Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ

Lamar, Kay Marie; Bogdanovich, Sasha; Gardner, Brandon; Gao, Quan; Miller, Tamari; Earley, Judy U.; Hadhazy, Michele; Vo, Andy H.; Wren, Lisa; Molkentin, Jeffery D.; McNally, Elizabeth M.

doi:10.1371/journal.pgen.1006019

Cited by 41 publications

(42 citation statements)

References 64 publications

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“…Third, the severity of disease can be modulated in a patient-specific fashion by disease modifiers located in other genes, while studies in mice are usually performed in a single genetic background. [201–203] Fourth, animal models typically only replicate certain aspects of human disease, with the severity, tissues affected, and onset of disease potentially differing from that in humans. [97] Fifth, the majority of drugs identified to work in animals fail to translate to the clinic due to differential toxicity between animal species.…”

Section: Disease Modeling With Engineered Human Musclementioning

confidence: 99%

“…[242,243] The severity of the DMD phenotype and efficacy of pharmacological treatments is significantly impacted by gene modifiers, [202] with effectors of TGF-beta signaling strongly implicated with disease pro-gression. [201,203,244,245] Together, the wide range of mutations and strong effects of gene modifiers on disease severity and response to treatment would greatly benefit from the use of patient-specific engineered muscle tissues to effectively model the disease and develop personalized therapeutic approaches.…”

Section: Disease Modeling With Engineered Human Musclementioning

confidence: 99%

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In Vitro Tissue‐Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease

Prabhu

Wang

Bursac

2018

Adv Healthcare Materials

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Healthy skeletal muscle possesses the extraordinary ability to regenerate in response to small-scale injuries; however, this self-repair capacity becomes overwhelmed with aging, genetic myopathies, and large muscle loss. The failure of small animal models to accurately replicate human muscle disease, injury and to predict clinically-relevant drug responses has driven the development of high fidelity in vitro skeletal muscle models. Herein, the progress made and challenges ahead in engineering biomimetic human skeletal muscle tissues that can recapitulate muscle development, genetic diseases, regeneration, and drug response is discussed. Bioengineering approaches used to improve engineered muscle structure and function as well as the functionality of satellite cells to allow modeling muscle regeneration in vitro are also highlighted. Next, a historical overview on the generation of skeletal muscle cells and tissues from human pluripotent stem cells, and a discussion on the potential of these approaches to model and treat genetic diseases such as Duchenne muscular dystrophy, is provided. Finally, the need to integrate multiorgan microphysiological systems to generate improved drug discovery technologies with the potential to complement or supersede current preclinical animal models of muscle disease is described.

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Section: Disease Modeling With Engineered Human Musclementioning

confidence: 99%

Section: Disease Modeling With Engineered Human Musclementioning

confidence: 99%

In Vitro Tissue‐Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease

Prabhu

Wang

Bursac

2018

Adv Healthcare Materials

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“…http://dx.doi.org/10.1101/286500 doi: bioRxiv preprint first posted online Mar. 23, 2018; which acts in a concerted fashion with protective modifiers such as Latent TGF-β binding protein (LTBP4) and Annexins 1 and 6 31,32 . The combinatorial effects of such modifiers, whether they are additive, synergistic or even opposing in action, represent a new paradigm for lessening disease phenotypes.…”

Section: E)mentioning

confidence: 99%

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

Kemaladewi

Lindsay

et al. 2018

Preprint

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Introductory paragraphIdentification of protective and/or pathogenic genetic modifiers provides important insight into the heterogeneity of disease presentations in individuals affected by neuromuscular disorders (NMDs), despite having well-defined pathogenic variants. Targeting modifier genes to improve disease phenotypes could be especially beneficial in cases where the causative genes are large, structurally complex and the mutations are heterogeneous. Here, we report a mutation-independent strategy to upregulate expression of a compensatory disease-modifying gene in Congenital Muscular Dystrophy type 1A (MDC1A) using a CRISPR/dCas9-based transcriptional activation system. MDC1A is caused by nonfunctional Laminin α2, which compromises muscle fibers stability and axon myelination in peripheral nerves 1. Transgenic overexpression of Lama1, encoding a structurally similar protein Laminin α1, ameliorates muscle wasting and paralysis in the MDC1A mouse models, demonstrating its role as a protective disease modifier 2. Yet, upregulation of Lama1 as a postnatal gene therapy is hampered by its large size, which exceeds the current genome packaging capacity of clinically relevant delivery vehicles such as adeno-associated viral vectors (AAVs). In this study, we sought to upregulate Lama1 using CRISPR/dCas9-based transcriptional activation system, comprised of catalytically inactive S. aureus Cas9 (dCas9) fused to VP64 transactivation domains and sgRNAs targeting the Lama1 promoter. We first demonstrated robust upregulation of Lama1 in myoblasts, and following AAV9-mediated intramuscular delivery, in skeletal muscles of dy2j/dy2j mouse model of MDC1A.We therefore assessed whether systemic upregulation of Lama1 would yield therapeutic benefits in dy2j/dy2j mice. When the intervention was started early in pre-symptomatic dy2j/dy2j mice, Lama1 upregulation prevented muscle fibrosis and hindlimb paralysis. An important question for future therapeutic approaches for a variety of disorders concerns the therapeutic window and phenotypic reversibility. This is particularly true for muscular dystrophies as it has long been hypothesized that fibrotic changes in skeletal muscle represent an irreversible disease state that would impair any therapeutic intervention at advanced stages of the disease. Here, we demonstrate that dystrophic features and disease progression were significantly improved and partially reversed when the treatment was initiated in symptomatic 3-week old dy2j/dy2j mice with already-apparent hind limb paralysis and significant muscle fibrosis.Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR/dCas9-mediated modulation of a disease modifier gene, which opens up an entirely new and mutation-independent treatment approach for all MDC1A patients. Moreover, this treatment strategy provides evidence that muscle fibrosis can be reversible, thus extending the therapeutic window for this disorder. Our data provide a proof-of-concept strategy that can be applied to a variety of disease modifier genes and a powerful therapeutic approach for various inherited and acquired diseases.

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“…Specifically, the IAAM protein bound more latent TGFβ than the VTTT allele [45], which would effectively limit the levels of free TGFβ in injured muscle. In addition, LTBP4 can be considered a multi-TGFβ family ligand binding protein, as it also binds and sequesters the latent forms of myostatin and GDF11, a protein highly related to myostatin [46], further enhancing its anti-wasting role in dystrophic muscle.…”

Section: Ltbp4 Modifies Availability Of Tgfβ and Myostatinmentioning

confidence: 99%

“…In addition, indirect approaches rely, among others, on modulation of LTBP4. Upregulation of the protective LTBP4 allele in dystrophic myofibers improved performance and partially corrected histopathology of dystrophin-deficient murine muscles [46]. Although indirect, LTBP4-involving strategies have the advantage of encompassing the latent forms of all TGFβ ligand isoforms and potentially myostatin.…”

Section: Genetic Modifiers In the Context Of Novel Drug Developmentmentioning

confidence: 99%

Outside in: The matrix as a modifier of muscular dystrophy

Quattrocelli

Spencer

McNally

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein’s function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFβ binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting.

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Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ

Cited by 41 publications

References 64 publications

In Vitro Tissue‐Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease

In Vitro Tissue‐Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

Outside in: The matrix as a modifier of muscular dystrophy

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