Article
Neurosciences
Nastasia Cardone, Valentina Taglietti, Serena Baratto, Kaouthar Kefi, Baptiste Periou, Ciryl Gitiaux, Christine Barnerias, Peggy Lafuste, France Leturcq Pharm, Juliette Nectoux Pharm, Chiara Panicucci, Isabelle Desguerre, Claudio Bruno, Francois-Jerome Authier, Chiara Fiorillo, Frederic Relaix, Edoardo Malfatti
Summary: In this study, we performed myopathologic analysis on muscle biopsies from DMD patients and found an increase in fibro-adipogenic progenitors, which contribute to fibrotic progression and lipid deposition. At the same time, there was a decline in muscle regenerative capacity, which was strongly correlated with compromised activation and expansion of muscle stem cells. Additionally, our study revealed an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. These findings highlight the importance of muscle stem cell senescence as a pivotal readout for future therapeutic interventions.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Laura Salvadori, Sara Chiappalupi, Iva Arato, Francesca Mancuso, Mario Calvitti, Maria Cristina Marchetti, Francesca Riuzzi, Riccardo Calafiore, Giovanni Luca, Guglielmo Sorci
Summary: Injecting microencapsulated Sertoli cells (SeC) in dystrophic mice leads to recovery of muscle morphology and performance through anti-inflammatory effects and induction of utrophin. SeC stimulate myoblast proliferation, delay differentiation marker expression, inhibit fibroblast fibrogenic potential, and provide functional replacement of dystrophin in DMD myotubes.
Review
Anatomy & Morphology
Romina L. Filippelli, Natasha C. Chang
Summary: DMD is a devastating muscle degenerative disease with no effective cure. Defective expression of the DMD gene and impaired muscle stem cell function contribute to the progression of the disease. Restoring muscle stem cell function may serve as a viable regenerative medicine strategy to mitigate DMD.
CELLS TISSUES ORGANS
(2023)
Article
Multidisciplinary Sciences
Michael J. Stec, Qi Su, Christina Adler, Lance Zhang, David R. Golann, Naveen P. Khan, Lampros Panagis, S. Armando Villalta, Min Ni, Yi Wei, Johnathon R. Walls, Andrew J. Murphy, George D. Yancopoulos, Gurinder S. Atwal, Sandra Kleiner, Gabor Halasz, Mark W. Sleeman
Summary: Using spatial transcriptomics and single-cell RNA sequencing datasets, a high-resolution cellular and molecular spatial atlas of the severely dystrophic D2-mdx mouse model was generated. Clustering analysis revealed the nonuniform distribution of unique cell populations associated with multiple regenerative timepoints, faithfully recapitulating the asynchronous regeneration observed in human DMD muscle. Through spatiotemporal gene expression signatures, it was found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and identifying targetable pathways for DMD therapy within discrete microenvironments. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Maria Sofia Falzarano, Martina Mietto, Fernanda Fortunato, Marianna Farne, Fernanda Martini, Pierpaolo Ala, Rita Selvatici, Francesco Muntoni, Alessandra Ferlini
Summary: This study investigated the transcription dynamics and spatial localization of the dystrophin (DMD) gene in DMD patients. The results showed significantly reduced DMD mRNA amount in the patients' cells and muscle biopsies, with a shift towards localization in the nuclei. This abnormal compartmentalization of mutant DMD mRNA contributes to the poor abundance and availability of dystrophin messenger in the cytoplasm.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Zhanguo Gao, Aiping Lu, Alexes C. Daquinag, Yongmei Yu, Matthieu Huard, Chieh Tseng, Xueqin Gao, Johnny Huard, Mikhail G. Kolonin
Summary: DMD, caused by the loss of dystrophin, leads to reduced muscle regeneration and accumulation of fibroadipogenic progenitors (FAPs) causing muscle damage. Targeting MSC-derived FAPs through genetic or pharmacologic methods in mouse models of DMD showed significant improvement in muscle function without affecting fibrosis. This suggests that depleting pathogenic MSCs could be a potential strategy for delaying muscle dysfunction in DMD.
Review
Cell Biology
Shanshan Yao, Zihao Chen, Yuanyuan Yu, Ning Zhang, Hewen Jiang, Ge Zhang, Zongkang Zhang, Baoting Zhang
Summary: Duchenne muscular dystrophy is a lethal neuromuscular disorder caused by the absence of dystrophin protein, with no cure currently available. The standard of care involves glucocorticoids treatments for symptom relief. Therapeutic strategies focus on restoring dystrophin function and targeting downstream pathological changes like inflammation and fibrosis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Veronica Pini, Virginie Mariot, Julie Dumonceaux, John Counsell, Helen C. O'Neill, Sarah Farmer, Francesco Conti, Francesco Muntoni
Summary: By using CRISPR/Cas9, this study demonstrates the restoration of DMD duplications and reveals that high transient expression of Cas9 can bypass the requirement of continuous expression, providing important insights for future therapeutic approaches for in vivo dystrophin restoration.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Martina Sandona, Federica Esposito, Anna Cargnoni, Antonietta Silini, Pietro Romele, Ornella Parolini, Valentina Saccone
Summary: This study demonstrates that the secretome and extracellular vesicles derived from mesenchymal stromal cells from the amniotic membrane (hAMSCs) can promote muscle regeneration by stimulating proliferation and differentiation of muscle stem cells. It also shows that these factors can modulate the muscle stem cell niche and reduce fibrosis and muscle exhaustion. These findings suggest a potential novel treatment for Duchenne muscular dystrophy (DMD).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Silvia Consalvi, Luca Tucciarone, Elisa Macri, Marco De Bardi, Mario Picozza, Illari Salvatori, Alessandra Renzini, Sergio Valente, Antonello Mai, Viviana Moresi, Pier Lorenzo Puri
Summary: Late-stage mdx FAPs exhibit abnormal HDAC activity and genome-wide alterations of histone acetylation that cannot be fully reversed by HDACi. HDACi show general resistance in inducing H3K9/14 hyperacetylation in late-stage mdx FAPs, but is effective in reducing promoter acetylation and blunting SASP gene activation.
Article
Cell Biology
Laura Young, William Morrison, Craig Campbell, Emma C. Moore, Michel G. Arsenault, Athan G. Dial, Sean Ng, Catherine A. Bellissimo, Christopher G. R. Perry, Vladimir Ljubicic, Adam P. Johnston
Summary: The study found the presence of cells with canonical markers of senescence in mouse models of Duchenne muscular dystrophy, particularly with more senescent cells associated with areas of inflammation in 8-week-old D2-mdx mice. These results provide new insights into the role of cellular senescence in dystrophic muscle.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2021)
Review
Cell Biology
Jimmy Massenet, Edward Gardner, Benedicte Chazaud, F. Jeffrey Dilworth
Summary: Muscle stem cells respond to muscle injury by integrating environmental cues to mediate regeneration, with changes in gene expression facilitated by cell signaling from the muscle environment. Age and disease alter the muscle environment, impacting the efficiency of cell fate transitions required for muscle repair, but the reversible nature of epigenetic changes offers potential for improving muscle regeneration in myopathies.
Review
Oncology
Anna Rugowska, Alicja Starosta, Patryk Konieczny
Summary: Duchenne muscular dystrophy is a multisystem disorder that predominantly affects boys, caused by mutations in the DMD gene leading to changes in dystrophin expression profile. Loss of dystrophin results in muscle fiber disintegration and impaired regeneration, with associations to the loss of neuronal nitric oxide synthase.
CLINICAL EPIGENETICS
(2021)
Article
Biochemistry & Molecular Biology
Pierre Meyer, Cecile Notarnicola, Albano C. Meli, Stefan Matecki, Gerald Hugon, Jeremy Salvador, Mirna Khalil, Leonard Feasson, Claude Cances, Jerome Cottalorda, Isabelle Desguerre, Jean-Marie Cuisset, Pascal Sabouraud, Alain Lacampagne, Hugues Chevassus, Francois Rivier, Gilles Carnac
Summary: The study highlights the role of RYR1-mediated Ca2+ leakage in human DMD myotubes and suggests that RYR1 stabilization may be a promising therapeutic strategy for DMD. The findings indicate that impaired myogenic differentiation in DMD is associated with altered RYR1-mediated Ca2+ release and suggests a potential relationship between RYR1 dysfunction and motor impairment in patients with DMD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Michael Ziemba, Molly Barkhouse, Kitipong Uaesoontrachoon, Mamta Giri, Yetrib Hathout, Utkarsh J. Dang, Heather Gordish-Dressman, Kanneboyina Nagaraju, Eric P. Hoffman
Summary: Duchenne muscular dystrophy is caused by dystrophin deficiency, leading to downstream pathophysiological pathways that drive disability. Dystrophin replacement strategies may trigger these pathways, so combination therapies targeting multiple downstream pathways are crucial. Blood biomarkers could be used to assess drug combinations for treating DMD in both mouse models and human studies.
Article
Cell & Tissue Engineering
Basma Benabdallah, Cynthia Desaulniers-Langevin, Marie-Lyn Goyer, Chloe Colas, Chantale Maltais, Yuanyi Li, Jean V. Guimond, Jacques P. Tremblay, Elie Haddad, Christian Beausejour
Summary: In the study, it was found that autologous cell engraftment was tolerated while allogeneic grafts were rejected in humanized mouse models. Additionally, hiPSC-derived myogenic progenitor cells (MPCs) were not targeted by autologous T cells and natural killer cells in vitro. These findings suggest that hiPSC-derived MPCs may be tolerated in the presence of a competent human immune system.
STEM CELLS TRANSLATIONAL MEDICINE
(2021)
Article
Medicine, Research & Experimental
Antoine Guyon, Joel Rousseau, Francis-Gabriel Begin, Tom Bertin, Gabriel Lamothe, Jacques P. Tremblay
Summary: The A673T mutation discovered in an Icelandic population may reduce the risk of Alzheimer's disease, offering a potential strategy for slowing down disease progression in patients. By modifying the APP gene using Cas9n-deaminase enzyme, researchers successfully introduced this mutation and observed further effects in reducing Aβ peptide accumulation. This study demonstrates the potential of base editing techniques for treating genetic diseases like Alzheimer's.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2021)
Article
Biochemistry & Molecular Biology
Pouire Yameogo, Benjamin L. Duchene, Nathalie Majeau, Jacques P. Tremblay
Summary: CRISPR/Cas9 has opened up opportunities for genetic mutation correction therapies, yet long-term expression of the Cas9 gene can lead to off-target mutations and immune responses. A drug-inducible system was proposed to limit the expression of Cas9 nuclease. Through introducing a premature termination codon (PTC) and treatment with an aminoglycoside drug, it was demonstrated that Cas9 protein expression can be controlled effectively.
Article
Clinical Neurology
Cedric Happi Mbakam, Gabriel Lamothe, Guillaume Tremblay, Jacques P. Tremblay
Summary: The discovery of CRISPR-Cas system has brought new possibilities in precision medicine, particularly in the correction of Duchenne muscular dystrophy mutations. However, there are challenges to be addressed before its clinical application, such as off-target editing, efficient delivery, immune response, and vector issues.
Article
Genetics & Heredity
Guillaume Tremblay, Joel Rousseau, Cedric Happi Mbakam, Jacques P. Tremblay
Summary: Alzheimer's disease is caused by abnormal processing of APP, which leads to the formation of toxic beta-amyloid peptides. The A673T mutation prevents this processing and protects against AD development. This study demonstrates the use of CRISPR prime editing to precisely introduce the A673T mutation, offering potential for further research and treatment of AD.
Article
Biotechnology & Applied Microbiology
Nathalie Majeau, Annabelle Fortin-Archambault, Catherine Gerard, Joel Rousseau, Pouire Yameogo, Jacques P. Tremblay
Summary: In this study, a simple method was developed to load CRISPR ribonucleoproteins (RNPs) into extracellular vesicles (EVs), which successfully restored the expression of fluorescent proteins in muscle fibers and achieved deletion of the DMD gene in mdx mice. This provides new opportunities for treating DMD.
Review
Medicine, General & Internal
Cedric Happi Mbakam, Gabriel Lamothe, Jacques P. Tremblay
Summary: This article provides an update on therapeutic strategies for Duchenne muscular dystrophy (DMD), including approaches to restore dystrophin expression and ongoing experimental methods.
FRONTIERS IN MEDICINE
(2022)
Review
Pharmacology & Pharmacy
Kelly Godbout, Jacques P. Tremblay
Summary: Gene therapy has the potential to treat genetic diseases, but the delivery of CRISPR-derived technologies to specific organs remains a challenge. Lipid nanoparticles (LNPs) have emerged as a promising delivery method, but most of the cargo is trapped by the liver when delivered intravenously, and directly injecting them into organs requires more invasive procedures. Therefore, developing more specific LNPs is crucial for their future clinical use.
Article
Multidisciplinary Sciences
Pouire Yameogo, Nathalie Majeau, Cedric Happi Mbakam, Jacques P. Tremblay
Summary: The small size of CjCas9 allows for easier vectorization in in vivo gene therapy. However, it is generally less efficient than SpCas9 in generating indels in target genes, and the factors affecting its efficiency have not been determined. In our study, we found that the protein levels of CjCas9 expressed in HEK293T cells were significantly lower than those of SpCas9. We investigated the effect of proteasome inhibitors on CjCas9 protein stability and its efficiency in editing the FXN gene.
Article
Medicine, Research & Experimental
Cedric Happi Mbakam, Joel Rousseau, Yaoyao Lu, Anne Bigot, Kamel Mamchaoui, Vincent Mouly, Jacques P. Tremblay
Summary: In this study, researchers used CRISPR-Cas9 prime editing technology to correct a mutation in the DMD gene, resulting in improved editing efficiency and restoration of dystrophin protein expression. Optimization of the reverse transcription template sequence led to a significant increase in the editing percentage of the target nucleotide.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Biochemistry & Molecular Biology
Pouire Yameogo, Catherine Gerard, Nathalie Majeau, Jacques P. Tremblay
Summary: Most cases of Friedreich ataxia (FRDA) are caused by the elongation of the GAA repeat sequence in the FXN gene, resulting in a decrease in frataxin protein expression. Deletion of the GAA repeat using CRISPR/Cas9 technology has been shown to increase frataxin expression in vitro. This study aims to develop a FRDA treatment by deleting the GAA repeat using CRISPR/Cas9 technology with a single AAV vector expressing CjCas9 and two sgRNAs targeting the FXN gene. Although some GAA repeat deletions were observed in the heart and liver of mouse models, the editing rate was not sufficient to increase frataxin mRNA in the heart. However, the correlation between the editing rate and AAV distribution suggests the potential of using a better delivery tool for the CRISPR/Cas9 system in FRDA therapy.
Review
Cell Biology
Kelly Godbout, Jacques P. Tremblay
Summary: Gene therapy has great potential in treating inherited diseases by addressing the root genetic mutations. The discovery of CRISPR/Cas9 in 2012 paved the way for the development of gene therapies, including the recent technology called prime editing, which enables targeted alterations in the human genome. Prime editing has been attempted in various preclinical studies and shows promise as a treatment for genetic diseases.
Article
Genetics & Heredity
Camille Bouchard, Catherine Gerard, Solange Gni-fiene Yanyabe, Nathalie Majeau, Malek Aloui, Gabrielle Buisson, Pouire Yameogo, Vanessa Couture, Jacques P. Tremblay
Summary: This study aimed to find an optimized mouse model with a phenotype comparable to human patients for studying the impact of therapy. By comparing two mouse models (YG8sR and YG8-800) with healthy mice (Y47R) in behavior tests, significant differences were noticed between YG8sR mice injected with anti-FXN shRNA and YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing anti-FXN shRNA does increase their phenotype; YG8-800 mice have a phenotype comparable to the human ataxic phenotype.
Review
Medicine, General & Internal
Camille Bouchard, Jacques P. Tremblay
Summary: Dysferlinopathy is a disease caused by mutations in the DYSF gene, leading to a deficiency of dysferlin. It typically manifests during teenage years or young adulthood with symptoms such as loss of Achilles tendon reflexes and difficulty in standing on tiptoes or climbing stairs, followed by progressive muscle weakness. Recent advancements in tools and mouse models have improved diagnosis and research for this condition.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Medicine, General & Internal
Camille Bouchard, Jacques P. Tremblay
Summary: This review article presents 39 genes associated with limb-girdle muscular dystrophies (LGMDs), which can be inherited dominantly or recessively. The classification of LGMDs has evolved over time and now requires a mutation causing proximal muscle weakness found in multiple unrelated families. The article also discusses available and developing therapies for LGMDs, aiming to address the root cause of the disease instead of treating individual symptoms.
JOURNAL OF CLINICAL MEDICINE
(2023)