A gene therapy for inherited blindness using dCas9-VPR–mediated transcriptional activation

Böhm, Sonja; Splith, Victoria; Riedmayr, Lisa Maria; Rötzer, René D.; Gasparoni, Gilles; Nordström, Karl; Wagner, Johanna; Hinrichsmeyer, Klara Sonnie; Walter, Jörn; Wahl‐Schott, Christian; Fenske, Stefanie; Biel, Martin; Michalakis, Stylianos; Becirovic, Elvir

doi:10.1126/sciadv.aba5614

Cited by 38 publications

(26 citation statements)

References 38 publications

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“…CRISPR-based synthetic transcriptional control may lay the basis for personalized and precision medicine. Efficient transcription regulation mediated by CRISPR-mediated gene activation (CRISPRa) systems was demonstrated in vivo in the brain, liver, kidney and skeletal muscle as well as mouse model of human diseases including muscle dystrophy, diabetes, kidney and brain diseases using different delivery methods (84)(85)(86)(87). Preclinical models using dCas9-targeted transcription factor regulation have shown great promise for treating disorders such as Duchenne's muscular dystrophy, type 1 diabetes, acute kidney disease and retinitis pigmentosa (84,85,88).…”

Section: Crispr-mediated Control Of Transcription In Preclinical Modelsmentioning

confidence: 99%

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Schoger

Panàkovà

Zelarayán

2022

Front. Cardiovasc. Med.

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Molecular and genetic differences between individual cells within tissues underlie cellular heterogeneities defining organ physiology and function in homeostasis as well as in disease states. Transcriptional control of endogenous gene expression has been intensively studied for decades. Thanks to a fast-developing field of single cell genomics, we are facing an unprecedented leap in information available pertaining organ biology offering a comprehensive overview. The single-cell technologies that arose aided in resolving the precise cellular composition of many organ systems in the past years. Importantly, when applied to diseased tissues, the novel approaches have been immensely improving our understanding of the underlying pathophysiology of common human diseases. With this information, precise prediction of regulatory elements controlling gene expression upon perturbations in a given cell type or a specific context will be realistic. Simultaneously, the technological advances in CRISPR-mediated regulation of gene transcription as well as their application in the context of epigenome modulation, have opened up novel avenues for targeted therapy and personalized medicine. Here, we discuss the fast-paced advancements during the recent years and the applications thereof in the context of cardiac biology and common cardiac disease. The combination of single cell technologies and the deep knowledge of fundamental biology of the diseased heart together with the CRISPR-mediated modulation of gene regulatory networks will be instrumental in tailoring the right strategies for personalized and precision medicine in the near future. In this review, we provide a brief overview of how single cell transcriptomics has advanced our knowledge and paved the way for emerging CRISPR/Cas9-technologies in clinical applications in cardiac biomedicine.

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Section: Crispr-mediated Control Of Transcription In Preclinical Modelsmentioning

confidence: 99%

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Schoger

Panàkovà

Zelarayán

2022

Front. Cardiovasc. Med.

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“…In addition to using CRISPR/Cas9 for gene editing, there are several alternative approaches that utilize a dead (d)Cas9/gRNA to target a transcriptional regulator to the appropriate place in the genome. A recent exciting study used this approach to target the VPR transcriptional activator (dCas9-VPR) to the M-opsin gene ( Opn1mw ) with an Opn1mw -specific gRNA where it activates gene transcription ( Bohm et al, 2020 ). When dCas9-VPR/ Opn1mw -gRNA under the control of the rhodopsin promoter was delivered to the Rho ± retina, researchers observed expression of M-opsin in rods, and importantly, improvements in scotopic vision and retinal structure.…”

Section: Gene Therapy In the Retina And Cochleamentioning

confidence: 99%

Gene Therapy to the Retina and the Cochlea

et al. 2021

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Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic therapies for any of the several hundred known causative genes underlying inherited retinal and cochlear disorders has been of great interest. Recent exciting advances in gene therapy have shown promise for the clinical treatment of inherited retinal diseases, and while clinical gene therapies for cochlear disease are not yet available, research in the last several years has resulted in significant advancement in preclinical development for gene delivery to the cochlea. Furthermore, the development of somatic targeted genome editing using CRISPR/Cas9 has brought new possibilities for the treatment of dominant or gain-of-function disease. Here we discuss the current state of gene therapy for inherited diseases of the retina and cochlea with an eye toward areas that still need additional development.

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“…Alternatively, HSF4 mutants that lead to defective gene function can be restored by using CRISPR-activation (CRISPRa) approach. Such a technique has been successfully carried out in treating other inherited blindness [ 119 ]. The study showed that transactivation of photoreceptor-specific M-opsin (Opn1mw) resulted in prolonged retinal function and delayed retinal degradation in a mouse model.…”

Section: Future Perspectives and Concluding Remarksmentioning

confidence: 99%

More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases

et al. 2021

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Cells encounter a myriad of endogenous and exogenous stresses that could perturb cellular physiological processes. Therefore, cells are equipped with several adaptive and stress-response machinery to overcome and survive these insults. One such machinery is the heat shock response (HSR) program that is governed by the heat shock factors (HSFs) family in response towards elevated temperature, free radicals, oxidants, and heavy metals. HSF4 is a member of this HSFs family that could exist in two predominant isoforms, either the transcriptional repressor HSFa or transcriptional activator HSF4b. HSF4 is constitutively active due to the lack of oligomerization negative regulator domain. HSF4 has been demonstrated to play roles in several physiological processes and not only limited to regulating the classical heat shock- or stress-responsive transcriptional programs. In this review, we will revisit and delineate the recent updates on HSF4 molecular properties. We also comprehensively discuss the roles of HSF4 in health and diseases, particularly in lens cell development, cataract formation, and cancer pathogenesis. Finally, we will posit the potential direction of HSF4 future research that could enhance our knowledge on HSF4 molecular networks as well as physiological and pathophysiological functions.

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A gene therapy for inherited blindness using dCas9-VPR–mediated transcriptional activation

Cited by 38 publications

References 38 publications

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Gene Therapy to the Retina and the Cochlea

More Than Meets the Eye: Revisiting the Roles of Heat Shock Factor 4 in Health and Diseases

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