Single-dose CRISPR–Cas9 therapy extends lifespan of mice with Hutchinson–Gilford progeria syndrome

Beyret, Ergin; Liao, Hsin-Kai; Yamamoto, Masaaki; Hernández-Benítez, Reyna; Fu, Yunpeng; Erikson, Galina; Reddy, Pradeep; Belmonte, Juan Carlos Izpisúa

doi:10.1038/s41591-019-0343-4

Cited by 132 publications

(115 citation statements)

References 20 publications

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“…When this ASO was administered to mice, a reduction in progerin expression was observed in murine tissues, highlighting the potential therapeutic use of ASOs in HGPS. Recently, for the first time, two papers have shown the benefit of CRISPR-therapies in vivo [85,86]. Injecting gRNAs into HGPS-Cas9 mice, via facial vein or intraperitoneally, both significantly increase lifespan of progeroid mice.…”

Section: Current Therapeutic Strategiesmentioning

confidence: 99%

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Kreienkamp

Gonzalo

2020

Cells

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Hutchinson–Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although HGPS does not totally recapitulate normal aging, it does harbor many similarities to the normal aging process, with patients also developing cardiovascular disease, alopecia, bone and joint abnormalities, and adipose changes. It is unsurprising, then, that as physicians and scientists have searched for treatments for HGPS, they have targeted many pathways known to be involved in normal aging, including inflammation, DNA damage, epigenetic changes, and stem cell exhaustion. Although less studied at a mechanistic level, severe metabolic problems are observed in HGPS patients. Interestingly, new research in animal models of HGPS has demonstrated impressive lifespan improvements secondary to metabolic interventions. As such, further understanding metabolism, its contribution to HGPS, and its therapeutic potential has far-reaching ramifications for this disease still lacking a robust treatment strategy.

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Section: Current Therapeutic Strategiesmentioning

confidence: 99%

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Kreienkamp

Gonzalo

2020

Cells

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“…The emergence of CRISPR/Cas9 has created new possibilities for gene therapy by making precise genome modifications possible in cultured cells and animal studies. 17,[20][21][22][45][46][47][48][49] Currently, gene editing based on CRISPR-Cas9 has been widely investigated to correct mutations of the dystrophin gene in Duchenne muscular dystrophy (DMD) patients and demonstrated a promising option for treatment of DMD in the future. 16,[18][19][20][50][51][52][53][54][55][56][57][58][59] Affection of grip strength by intramuscular injection of virus or recombinant protein into gastrocnemius muscle has been previously reported.…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-Mediated miR-29b Editing as a Treatment of Different Types of Muscle Atrophy in Mice

Wang

Hua

et al. 2020

Molecular Therapy

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Muscle atrophy is the loss of skeletal muscle mass and strength in response to diverse catabolic stimuli. At present, no effective treatments except exercise have been shown to reduce muscle atrophy clinically. Here, we report that CRISPR/Cas9-mediated genome editing through local injection into gastrocnemius muscles or tibialis anterior muscle efficiently targets the biogenesis processing sites in pre-miR-29b. In vivo, this CRISPR-based treatment prevented the muscle atrophy induced by angiotensin II (AngII), immobilization, and denervation via activation of the AKT-FOXO3A-mTOR signaling pathway and protected against AngII-induced myocyte apoptosis in mice, leading to significantly increased exercise capacity. Our work establishes CRISPR/Cas9-based gene targeting on miRNA as a potential durable therapy for the treatment of muscle atrophy and expands the strategies available interrogating miRNA function in vivo.

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“…We simply encourage instructors to make the students think about human applications of genetic techniques in terms of equity, accessibility, beneficence, consent and safety. A possible approach may be to first highlight a real-life example of gene therapies that have shown impressive rescues of orphan diseases in human infants or mouse models (Beyret et al, 2019;Mendell et al, 2017). The reversal of color-blindness, which used a similar viral delivery technique in adult squirrel monkeys, can be interesting for discussion in comparison (Mancuso et al, 2009).…”

Section: Medical Versus Enhancementmentioning

confidence: 99%

Bringing immersive science to undergraduate laboratory courses using CRISPR gene knockouts in frogs and butterflies

Martin

Wolcott

O’Connell

2020

Journal of Experimental Biology

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The use of CRISPR/Cas9 for gene editing offers new opportunities for biology students to perform genuine research exploring the gene-to-phenotype relationship. It is important to introduce the next generation of scientists, health practitioners and other members of society to the technical and ethical aspects of gene editing. Here, we share our experience leading hands-on undergraduate laboratory classes, where students formulate hypotheses regarding the roles of candidate genes involved in development, perform loss-of-function experiments using programmable nucleases and analyze the phenotypic effects of mosaic mutant animals. This is enabled by the use of the amphibian Xenopus laevis and the butterfly Vanessa cardui, two organisms that reliably yield hundreds of large and freshly fertilized eggs in a scalable manner. Frogs and butterflies also present opportunities to teach key biological concepts about gene regulation and development. To complement these practical aspects, we describe learning activities aimed at equipping students with a broad understanding of genome editing techniques, their application in fundamental and translational research, and the bioethical challenges they raise. Overall, our work supports the introduction of CRISPR technology into undergraduate classrooms and, when coupled with classroom undergraduate research experiences, enables hypothesis-driven research by undergraduates.

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Single-dose CRISPR–Cas9 therapy extends lifespan of mice with Hutchinson–Gilford progeria syndrome

Cited by 132 publications

References 20 publications

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

CRISPR/Cas9-Mediated miR-29b Editing as a Treatment of Different Types of Muscle Atrophy in Mice

Bringing immersive science to undergraduate laboratory courses using CRISPR gene knockouts in frogs and butterflies

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