Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy

Abreu, Nicolas J.; Waldrop, Megan A.

doi:10.1002/ppul.25055

Cited by 36 publications

(34 citation statements)

References 102 publications

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“…Still, only 14% of RNase-H-based ASOs and 20–40% of other ASO subclasses were tested in minipigs for non-rodent toxicity studies. ASOs are also of interest for pediatric indications, including neuromuscular diseases [ 34 , 35 , 36 ], such as spinal muscular atrophy [ 37 ] and Duchenne muscular dystrophy [ 38 ], which have already been treated successfully [ 6 ]. Moreover, ASOs are also being explored for the treatment of several other diseases in children such as retinopathy of prematurity [ 39 ], leukodystrophies [ 40 ], and inherited lung diseases [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Valenzuela

Tardiveau²,

Ayuso

et al. 2021

Pharmaceutics

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The adult Göttingen Minipig is an acknowledged model for safety assessment of antisense oligonucleotide (ASO) drugs developed for adult indications. To assess whether the juvenile Göttingen Minipig is also a suitable nonclinical model for pediatric safety assessment of ASOs, we performed an 8-week repeat-dose toxicity study in different age groups of minipigs ranging from 1 to 50 days of age. The animals received a weekly dose of a phosphorothioated locked-nucleic-acid-based ASO that was assessed previously for toxicity in adult minipigs. The endpoints included toxicokinetic parameters, in-life monitoring, clinical pathology, and histopathology. Additionally, the ontogeny of key nucleases involved in ASO metabolism and pharmacologic activity was investigated using quantitative polymerase chain reaction and nuclease activity assays. Similar clinical chemistry and toxicity findings were observed; however, differences in plasma and tissue exposures as well as pharmacologic activity were seen in the juvenile minipigs when compared with the adult data. The ontogeny study revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. These data indicate that the juvenile Göttingen Minipig is a promising nonclinical model for safety assessment of ASOs intended to treat disease in the human pediatric population.

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Section: Introductionmentioning

confidence: 99%

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Valenzuela

Tardiveau²,

Ayuso

et al. 2021

Pharmaceutics

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“…Transplantation of ex vivo edited stem cells has the potential to generate new healthy myofibers, while in vivo gene therapy, although most effective before extensive loss of muscle mass, has demonstrated the most dramatic and widespread effects in animal models (6). Multiple in vivo gene therapy human clinical trials are currently underway (14). In vivo CRISPR-Cas9mediated exon skipping, to ultimately yield truncated yet functional dystrophin, ameliorated pathology in both mouse and canine models of Duchenne muscular dystrophy (DMD) (12,(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy

Raimondo

Mooney

2021

Sci. Adv.

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Chronic inflammation contributes to the pathogenesis of all muscular dystrophies. Inflammatory T cells damage muscle, while regulatory T cells (Tregs) promote regeneration. We hypothesized that providing anti-inflammatory cytokines in dystrophic muscle would promote proregenerative immune phenotypes and improve function. Primary T cells from dystrophic (mdx) mice responded appropriately to inflammatory or suppressive cytokines. Subsequently, interleukin-4 (IL-4)– or IL-10–conjugated gold nanoparticles (PA4, PA10) were injected into chronically injured, aged, mdx muscle. PA4 and PA10 increased T cell recruitment, with PA4 doubling CD4+/CD8− T cells versus controls. Further, 50% of CD4+/CD8− T cells were immunosuppressive Tregs following PA4, versus 20% in controls. Concomitant with Treg recruitment, muscles exhibited increased fiber area and fourfold increases in contraction force and velocity versus controls. The ability of PA4 to shift immune responses, and improve dystrophic muscle function, suggests that immunomodulatory treatment may benefit many genetically diverse muscular dystrophies, all of which share inflammatory pathology.

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“…[3][4][5] Several other promising gene therapies for hemophilia, Duchenne's muscular dystrophy (DMD), immunodeficiency, and Pompe disease are also progressing through clinical trials. [6][7][8][9] All of these therapies have demonstrated that gene delivery can be a lifesaving treatment for patients where other treatment mechanisms have failed. 4 However, several issues have arisen in regards to LV and AAV vehicles, including high treatment costs (e.g., $2M for Zolgensma®), safety concerns, and relatively low transduction efficiencies in some patients.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Analysis of the Innate Immune Response toin vitroTransfection of Plasmid DNA

Warga

Tucker

Harris

et al. 2021

Preprint

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The innate immune response to cytosolic DNA is intended to protect the host from viral infections, but it can also inhibit the delivery and expression of therapeutic transgenes in gene and cell therapies. The goal of this work was to use mRNA-sequencing to reveal correlations between the transfection efficiencies of four cell types (PC-3, Jurkat, HEK-293T, and primary CD3+ T cells) and their innate immune responses to nonviral gene delivery. Overall, the highest transfection efficiency was observed in HEK-293T cells (87%), which upregulated only 142 genes with no known anti-viral functions. Lipofection upregulated a much larger number (n = 1,057) of cytokine-stimulated genes (CSGs) in PC-3 cells, which also exhibited a significantly lower transfection efficiency. However, the addition of serum during Lipofection and electroporation significantly increased transfection efficiencies and decreased the number of upregulated genes in PC-3 cells. Finally, while Lipofection of Jurkat and Primary T cells only upregulated a few genes, several anti-viral CSGs that were absent in HEK and upregulated in PC-3 cells were observed to be constitutively expressed in T cells, which may explain their relatively low Lipofection efficiencies (8-21%). Indeed, overexpression of one such CSG (IFI16) significantly decreased transfection efficiency in HEK cells to 33%.

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Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy

Cited by 36 publications

References 102 publications

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy

Transcriptomic Analysis of the Innate Immune Response toin vitroTransfection of Plasmid DNA

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