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PRIMA-1MET/APR-246 can partially rescue in vitro cell adhesion of patient-derived junctional epidermolysis bullosa epidermal cells, independently of p63

ABSTRACT: The epithelial transcription factor p63 is critical for basal epithelial cell adhesion, wound healing and survival. Mutations on the TP63 gene are responsible for ectodermal dysplasia syndrome subgroup, characterized by severe skin erosions. Recently, we demonstrated that PRIMA-1MET/APR-246, a small compound able to re-activate mutated p53 in human cancers, can be repurposed to treat AEC patients with success. Since cell adhesion and differentiation were rescued by the compound, we hypothesized that PRIMA-1MET could alleviate altered cell adhesion found in other genodermatoses. Treatment of PRIMA-1METrescued cell adhesion in a dose-dependent manner of primary cells isolated from patients affected by junctional epidermolysis bullosa (JEB). A comparative RNA-seq analysis highlights mainly cell adhesion coupled to extracellular matrix (ECM) structure and organization and focal adhesion, strongly suggesting that the MOA of PRIMA-1MET is directly related to ECM rearrangement. There is no effective treatment available for severe JEB patient blistering. Repurposing of the molecule for JEB treatment could be translated rapidly to patients.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1020 | biostudies-other |

REPOSITORIES: biostudies-other

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A mouse model of generalized non-Herlitz junctional epidermolysis bullosa.

Project description:Epidermolysis bullosa (EB) is a class of intractable, rare, genetic disorders characterized by fragile skin and blister formation as a result of dermal-epidermal mechanical instability. EB presents with considerable clinical and molecular heterogeneity. Viable animal models of junctional EB (JEB), that both mimic the human disease and survive beyond the neonatal period, are needed. We identified a spontaneous, autosomal recessive mutation (Lamc2(jeb)) due to a murine leukemia virus long terminal repeat insertion in Lamc2 (laminin gamma2 gene) that results in a hypomorphic allele with reduced levels of LAMC2 protein. These mutant mice develop a progressive blistering disease validated at the gross and microscopic levels to closely resemble generalized non-Herlitz JEB. The Lamc2(jeb) mice display additional extracutaneous features such as loss of bone mineralization and abnormal teeth, as well as a respiratory phenotype that is recognized but not as well characterized in humans. This model faithfully recapitulates human JEB and provides an important preclinical tool to test therapeutic approaches.

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PDigenic Mutations in Junctional Epidermolysis Bullosa in An Iranian Family.

Project description:In this study, we describe one Iranian patient who was diagnosed with Epidermolysis Bullosa (EB) because of mutations in three candidate genes, including 3 mutations. Two missense mutations in the LAMA3 (D3134H) and LAMB3 (Y339H) genes and also, a synonymous mutation in the ITGB4 (H422H) gene were identified that leads to the Junctional-EBHerlitz (JEB-Herlitz) clinical phenotype. The patient had a heterozygous LAMA3 mutation combined with a heterozygous mutation in LAMB3. Our results propose that these mutations produce novel protein-coding transcripts which explain the JEB-Herlitz phenotype in the patient. Interestingly, this is the first report indicating that a digenic inheritance in the LAMA3 and LAMB3 which is responsible for JEB-Herlitz. Also, this is the first digenic inheritance recognized in the JEB-Herlitz family. This study provides a new way to clarify the molecular mechanisms of LAMA3 and LAMB3 genes in JEB-Herlitz.

| S-EPMC8588817 | biostudies-literature

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Project description: Not available

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Independent <i>COL17A1</i> Variants in Cats with Junctional Epidermolysis Bullosa.

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LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa.

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Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants.

Project description:IntroductionEpidermolysis bullosa (EB), a group of autosomal heritable blistering diseases, is characterised by extensive phenotypic variability with considerable morbidity and mortality. EB is classified into distinct subtypes depending on the location of blistering within the cutaneous dermoepidermal basement membrane zone. Ten genes are known to harbour mutations in the major types of EB, and the level of expression of these genes within the cutaneous basement membrane zone and in extracutaneous tissues, as well as the types and combinations of the mutations, explain in general terms the phenotypic variability.MethodsThe DebRA Molecular Diagnostics Laboratory, established in 1996 and supported in part by the patient advocacy organisation DebRA of America, has analysed over 1000 families with different forms of EB.ResultsIn total, 265 cases were submitted with the preliminary diagnosis of junctional or hemidesmosomal forms of EB. We found 393 mutant alleles in seven different genes, with 173 of the mutations being distinct and 71 previously unpublished.DiscussionThese findings attest to the clinical and molecular heterogeneity of the junctional and hemidesmosomal subtypes of EB. The results also reveal exceptions to the general rules on genotype-phenotype correlations, unusual phenotypes, and surprising genetics. Collectively, mutation analysis in different forms of EB provides the basis for improved classification with prognostic implications and for prenatal and preimplantation diagnosis in families at risk for recurrence of EB.

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Somatic correction of junctional epidermolysis bullosa by a highly recombinogenic AAV variant.

Project description:Definitive correction of disease causing mutations in somatic cells by homologous recombination (HR) is an attractive therapeutic approach for the treatment of genetic diseases. However, HR-based somatic gene therapy is limited by the low efficiency of gene targeting in mammalian cells and replicative senescence of primary cells ex vivo, forcing investigators to explore alternative strategies such as retro- and lentiviral gene transfer, or genome editing in induced pluripotent stem cells. Here, we report correction of mutations at the LAMA3 locus in primary keratinocytes derived from a patient affected by recessive inherited Herlitz junctional epidermolysis bullosa (H-JEB) disorder using recombinant adenoassociated virus (rAAV)-mediated HR. We identified a highly recombinogenic AAV serotype, AAV-DJ, that mediates efficient gene targeting in keratinocytes at clinically relevant frequencies with a low rate of random integration. Targeted H-JEB patient cells were selected based on restoration of adhesion phenotype, which eliminated the need for foreign sequences in repaired cells, enhancing the clinical use and safety profile of our approach. Corrected pools of primary cells assembled functional laminin-332 heterotrimer and fully reversed the blistering phenotype both in vitro and in skin grafts. The efficient targeting of the LAMA3 locus by AAV-DJ using phenotypic selection, together with the observed low frequency of off-target events, makes AAV-DJ based somatic cell targeting a promising strategy for ex vivo therapy for this severe and often lethal epithelial disorder.

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Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa.

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Detection of novel LAMC2 mutations in Herlitz junctional epidermolysis Bullosa.

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