Results in Journal Journal of Investigative Dermatology: 35,344
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Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.07.035
Autosomal recessive congenital ichthyosis (ARCI) is a diverse group of cornification diseases associated with severe clinical complications and decreased quality of life. Germline mutations in the TGM1 gene, which encodes the enzyme transglutaminase 1 (TGM1), are the predominant cause of ARCI. These TGM1 mutations trigger the abnormal epidermal differentiation and impaired cutaneous barrier function observed in ARCI patients. Unfortunately, current ARCI therapies focus solely on symptomatic relief. Thus, there is a significant unmet need for therapeutic strategies aimed at correcting the TGM1 deficiency underlying ARCI. Here, we investigated the ability of KB105, a gene therapy vector encoding full-length human TGM1, to deliver functional human TGM1 to keratinocytes. In vitro, KB105 efficiently infected TGM1-deficient human keratinocytes, produced TGM1 protein, and rescued transglutaminase enzyme function. In vivo studies demonstrated that both single and repeated topical KB105 administration induced TGM1 protein expression in the target epidermal layer without triggering fibrosis, necrosis, or acute inflammation. Toxicity and biodistribution assessments upon repeat-dosing indicated that KB105 was well tolerated and restricted to the dose site. Overall, our results demonstrate that rescuing TGM1 deficiency in ARCI patients via topical KB105 application represents a promising strategy for safely and non-invasively treating this debilitating disease.
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.07.036
SummaryLong-term use of vismodegib is associated with treatment-emergent adverse drug reactions in clinical trials of patients with locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC). Treatment interruptions have been recommended for management of adverse drug reactions, but there is no clear guidance on the duration of those interruptions. A model-based evaluation was conducted to assess the impact of treatment interruptions on vismodegib efficacy. A tumor growth–inhibition model was developed and model-based simulations were performed to assess the proportion of patients achieving ≥30% reduction from baseline in tumor size (ie, proportion of responders) for various dosing schedules. The most conservative simulated scenario compared an intermittent dosing schedule of 12 weeks of vismodegib treatment followed by 8-week dosing interruption (repeated four times for a total duration of 80 weeks) versus 80 weeks of continuous dosing, which predicted a decrease in responders of –4.7% from 90.7% in laBCC and –3.7% from 63.0% in mBCC. These results demonstrated maintenance of vismodegib efficacy with the intermittent dosing schedule and support the recently approved recommendations of treatment interruptions of up to 8 weeks to manage tolerability in laBCC or mBCC patients in the vismodegib US prescribing information.
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.08.021
Skin squamous cell carcinomas (sSCCs) are a major cause of death in organ transplant patients (OTPs). Moreover, these neoplasms cause significant disease and economic burden and diminish patients' life quality. However, no effective treatment or intervention strategies are available. Here, we investigated the pathologic role of 5'-cap-translation, which is regulated by the formation of a translation initiation factor complex (TIFC) involving eukaryotic initiation factor 4E (eIF4E), eIF4G, and eIF4A1. We detected increased expression of phosphorylated-eIF4E (p-eIF4E), eIF4G, and eIF4A1 in human and murine sSCCs. The increase in these TIFC proteins was associated with enhanced eIF4E translation targets cyclin D1 and c-Myc. Conversely, siRNA-mediated depletion of eIF4E in human SCC cells (A431 & SCC-13) reduced eIF4G and proteins that regulate the cell cycle and proliferation. Notably, inhibition of Raf/MAPK/ERK signaling decreased eIF4E and p-eIF4E accumulation, significantly diminished cell cycle gene expression and tumor volume of A431-derived xenograft tumors. Furthermore, disrupting the eIF4E with an allosteric inhibitor of eIF4E/eIF4G binding, 4EGI-1, decreased the eIF4E/eIF4G expression and reduced proliferation. Finally, combined inhibition of the Raf/MAPK/ERK axis and eIF4E impaired 5'-cap-dependent translation and abrogated tumor cell proliferation. These data demonstrate that 5'-cap-dependent translation is a potential therapeutic target for abrogating lethal sSCCs in OTPs.
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.06.039
Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor ≥30% at 6 months or at surgery. Twenty-three patients, including one pre-treated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range 5.6-7.8), 5 patients (22%, 95%CI: 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95%CI 13-53%) using RECIST. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine (39%) patients discontinued the treatment due to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP.
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.09.002
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.07.031
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.05.122
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.08.018
Dystrophic epidermolysis bullosa (DEB) is a blistering skin disease caused by mutations in the gene COL7A1 encoding collagen VII. DEB can be inherited in a recessive (RDEB) or dominant (DDEB) manner and is associated with a high wound burden. Perpetual cycles of wounding and healing drive fibrosis in DDEB and RDEB, as well as the formation of a tumor-permissive microenvironment. Prolonging wound free episodes by improving the quality of wound healing would therefore confer substantial benefit for individuals with DEB. The collagenous domain of collagen VII is encoded by 82 in-frame exons, which makes splice-modulation therapies attractive for DEB. Indeed, antisense oligonucleotide (AON)-based exon skipping has shown promise for RDEB. However, the suitability of AONs for treatment of DDEB remains unexplored. Here, we developed QR-313 - a clinically applicable, potent AON specifically targeting exon73. We show the feasibility of topical delivery of QR-313 in a carbomer-composed gel for treatment of wounds to restore collagen VII abundance in human RDEB skin. Importantly, our data reveal that QR-313 also shows direct benefit for DDEB caused by exon73 mutations. Thus, the same topically applied therapeutic could be used to improve the wound healing quality in RDEB and DDEB.
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.09.001
The staphylococcal α-hemolysin (Hla) is critical for the pathogenesis of S. aureus skin and soft tissue infection (SSTI). Vaccine and infection-elicited Hla-specific antibodies protect against S. aureus-induced dermonecrosis, a key feature of SSTI. Many interactions between Hla and host cells have been identified that promote tissue damage and modulate immune responses, but the mechanisms by which protective adaptive responses "crosstalk" with innate responses at the tissue level are not clear. Using an established mouse model of SSTI and a newly developed histopathologic scoring system, we observed pathological correlates early after infection predicting protection against dermonecrosis by anti-Hla antibody. Protection was characterized by robust neutrophilic inflammation and compartmentalization of bacteria into discrete abscesses, which led to attenuation of dermonecrosis and enhancement of bacterial clearance later in infection. The ultimate outcome of infection was driven by recruitment of neutrophils within the first day after infection, but not later. Antibody-mediated protection was dependent on toxin neutralization, rather than enhanced opsonophagocytic killing by neutrophils or protection against toxin-mediated neutrophil lysis. Together, these findings advance our understanding of the mechanisms by which the early synergism between antibody-mediated toxin neutralization and tissue-specific neutrophilic inflammation preserve tissue integrity during infection.
Journal of Investigative Dermatology; doi:10.1016/j.jid.2020.06.037
Persistent and impaired inflammation impedes tissue healing and is characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. Here we show that in human wound-edge keratinocytes, the expression of miR-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, is upregulated during wound repair. However, their levels are lower in chronic ulcers than acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound-edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines/cytokines by keratinocytes. Thus, as crucial regulators of wound inflammation, lack of miR-19a/b and miR-20a may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.