Development of a CRISPR/Cas9-based therapy for Hutchinson–Gilford progeria syndrome

Santiago‐Fernández, Olaya; Osorio, Fernando G.; Quesada, Vı́ctor; Rodríguez, Francisco; Basso, Sammy; Maeso, Daniel; Rolas, Loïc; Barkaway, Anna; Nourshargh, Sussan; Folgueras, Alicia R.; Freije, José M.P.; López-Otı́n, Carlos

doi:10.1038/s41591-018-0338-6

Cited by 139 publications

(120 citation statements)

References 21 publications

(24 reference statements)

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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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“…[43][44][45] The CRISPR/Cas9 is a prokaryotic nucleic acid-based adaptive immune system to confer resistance to foreign genetic elements such as viral DNA or other foreign DNA. 46,47 Due to the guidance of sgRNA complementary to the target DNA sequence, Cas9 protein binds to a specific genomic locus and creates a site-specific DSB. 48 DSB initiates inaccurate but dominant NHEJ or low efficient but more precise HDR.…”

Section: Discussionmentioning

confidence: 99%

<p>Cas9 Mediated Correction of β-<em>catenin</em> Mutation and Restoring the Expression of Protein Phosphorylation in Colon Cancer HCT-116 Cells Decrease Cell Proliferation in vitro and Hamper Tumor Growth in Mice in vivo</p>

Li¹,

Li²,

Qu³

et al. 2020

OTT

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Colorectal cancer (CRC) is one of the major contributors to cancer mortality and morbidity. Finding strategies to fight against CRC is urgently required. Mutations in driver genes of APC or β-catenin play an important role in the occurrence and progression of CRC. In the present study, we jointly apply CRISPR/Cas9-sgRNA system and Single-stranded oligodeoxynucleotide (ssODN) as templates to correct a heterozygous ΔTCT deletion mutation of β-catenin present in a colon cancer cell line HCT-116. This method provides a potential strategy in gene therapy for cancer. Methods: A Cas9/β-catenin-sgRNA-eGFP co-expression vector was constructed and cotransfected with ssODN into HCT-116 cells. Mutation-corrected single-cell clones were sorted by FACS and judged by TA cloning and DNA sequencing. Effects of CRISPR/Cas9mediated correction were tested by real-time quantitative PCR, Western blotting, CCK8, EDU dyeing and cell-plated clones. Moreover, the growth of cell clones derived tumors was analyzed at nude mice xenografts. Results: CRISPR/Cas9-mediated β-catenin mutation correction resulted in the presence of TCT sequence and the re-expression of phosphorylation β-catenin at Ser45, which restored the normal function of phosphorylation β-catenin including reduction of the transportation of nuclear βcatenin and the expression of downstream c-myc, survivin. Significantly reduced cell growth was observed in β-catenin mutation-corrected cells. Mice xenografted with mutation-corrected HCT-116 cells showed significantly smaller tumor size than uncorrected xenografts. Conclusion: The data of this study documented that correction of the driven mutation by the combination of CRISPR/Cas9 and ssODN could greatly remedy the biological behavior of the cancer cell line, suggesting a potential application of this strategy in gene therapy of cancer.

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Development of a CRISPR/Cas9-based therapy for Hutchinson–Gilford progeria syndrome

Cited by 139 publications

References 21 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

<p>Cas9 Mediated Correction of β-<em>catenin</em> Mutation and Restoring the Expression of Protein Phosphorylation in Colon Cancer HCT-116 Cells Decrease Cell Proliferation in vitro and Hamper Tumor Growth in Mice in vivo</p>

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