Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa

Hong, Sung-Ah; Kim, Song-Ee; Lee, A-young; Hwang, Gue‐Ho; Kim, Jong Hoon; Iwata, Hiroaki; Kim, Soo Chan; Bae, Sangsu; Lee, Sang Eun

doi:10.1016/j.ymthe.2022.06.005

Cited by 29 publications

(24 citation statements)

References 65 publications

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“…The findings of the present study may also have some implications for the recent insights into the pathogenesis of IEB and the emerging potential for new therapies. For example, a recent study on applied Adenine Base Editors to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in fibroblasts of patients produced encouraging results ( 38 ). Another study identified several molecules that effectively increased the expression of type 7 collagen in keratinocytes, showing some therapeutic promise ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Diverse clinical and genetic characteristics of six cases of inherited epidermolysis bullosa

Yao

Yang

et al. 2022

Exp Ther Med

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Inherited epidermolysis bullosa (IEB) represents a group of rare genetic dermatoses comprising various phenotypes ranging from severe cutaneous and extracutaneous involvement to mild cutaneous fragility. Pathogenic variants have been identified in at least 20 genes responsible for IEB.In the present study, six cases of epidermolysis bullosa were recruited and subjected to a combination of clinical and genetic analysis. The family history of each case was surveyed. Whole exome sequencing was performed to identify the causative variation. The six patients showed typical EB symptoms. In all cases, WES detected the diagnostic variations of the COL7A1 or DST gene. A total of 10 variants were identified and verified. The findings of the present study further expanded the mutation spectrum of IEB, provided evidence for genetic counseling to the affected families, as well as highlighted the complexity of the pathogenesis of IEB.

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Section: Discussionmentioning

confidence: 99%

Diverse clinical and genetic characteristics of six cases of inherited epidermolysis bullosa

Yao

Yang

et al. 2022

Exp Ther Med

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“… 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. 36 The PE3 demonstrated higher editing efficiency compared to ABEmax, while both approaches successfully generated gene-edited skin grafts with C7 and AF restoration. 36 …”

Section: Gene Therapymentioning

confidence: 96%

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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“…Using optimized PEs, Jiang et al removed a 1.38-kb pathogenic insertion within the Fah gene and precisely repaired the deletion junction to restore FAH expression in the liver of a tyrosinemia mouse model (146). PEs have also been utilized to correct COL7A1 mutations in recessive dystrophic epidermolysis bullosa (RDEB) patient-derived fibroblasts, and functional rescue was observed (203). Correction of a disease-related mutation in a 1antitrypsin (A1AT)-deficient patient-derived induced pluripotent stem cells (iPSCs) has been achieved, and guide RNA-independent off-target mutations have not been detected in the genome (155).…”

Section: Crispr/cas Based Gene Therapy For Ieismentioning

confidence: 99%

Advances in CRISPR/Cas gene therapy for inborn errors of immunity

Liu

et al. 2023

Front. Immunol.

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Inborn errors of immunity (IEIs) are a group of inherited disorders caused by mutations in the protein-coding genes involved in innate and/or adaptive immunity. Hematopoietic stem cell transplantation (HSCT) is a mainstay definitive therapy for many severe IEIs. However, the lack of HLA-matched donors increases the risk of developing severe immunological complications. Gene therapy provides long-term clinical benefits and could be an attractive therapeutic strategy for IEIs. In this review, we describe the development and evolution of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) gene-editing systems, including double-strand break (DSB)-based gene editing and DSB-free base editing or prime editing systems. Here, we discuss the advances in and issues associated with CRISPR/Cas gene editing tools and their potential as therapeutic alternatives for IEIs. We also highlight the progress of preclinical studies for the treatment of human genetic diseases, including IEIs, using CRISR/Cas and ongoing clinical trials based on this versatile technology.

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Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa

Cited by 29 publications

References 65 publications

Diverse clinical and genetic characteristics of six cases of inherited epidermolysis bullosa

Diverse clinical and genetic characteristics of six cases of inherited epidermolysis bullosa

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

Advances in CRISPR/Cas gene therapy for inborn errors of immunity

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