoid the mutation. This approach, referred to as exon skipping, takes advantage of naturally occurring splice forms or creates newly engineered, internally truncated proteins (Veltrop and Aartsma-Rus, 2014). As long as there is physiological evidence that such internally truncated proteins can compensate, these approaches may be useful for some genes linked to cardiomyopathy.…”

Section: Implications For Gene-based Therapy and Drug Developmentmentioning

confidence: 99%

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

2015

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Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output. Dilated cardiomyopathy is often triggered by mutations that disrupt the giant protein titin. The energetic consequences of these mutations offer molecular targets and opportunities for new drug development and gene correction therapies.

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“…If successful, correcting the LIFR gene could result in the expression of a normal and functional LIFR protein. Antisense mediated exon skipping may also be a useful strategy in cases where exons encode independently folding domains within the protein or where the remaining domain can still fold stably and correctly and carry out the function of the normal protein 81 Exon skipping strategies may be especially applicable in cases where a mutation causes a change in reading frame, and skipping of an exon will restore the proper reading frame. Many of the identified disease causing mutations are nonsense mutations, introducing a premature stop codon within the coding regions, resulting in the production of a truncated protein or alternatively, mRNA template degradation.…”

Section: Future Directionsmentioning

confidence: 99%

Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene

Oxford

Jorcyk

Oxford

2016

J Neurol Neuromedicine

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Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature. In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes. Individuals may sweat excessively when body temperature is not elevated. Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk. STWS usually results in infant mortality, yet some STWS patients survive into early adulthood. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomal-recessive pattern. Most LIFR mutations resulting in STWS cause instability of the mRNA due to frameshift mutations leading to premature stop codons, which prevent the formation of LIFR protein. STWS is managed on a symptomatic basis as no treatment is currently available.

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Antisense-mediated exon skipping: Taking advantage of a trick from Mother Nature to treat rare genetic diseases

Cited by 34 publications

References 43 publications

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene

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