Cytosine Deaminase Base Editing to Restore COL7A1 in Dystrophic Epidermolysis Bullosa Human: Murine Skin Model

Naso, G.; Gkazi, Athina Soragia; Georgiadis, Christos; Jayarajan, Vignesh; Jacków, J.; Fleck, Roland A.; Allison, Leanne; Ogunbiyi, Olumide; McGrath, John A.; Ilić, Duško; Di, Wei‐Li; Petrova, Anastasia; Qasim, Waseem

doi:10.1016/j.xjidi.2023.100191

Cited by 10 publications

(5 citation statements)

References 78 publications

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“…Furthermore, intradermal injection of BE-treated patient fibroblasts in immunodeficient mice revealed the correct deposition of C7 between the epidermis and dermis [145]. Naso et al used mRNA synthesised from a plasmid encoding a 3rd generation cytosine base editor as well as a synthetic sgRNA specifically engineered for an optimised targeting window to edit RDEB patient-induced pluripotent stem cells (iPSC) and fibroblasts [172]. According to next-generation sequencing (NGS), around 59 and 45% of alleles were successfully edited, respectively.…”

Section: Cas9 Variants and Their Impact On Editing Specificitymentioning

confidence: 99%

“…Although the signal remained patchy, C7 levels were greatly improved when compared to grafts engineered with untreated patient fibroblasts. Furthermore, transmission electron microscopy (TEM) revealed the presence of anchoring fibrils (AF) at around 50% of the levels detected in WT control grafts [172]. Brooks et al targeted patient fibroblasts harbouring a mutation in COL7A1 with the novel ABE8e adenosine base editor system.…”

Section: Cas9 Variants and Their Impact On Editing Specificitymentioning

confidence: 99%

“…BE is clearly a powerful gene editing tool, as evidenced by the fact that it has entered the clinical trial phase [174]. Unfortunately, no trials for EB are currently on the way, although the general suitability as well as the relative safety of BE for gene editing in EB patient cells has been demonstrated by the groups mentioned above [145,171,172]. However, two main issues are still worth noting.…”

Section: Cas9 Variants and Their Impact On Editing Specificitymentioning

confidence: 99%

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Emerging Gene Therapeutics for Epidermolysis Bullosa under Development

Bischof,

Hierl,

Koller

2024

IJMS

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The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress. Causal for this severe condition are genetic mutations in genes, leading to the functional impairment, reduction, or absence of the encoded protein within the skin’s basement membrane zone connecting the epidermis to the underlying dermis. The major burden of affected families justifies the development of long-lasting and curative therapies operating at the genomic level. The landscape of causal therapies for EB is steadily expanding due to recent breakthroughs in the gene therapy field, providing promising outcomes for patients suffering from this severe disease. Currently, two gene therapeutic approaches show promise for EB. The clinically more advanced gene replacement strategy was successfully applied in severe EB forms, leading to a ground-breaking in vivo gene therapy product named beremagene geperpavec (B-VEC) recently approved from the US Food and Drug Administration (FDA). In addition, the continuous innovations in both designer nucleases and gene editing technologies enable the efficient and potentially safe repair of mutations in EB in a potentially permanent manner, inspiring researchers in the field to define and reach new milestones in the therapy of EB.

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Section: Cas9 Variants and Their Impact On Editing Specificitymentioning

confidence: 99%

Section: Cas9 Variants and Their Impact On Editing Specificitymentioning

confidence: 99%

Section: Cas9 Variants and Their Impact On Editing Specificitymentioning

confidence: 99%

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Emerging Gene Therapeutics for Epidermolysis Bullosa under Development

Bischof,

Hierl,

Koller

2024

IJMS

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Section: Gene Therapymentioning

confidence: 99%

“…33 Similarly, CBE has been applied to correct COL7A1 variants in RDEB-derived primary fibroblasts and iPSCs, with restoration of C7 and AFs, highlighting the future translational potential of this approach. 34 Besides base editing, the advent of search-and-replace genome editing has expanded to encompass correction of a wider collection of COL7A1 variants using prime editors (PE), which contain a reverse transcriptase domain and a prime editing guide RNA to attain any site-specific edit. 35 In a preclinical study by Hong et al, both BE (ABEmax) and PE (PE3) were used to edit the COL7A1 gene in primary RDEB fibroblasts.…”

Section: Gene Editingmentioning

confidence: 99%

Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects

Hou,

del Agua,

Lwin

et al. 2023

TCRM

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Dystrophic epidermolysis bullosa (DEB) is one of the major types of EB, a rare hereditary group of trauma-induced blistering skin disorders. DEB is caused by inherited pathogenic variants in the COL7A1 gene, which encodes type VII collagen, the major component of anchoring fibrils which maintain adhesion between the outer epidermis and underlying dermis. DEB can be subclassified into dominant (DDEB) and recessive (RDEB) forms. Generally, DDEB has a milder phenotype, while RDEB patients often have more extensive blistering, chronic inflammation, skin fibrosis, and a propensity for squamous cell carcinoma development, collectively impacting on daily activities and life expectancy. At present, best practice treatments are mostly supportive, and thus there is a considerable burden of disease with unmet therapeutic need. Over the last 20 years, considerable translational research efforts have focused on either trying to cure DEB by direct correction of the COL7A1 gene pathology, or by modifying secondary inflammation to lessen phenotypic severity and improve patient symptoms such as poor wound healing, itch, and pain. In this review, we provide an overview and update on various therapeutic innovations for DEB, including gene therapy, cell-based therapy, protein therapy, and disease-modifying and symptomatic control agents. We outline the progress and challenges for each treatment modality and identify likely prospects for future clinical impact.

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