Novel therapies for Duchenne muscular dystrophy

doi:10.1016/S1474-4422(03)00382-X

The Lancet Neurology

Volume 2, Issue 5, May 2003, Pages 299-310

https://doi.org/10.1016/S1474-4422(03)00382-X Get rights and content

Summary

The development of therapeutic strategies that overcome the unique problems posed by Duchenne muscular dystrophy (DMD) has lead to the development of many contemporary approaches to human disease in general. Various treatment approaches have been explored—such as pharmacological therapies and cell-based, cytokine, and genetic therapies—that are all targeted to specific features of dystrophic DMD muscle pathology. In genetic therapies, the large size of the dystrophin gene has necessitated the development and use of novel functional minidystrophin and microdystrophin genes, muscle-specific promoter systems, and gutted adenoviral systems. In addition to these well defined viral strategies, plasmid vectors and the upregulation of utrophin (a dystrophin homologue) have potential. Various novel genetic approaches—such as antisense-mediated exon skipping, gene correction, and new cytokine approaches—are also being developed. Together these exciting developments bring an effective treatment for DMD closer than ever before.

Section snippets

Molecular pathology of DMD

Dystrophin, the product of the human dystrophin gene (dys), is a 427 kDa protein composed of 3685 amino acid residues. The protein localises to the sarcolemma,¹ where is constitutes 5% of sarcolemmal protein² and 0·002% of total striated muscle protein.³ Dystrophin contains four distinct domains⁴ and shows structural homology with spectrin and α-actinin. In myogenic cells, the N-terminal and parts of the helical-rod domain bind to actin whereas the C-terminal and a cysteine-rich domain distal

Genetic therapies in DMD

Both viral and plasmid vectors have been used to deliver dystrophin to dystrophin-deficient muscle in vivo (figure 3). The efficiency with which these vectors express dystrophin, or other transgenes, in muscle cells is dependent on various factors. These include transgene size, delivery, expression, persistence, immune response, maturation dependent loss of muscle-fibre transducibility (for viral vectors), and inefficient passage of vectors through the extracellular matrix.

Targeted corrective gene conversion therapies

The introduction of construct of homologous DNA containing a non-homologous sequence into mammalian cells in vitro induces specific genetic transformations in the host chromosomal DNA.⁷⁹ The size of the non-homologous sequence in the introduced construct does not affect gene targeting efficiency,⁸⁰ but the extent of homology between the target sequence and the introduced sequence has a direct influence on targeting efficiency.⁸¹ High targeting efficiency (1 in 150 cells) can be achieved by

Cell-mediated delivery of dys

Cell transplantation can be used to deliver normal (nondystrophic) dys to dystrophic muscle. Donor myogenic precursor cells can be used to remodel the dystrophic muscle of the recipient. However, graft rejection is a major problem as non-self antigens on the donor cells elicit an immune response.¹⁰⁶ A second problem with this approach is the low survival rate of implanted cells; up to 99% survive for less than a week after injection.¹⁰⁷ In addition, for treatment to be successful, the cells

Conclusion

Several exciting options are currently being explored in the search for an effective therapy for DMD. There are still, however, major challenges facing all of the strategies discussed in this review. In particular, the likelihood that gentamicin, upregulation of utrophin or α7β1 integrin, and targeted corrective gene conversion are likely to induce changes at non-target loci needs to be considered. The targeting capacities of the various therapies are also important: strategies that target

Search strategy and selection criteria

Data for this review were identified by searches of Medline using the search terms “dystrophin”, “gene therapy”, “Duchenne”, “mdx”, “DMD”, “utrophin”, and “muscular dystrophy” on the NCBI Pubmed database. These terms were used singly and in combination to maximise the numbers of relevant papers obtained. The main database was then supplemented by references obtained from several reviews and key papers from RK's private collection and with references obtained by searches for specific

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It is still a matter of investigation, how much this mechanism is able to confer protection to female cells by potentially re-activating disease-compensatory genes. In fact, male cells that contain only one X chromosome lack the protective compensation by the other X and are highly susceptible to a number of X-linked recessive diseases, i.e. haemophilia A, Duchenne muscular dystrophy or X-linked mental retardation (Hoyer, 1994; Kapsa et al., 2003; Raymond, 2006). In females, the genetic material on the second X chromosome compensates the expression of these diseases.
Sex and gender differences affect all dimensions of human health ranging from the biological basis of disease to therapeutic access, choice and response. Genomics research has long ignored the role of sex differences as potential modulators and the concept is gaining more attention only recently. In the present review we summarize the current knowledge of the impact of sex differences on genomic and epigenomic research, the potential interaction of genomics and gender and the role of these differences in disease etiopathogenesis. Sex differences can emerge from differences in the sex chromosomes themselves, from their interaction with the genome and from the influence of hormones on genomic processes. The impact of these processes on the incidence of autoimmune and oncologic disease is well documented. The growing field of systems biology, which aims at integrating information from different networks of the human body, could also greatly benefit from this approach. In the present review we summarize the current knowledge and provide recommendations for the future performance of sex-sensitive genomics research.
Interleukin-6 and neuregulin-1 as regulators of utrophin expression via the activation of NRG-1/ErbB signaling pathway in mdx cells
2017, Biochimica et Biophysica Acta - Molecular Basis of Disease
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Lack of dystrophin in dystrophic muscle results in both loss of DAPs and impairment of plasma membrane stability, causing mechanical stress and fragility [7]. Although no therapy has been described that effectively slow or halt muscle degeneration in dystrophic patients [8], a promising pharmacological approach for DMD treatment aims to compensate dystrophin absence by increasing the expression of utrophin [9], a protein that shares a high degree of sequence identity with dystrophin, and also associates with members of the DAPs complex [10–18]. Utrophin is expressed abundantly throughout the sarcolemma in fetal muscle, where it has been suggested to fulfill the function of dystrophin [19].
Duchenne muscular dystrophy (DMD) is a neuromuscular disease originated by mutations in the dystrophin gene. A promising therapeutic approach deals with functional substitution of dystrophin by utrophin, a structural homolog that might be able to compensate dystrophin absence in DMD muscle fibers.
It has been described that both interleukin-6 (IL-6) and neuregulin-1 (NRG-1; Heregulin-HRG) induce utrophin expression in skeletal muscle. We investigated a possible functional link among IL-6, NRG-1 and utrophin, in normal (C57) and dystrophic (mdx) skeletal muscle cells. Western Blot analysis allowed us to demonstrate that IL-6 (100 ng/mL) induces NRG-1 receptor phosphorylation (ErbB2/ErbB3) in both cell types, in a process that depends on intracellular Ca^2 + and metalloproteinase activity; it also induces a transient increase of ERK1 and GABPα phosphorylation only in dystrophic myotubes. Semiquantitative PCR showed that IL-6 treatment increases utrophin mRNA levels just in mdx myotubes. We observed that utrophin mRNA induction was abolished by BAPTA-AM (an intracellular Ca^2 + chelator), GM6001 (a general metalloproteinase inhibitor), genistein (a general protein tyrosine kinase inhibitor), PD-158780 (an ErbB receptor tyrosine kinase inhibitor) and PD-98059 (a MEK inhibitor), whereas Ly-294002 and wortmannin (PI3K inhibitors) did not affect utrophin induction evoked by IL-6 in dystrophic myotubes.
Our results suggest that IL-6 induces utrophin expression in mdx myotubes through activation of a NRG-1/ErbBs signaling cascade. Soluble NRG-1 elicited by proteolytic processing of transmembrane NRG-1 might induce ErbBs phosphorylation and ERK1/2 pathway activation, leading to utrophin up-regulation.
Relationships of thigh muscle contractile and non-contractile tissue with function, strength, and age in boys with Duchenne muscular dystrophy
2012, Neuromuscular Disorders
Citation Excerpt :
DMD is caused by a genetic defect on the short arm of the X-chromosome at Xp21, which results in the absence of the cytoskeletal protein dystrophin [1]. The disease is characterized by progressive weakness of skeletal muscle leading to loss of ambulation between the age of 10 and 15 years and premature death due to cardiopulmonary complications in the late teens or twenties [2,3]. Skeletal muscles in boys with DMD display important structural and compositional changes, with progressive fatty tissue infiltration and muscle atrophy, secondary to structural weakness of the sarcolemma [4–7].
The purpose of this study was to assess the contractile and non-contractile content in thigh muscles of patients with Duchenne muscular dystrophy (DMD) and determine the relationship with functional abilities. Magnetic resonance images of the thigh were acquired in 28 boys with DMD and 10 unaffected boys. Muscle strength, timed functional tests, and the Brookes Lower Extremity scale were also assessed. Non-contractile content in the DMD group was significantly greater than in the control group for six muscles, including rectus femoris, biceps femoris-long head and adductor magnus. Non-contractile content in the total thigh musculature assessed by MRI correlated with the Brookes scale (r_s = 0.75) and supine-up test (r_s = 0.68), as well as other functional measures. An age-related specific torque increase was observed in the control group (r_s = 0.96), but not the DMD (r_s = 0.06). These findings demonstrate that MRI measures of contractile and non-contractile content can provide important information about disease progression in DMD.
Targeted gene therapy for the treatment of heart failure
2011, Canadian Journal of Cardiology
Chronic heart failure is one of the leading causes of morbidity and mortality in Western countries and is a major financial burden to the health care system. Pharmacologic treatment and implanting devices are the predominant therapeutic approaches. They improve survival and have offered significant improvement in patient quality of life, but they fall short of producing an authentic remedy. Cardiac gene therapy, the introduction of genetic material to the heart, offers great promise in filling this void. In-depth knowledge of the underlying mechanisms of heart failure is, obviously, a prerequisite to achieve this aim. Extensive research in the past decades, supported by numerous methodological breakthroughs, such as transgenic animal model development, has led to a better understanding of the cardiovascular diseases and, inadvertently, to the identification of several candidate genes. Of the genes that can be targeted for gene transfer, calcium cycling proteins are prominent, as abnormalities in calcium handling are key determinants of heart failure. A major impediment, however, has been the development of a safe, yet efficient, delivery system. Nonviral vectors have been used extensively in clinical trials, but they fail to produce significant gene expression. Viral vectors, especially adenoviral, on the other hand, can produce high levels of expression, at the expense of safety. Adeno-associated viral vectors have emerged in recent years as promising myocardial gene delivery vehicles. They can sustain gene expression at a therapeutic level and maintain it over extended periods of time, even for years, and, most important, without a safety risk.
L'insuffisance cardiaque chronique est l'une des causes principales de morbidité et de mortalité dans les pays occidentaux et un fardeau financier majeur du système de soins de santé. Le traitement pharmacologique et l'implantation de dispositifs sont les approches thérapeutiques prédominantes. Elles augmentent les chances de survie et elles ont amélioré significativement la qualité de vie des patients, mais elles ne constituent pas un remède authentique. La thérapie génique cardiaque, l'introduction de matériel génétique dans le cœur, est grandement prometteuse pour combler ce manque. Évidemment, une connaissance approfondie des mécanismes sous-jacents de l'insuffisance cardiaque est un préalable pour atteindre ce but. Une recherche de grande envergure dans les dernières décennies, supportée par de nombreuses percées méthodologiques comme le développement du modèle animal transgénique, a mené à une meilleure compréhension des maladies cardiovasculaires et, par inadvertance, à l'identification de plusieurs gènes candidats. Parmi les gènes qui peuvent être ciblés pour le transfert de gènes, les protéines du cycle de calcium sont importantes, comme les anormalités dans la manipulation du calcium sont les déterminants clés de l'insuffisance cardiaque. Cependant, un grand obstacle a été le développement d'un mode d'administration sécuritaire et efficace. Les vecteurs non viraux ont beaucoup été utilisés dans les essais cliniques, mais ils ne parviennent pas à produire une expression génétique significative. En revanche, les vecteurs viraux, particulièrement adénoviraux, peuvent produire des niveaux élevés d'expression, au détriment de la sécurité. Les vecteurs viraux associés aux adénovirus sont apparus dans les dernières années comme des vecteurs prometteurs des gènes myocardiques. Ils peuvent soutenir l'expression génétique à un niveau thérapeutique et le maintenir durant de longues périodes, voire des années, et ce qui est plus important, sans risque pour la sécurité.
Identification of a novel muscle targeting peptide in mdx mice
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Exon-skipping oligonucleotides are a well-researched therapeutic strategy for Duchenne's muscular dystrophy (DMD). Despite remarkable successes in animal models with intramuscular and intravenous delivery of unmodified oligonucleotides, the ability to specifically target both normal and dystrophic muscle with a simple peptide ligand could decrease the therapeutic dose required and reduce the potential for toxicity. Thus, 3 rounds of in vivo phage display utilizing a 12-mer peptide library were performed with mdx mice and a peptide motif with potential for targeting to muscle but not liver was identified. This motif was shown to have enhanced binding affinity to C2C12 myoblasts over a scrambled control peptide and in vivo application of a fluorescein-labeled peptide containing the identified motif resulted in increased specificity for the heart and quadriceps muscle after tail-vein administration in C57BL/6 mice. This work has many potential applications for oligonucleotide or drug delivery to muscle for myopathies.
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The character of the rAAV vector makes it to be capable of highly efficient transduction in numerous target cells and tissues,8 particularly, in nondividing cells, such as muscle cells.9 These properties and the broad host range of the rAAV have established it over the past decade to be a promising vector system for gene therapy of muscle disorders.10-16 In the rAAV gene therapy vectors, all the viral genes encoding replication (Rep) and capsid (Cap) have been eliminated from wild-type AAV and replaced with a transgene expression cassette (up to 4.5 kb).
Unlike most conventional medicines to treat musculoskeletal disorders, gene therapy focuses on replacing and correcting defective gene. On the basis of evidences of the long-term efficient therapeutic gene expression in the muscle, the recombinant adeno-associated viral (rAAV) vectors are used in the treatment of many life-threatening diseases, especially muscle diseases. The clinical trials for muscle diseases, such as Duchenne muscular dystrophy began 3 years ago. However, the challenges, such as host cytotoxic T lymphocyte response to the vector caspid or/and transgene product are found to interfere with the successful outcome of the rAAV-mediated gene therapy. Further investigation in mechanism and risks associated with immune responses in human as well as a well-designed monitoring plan in clinical trials are essential to achieve the goal of efficacy and safety of the rAAV vectors in clinical trials. Scientists are looking to the novel strategies to optimize the rAAV vectors as a treatment option for human muscle diseases. This review summarizes the development of the rAAV vectors and the treatment of muscular dystrophy by using the rAAV vectors.

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ReviewNovel therapies for Duchenne muscular dystrophy

Summary

Section snippets

Molecular pathology of DMD

Genetic therapies in DMD

Targeted corrective gene conversion therapies

Cell-mediated delivery of dys

Conclusion

Search strategy and selection criteria

FEBS Lett

Cell

Cell

Genomics

Genomics

J Biol Chem

FEBS Lett

Biochem Biophys Res Commun

Mol Ther

Mol Ther

Mol Ther

Neuromuscul Disord

Neuromuscul Disord

Neuromuscul Disord

Cell

Cell

Neuromuscul Disord

Neuromuscul Disord

Immunoelectron microscopic localization of dystrophin in myofibres

Nature

The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein

Cell

Dystrophin-associated proteins are greatly reduced in skeletal muscle from mdx mice

J Cell Biol

Duchenne muscular dystrophy: deficiency of dystrophin-associated proteins in the sarcolemma

Neurology

Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy

N Engl J Med

Defective myoblasts identified in Duchenne muscular dystrophy

Proc Natl Acad Sci USA

Conservation of the Duchenne muscular dystrophy gene in mice and humans

Science

Localization and cloning of Xp21 deletion breakpoints involved in muscular dystrophy

HumGenet

Human and murine dystrophin mRNA transcripts are differentially expressed during skeletal muscle, heart, and brain development

Nucleic Acids Res

Dystrophin is transcribed in brain from a distant upstream promoter

Proc Natl Acad Sci USA

Expression of four alternative dystrophin transcripts in brain regions regulated by different promoters

Hum Mol Genet

A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues

Proc Natl Acad Sci USA

A novel dystrophin isoform is required for normal retinal electrophysiology

Hum Mol Genet

Dp140: a novel 140 kDa CNS transcript from the dystrophin locus

Hum Mol Genet

Characterization of a 4.8kb transcript from the Duchenne muscular dystrophy locus expressed in Schwannoma cells

Hum Mol Genet

Dystrophinopathies

X chromosome-linked muscular dystrophy (mdx) in the mouse

Proc Natl Acad Sci USA

The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs

Nature

Feline muscular dystrophy with dystrophin deficiency

Am J Pathol

Differential expression of dystrophin isoforms in strains of mdx mice with different mutations

Hum Mol Genet

The molecular basis of muscular dystrophy in the mdx mouse: a point mutation

Science

Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity

Nature

Contraction-induced injury to single permeabilized muscle fibres from mdx, transgenic mdx, and control mice

Am J Physiol Cell Physiol

Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice

Hum Mol Genet

Dystrophin levels required for genetic correction of Duchenne muscular dystrophy

Basic Appl Myol

Very mild muscular dystrophy associated with the deletion of 46% of dystrophin

Nature

Dp71 can restore the dystrophin-associated glycoprotein complex in muscle but fails to prevent dystrophy

Nat Genet

Review
Novel therapies for Duchenne muscular dystrophy