Gene and Cell Therapy for Muscular Dystrophies: Are We Getting There?

Galli, Francessco; Bragg, Laricia; Meggiolaro, Linda; Rossi, Maira; Caffarini, Miriam; Naz, Naila; Santoleri, Sabrina; Cossu, Giulio

doi:10.1089/hum.2018.151

Cited by 16 publications

(13 citation statements)

References 54 publications

(54 reference statements)

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“…In recent years, the number of clinical trials in which AAVs have been used for in vivo gene therapy has steadily increased [73]. It still remains challenging to achieve expression of an effective CRISPR/Cas system at therapeutic levels.…”

Section: Therapeutic Outlook For Crispr/cas-mediated Ex Vivo and Imentioning

confidence: 99%

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

Raaijmakers

Ripken

Ausems

et al. 2019

IJMS

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CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the DMPK/DM1-AS gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in DMPK. Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients.

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Section: Therapeutic Outlook For Crispr/cas-mediated Ex Vivo and Imentioning

confidence: 99%

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

Raaijmakers

Ripken

Ausems

et al. 2019

IJMS

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“…Each strategy has its own benefits and potential caveats. Dystrophin restoration-based strategies, such as termination codon read-through and exon-skipping, are only applicable to a specific subset of DMD patients, and gene therapy is limited by poor targeting and low efficiency in fibrotic dystrophic muscle and challenges in virus production and systemic delivery (11,15). Truncated micro-dystrophin and utrophin overexpression strategies will not recapitulate the benefit of the full-length dystrophin.…”

Section: Introductionmentioning

confidence: 99%

The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy

Guiraud¹,

Edwards²,

Babbs³

et al. 2019

Human Molecular Genetics

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Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Several therapeutic modalities are currently in clinical trials but none will achieve maximum functional rescue and full disease correction. Therefore, we explored the potential of combining the benefits of dystrophin with increases of utrophin, an autosomal paralogue of dystrophin. Utrophin and dystrophin can be co-expressed and co-localized at the same muscle membrane. Wild-type (wt) levels of dystrophin are not significantly affected by a moderate increase of utrophin whereas higher levels of utrophin reduce wt dystrophin, suggesting a finite number of actin binding sites at the sarcolemma. Thus, utrophin upregulation strategies may be applied to the more mildly affected Becker patients with lower dystrophin levels. Whereas increased dystrophin in wt animals does not offer functional improvement, overexpression of utrophin in wt mice results in a significant supra-functional benefit over wt. These findings highlight an additive benefit of the combined therapy and potential new unique roles of utrophin. Finally, we show a 30% restoration of wt dystrophin levels, using exon-skipping, together with increased utrophin levels restores dystrophic muscle function to wt levels offering greater therapeutic benefit than either single approach alone. Thus, this combination therapy results in additive functional benefit and paves the way for potential future combinations of dystrophin- and utrophin-based strategies.

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“…Only b-thalassemia was considered, but other pathologies can be treated by gene therapy such as sickle-cell disease, severe combined immunodeficiency, Wiskott-Aldrich syndrome, muscular dystrophy, or chronic granulomatous disease. 17 Treating more patients would lower the average cost per patient of gene therapy. The manufacturing cost decrease depending on the duration of equipment amortization was compared: 5 versus 10 years.…”

Section: Resultsmentioning

confidence: 99%

“…Necker Hospital purchased the lentiviral vector in quantities established a priori to ensure transfusion independence; the vector was re-engineered by the transplant team with highly skilled human resources, requirements in safety, quality efficacy, and regulatory compliance to advanced therapy medicinal products and Good Manufacturing Practice demands. [16][17][18] Patients' genetic characteristics also had an impact: gene therapy patients were aged on average 18 years, and three of the four patients had b E /b 0 genotypes, b 0 mutations being more difficult to treat than b + . 10 At the moment, preparation and procedure costs are higher for gene therapy than for HSCT.…”

Section: Discussionmentioning

confidence: 99%

Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation

et al. 2019

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Seventy-five percent of patients with beta thalassemia (b-thalassemia) do not have human leukocyte antigen-matched siblings and until recently had no access to a curative treatment. Gene therapy is a promising treatment that can be proposed to these patients. This study estimates its cost and efficacy. In a monocentric retrospective study and cost-efficacy analysis, this study compared the two-year outcomes and costs of patients with b-thalassemia treated by gene therapy and hematopoietic stem-cell transplantation (HSCT). Grade III and grade IV complications, hospitalizations, and length of stay were extracted from the hospital discharge data. Costs were estimated from hospital accounting information and national cost studies. A total of seven patients with b-thalassemia treated between 2009 and 2016 were included, of whom four received gene therapy. Patients treated by gene therapy were older and had fewer complications and hospital admissions. Infectious complications were three times more frequent for patients treated with HSCT than for gene therapy. Average costs were e608,086 for patients treated by gene therapy and e215,571 for HSCT. The total cost of the vector was 48% of the total cost of gene therapy. Gene therapy as a curative alternative for patients lacking human leukocyte antigen-matched donors was costlier but resulted in fewer complications than HSCT.

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Gene and Cell Therapy for Muscular Dystrophies: Are We Getting There?

Cited by 16 publications

References 54 publications

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy

Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation

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