The DMD gene and therapeutic approaches to restore dystrophin

Fortunato, F.; Farnè, Marianna; Ferlini, Alessandra

doi:10.1016/j.nmd.2021.08.004

Cited by 34 publications

(30 citation statements)

References 36 publications

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“…Cutting edge genetic medicines for DMD are in clinical trials or pre-clinical development including exon-skipping, gene therapy, and genome editing ( Fortunato et al, 2021 ). Gene replacement strategies using adeno-associated virus (AAV) to deliver a packageable form of dystrophin, called micro-dystrophin, are in numerous clinical trials following decades of preclinical studies demonstrating efficacy in skeletal muscles ( Gregorevic et al, 2004 ; Gregorevic et al, 2008 ; Duan, 2018 ; Crudele and Chamberlain, 2019 ; Ramos et al, 2019 ).…”

Section: Introduction: Duchenne Muscular Dystrophy and Chronic Inflam...mentioning

confidence: 99%

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

et al. 2022

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Duchenne muscular dystrophy (DMD) is a striated muscle degenerative disease due to loss of functional dystrophin protein. Loss of dystrophin results in susceptibility of muscle membranes to damage, leading to muscle degeneration and continuous inflammation and fibrosis that further exacerbate pathology. Long-term glucocorticoid receptor (GR) agonist treatment, the current standard-of-care for DMD, modestly improves prognosis but has serious side effects. The mineralocorticoid receptor (MR), a ligand-activated transcription factor present in many cell types, has been implicated as a therapeutic target for DMD. MR antagonists (MRAs) have fewer side effects than GR agonists and are used clinically for heart failure. MRA efficacy has recently been demonstrated for DMD cardiomyopathy and in preclinical studies, MRAs also alleviate dystrophic skeletal muscle pathology. MRAs lead to improvements in muscle force and membrane stability and reductions in degeneration, inflammation, and fibrosis in dystrophic muscles. Myofiber-specific MR knockout leads to most of these improvements, supporting an MR-dependent mechanism of action, but MRAs additionally stabilize myofiber membranes in an MR-independent manner. Immune cell MR signaling in dystrophic and acutely injured normal muscle contributes to wound healing, and myeloid-specific MR knockout is detrimental. More research is needed to fully elucidate MR signaling in striated muscle microenvironments. Direct comparisons of genomic and non-genomic effects of glucocorticoids and MRAs on skeletal muscles and heart will contribute to optimal temporal use of these drugs, since they compete for binding conserved receptors. Despite the advent of genetic medicines, therapies targeting inflammation and fibrosis will be necessary to achieve optimal patient outcomes.

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Section: Introduction: Duchenne Muscular Dystrophy and Chronic Inflam...mentioning

confidence: 99%

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

et al. 2022

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“…Myopathies (e.g., Duchenne’s muscular dystrophy (DMD) [ 55 , 56 ], Steinert’s myopathy [ 57 ], diseases related to a mutation in the RYR1 gene [ 58 ], and many others [ 59 ]) greatly affect the quality of life and the life expectancy of many patients. To eventually treat these patients, many researchers have developed drugs [ 60 ] or used gene therapy [ 61 , 62 ].…”

Section: Targeting the Musclesmentioning

confidence: 99%

Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy

Godbout

Tremblay

2022

Pharmaceutics

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Gene therapy holds great promise in the treatment of genetic diseases. It is now possible to make DNA modifications using the CRISPR system. However, a major problem remains: the delivery of these CRISPR-derived technologies to specific organs. Lipid nanoparticles (LNPs) have emerged as a very promising delivery method. However, when delivering LNPs intravenously, most of the cargo is trapped by the liver. Alternatively, injecting them directly into organs, such as the brain, requires more invasive procedures. Therefore, developing more specific LNPs is crucial for their future clinical use. Modifying the composition of the lipids in the LNPs allows more specific deliveries of the LNPs to some organs. In this review, we have identified the most effective compositions and proportions of lipids for LNPs to target specific organs, such as the brain, lungs, muscles, heart, liver, spleen, and bones.

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“…Neurological studies on humans have been, so far, mostly concentrated on the gene addition methods with approval of gene transfer therapy for spinal muscular atrophy, 21 and ongoing clinical studies in Duchene muscular dystrophy. [22][23][24] Early investigations of the use of ASOs in the treatment of Dravet syndrome are currently underway. Gene editing and base pair editing are still in the laboratory investigations stages.…”

Section: Gene Therapymentioning

confidence: 99%

US Food and Drug Administration Facilitated Pediatric Approval Programs: Application to Pediatric Neurological Disorders

et al. 2022

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Crucial time is often lost while waiting for approval of therapies for pediatric neurological disorders, many of which have aggressive manifestations with devastating effects. There are logistical, ethical, and financial impediments that face the studies needed to determine efficacy and safety of therapies in children. In this article, the authors present the Food and Drug Administration’s programs aimed at facilitating the development of pediatric drugs, focusing on their application to pediatric neurological disorders. They also provide examples of drugs that received, or are currently enrolled in, these programs. Reflecting upon the commonalities of drugs receiving these designations, the authors highlight underlying ethical issues related to pediatric drug development and emphasize the need for structured incentives to stimulate approval and production of drug therapies for pediatric neurology patients. By consolidating information that applies to drug approval of pediatric neurological disorders, stakeholders in drug development can enhance treatment development for these disorders.

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The DMD gene and therapeutic approaches to restore dystrophin

Cited by 34 publications

References 36 publications

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy

US Food and Drug Administration Facilitated Pediatric Approval Programs: Application to Pediatric Neurological Disorders

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