CRISPR Modeling and Correction of Cardiovascular Disease

Liu, Ning; Olson, Eric N.

doi:10.1161/circresaha.122.320496

Cited by 42 publications

(44 citation statements)

References 274 publications

(424 reference statements)

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“…Most therapies for DCM address the symptoms of the disease or target secondary effects, whereas the genetic mutations underlying the disease remain unchanged. CRISPR-Cas9 gene editing technologies, such as base editing (BE) (18)(19)(20) and prime editing (PE) (21), offer the potential to correct disease-causing mutations precisely and permanently and provide therapeutic approaches to treat cardiomyopathy (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy

et al. 2022

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Mutations in RNA binding motif protein 20 ( RBM20 ) are a common cause of familial dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine-rich (RS-rich) domain, which mediates nuclear localization. These mutations induce RBM20 mis-localization to form aberrant ribonucleoprotein (RNP) granules in the cytoplasm of cardiomyocytes and abnormal alternative splicing of cardiac genes, contributing to DCM. We used adenine base editing (ABE) and prime editing (PE) to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell (iPSC)–derived cardiomyocytes. Using ABE to correct RBM20 R634Q human iPSCs, we achieved 92% efficiency of A-to-G editing, which normalized alternative splicing of cardiac genes, restored nuclear localization of RBM20, and eliminated RNP granule formation. In addition, we developed a PE strategy to correct the RBM20 R636S mutation in iPSCs and observed A-to-C editing at 40% efficiency. To evaluate the potential of ABE for DCM treatment, we also created Rbm20 R636Q mutant mice. Homozygous (R636Q/R636Q) mice developed severe cardiac dysfunction, heart failure, and premature death. Systemic delivery of ABE components containing ABEmax-VRQR-SpCas9 and single-guide RNA by adeno-associated virus serotype 9 in these mice restored cardiac function as assessed by echocardiography and extended life span. As seen by RNA sequencing analysis, ABE correction rescued the cardiac transcriptional profile of treated R636Q/R636Q mice, compared to the abnormal gene expression seen in untreated mice. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.

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Section: Introductionmentioning

confidence: 99%

Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy

et al. 2022

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“…However, with the development of CRISPR/Cas9 technology, a combination of viral-based vector delivery systems and CRISPR/Cas9 systems could provide a target-specific and highly efficient strategy for in vivo transcriptional factor reprogramming [ 85 ]. It has been reported that the AAV-mediated CRISPR genome editing system has been used in many cardiovascular disease treatments with great progress [ 86 ]. In addition, encouragingly, AAV serotype1 was found to have selectivity towards cardiac fibroblasts, which could promote efficient reprogramming and potentially reduce the risk of insertional mutagenesis [ 87 ].…”

Section: Cardiac Reprogramming For Heart Regenerationmentioning

confidence: 99%

Advances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair

Liang

Paul

et al. 2022

Cells

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Continuous loss of cardiomyocytes (CMs) is one of the fundamental characteristics of many heart diseases, which eventually can lead to heart failure. Due to the limited proliferation ability of human adult CMs, treatment efficacy has been limited in terms of fully repairing damaged hearts. It has been shown that cell lineage conversion can be achieved by using cell reprogramming approaches, including human induced pluripotent stem cells (hiPSCs), providing a promising therapeutic for regenerative heart medicine. Recent studies using advanced cellular reprogramming-based techniques have also contributed some new strategies for regenerative heart repair. In this review, hiPSC-derived cell therapeutic methods are introduced, and the clinical setting challenges (maturation, engraftment, immune response, scalability, and tumorigenicity), with potential solutions, are discussed. Inspired by the iPSC reprogramming, the approaches of direct cell lineage conversion are merging, such as induced cardiomyocyte-like cells (iCMs) and induced cardiac progenitor cells (iCPCs) derived from fibroblasts, without induction of pluripotency. The studies of cellular and molecular pathways also reveal that epigenetic resetting is the essential mechanism of reprogramming and lineage conversion. Therefore, CRISPR techniques that can be repurposed for genomic or epigenetic editing become attractive approaches for cellular reprogramming. In addition, viral and non-viral delivery strategies that are utilized to achieve CM reprogramming will be introduced, and the therapeutic effects of iCMs or iCPCs on myocardial infarction will be compared. After the improvement of reprogramming efficiency by developing new techniques, reprogrammed iCPCs or iCMs will provide an alternative to hiPSC-based approaches for regenerative heart therapies, heart disease modeling, and new drug screening.

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“…Overall, the CRISPR-Cas9 system, with its variations, is considered a great promise for the treatment of human genetic diseases, including cardiovascular diseases, neurodegenerative disorders, and cancer [ 9 , 10 , 11 ], and to generate novel animal models of Alzheimer’s disease (AD) and related disorders [ 6 ]. In this work, we will provide a short historical perspective of the CRISPR-Cas9 system and discuss its advantages and limitations.…”

Section: Introductionmentioning

confidence: 99%

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Plano

Calabrese

Conoci

et al. 2022

IJMS

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Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders.

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CRISPR Modeling and Correction of Cardiovascular Disease

Cited by 42 publications

References 274 publications

Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy

Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy

Advances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

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