Isin Sinem Bagci

All Publications

• Practical considerations relevant to treatment with the gene therapy beremagene geperpavec-svdt for dystrophic epidermolysis bullosa. The Journal of dermatological treatment Paller, A. S., Guide, S. V., Ayala, D., Gonzalez, M. E., Lucky, A. W., Bagci, I. S., Marinkovich, M. P. 2024; 35 (1): 2350232

  Abstract

  Dystrophic epidermolysis bullosa (DEB), a rare genetic skin disease caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (COL7), is characterized by skin blistering, scarring, and extracutaneous manifestations that markedly reduce patient quality-of-life. Beremagene geperpavec-svdt ('B-VEC') is a gene therapy employing a non-integrating, replication-defective herpes simplex virus type 1 (HSV-1)-based vector encoding two copies of full-length human COL7A1 to restore COL7 protein after topical administration to DEB wounds. B-VEC was approved in the United States in 2023 as the first topical gene therapy and the first approved treatment for DEB. However, few providers have experience with use of this gene therapy.Data was obtained through literature review and the experience of providers who participated in the B-VEC clinical study or initiated treatment after B-VEC approval.This review discusses the burden of disease, describes the clinical trial outcomes of B-VEC, and provides physician and patient/caregiver recommendations as a practical guide for the real-world use of B-VEC, which can be administered in-office or at the patient's home.By continuing to optimize the practical aspects of B-VEC administration, the focus will continue to shift to patient-centric considerations and improved patient outcomes.

  View details for DOI 10.1080/09546634.2024.2350232

  View details for PubMedID 38724041

• Divergent in situ expression of IL-31 and IL-31RA between bullous pemphigoid and pemphigus vulgaris. Experimental dermatology Ergun, E. Z., Aoki, R., Horváth, O. N., Hartmann, D., Satoh, T. K., Calabrese, L., Aksu, A. E., Gürel, M. S., Manav, V., Flaig, M. J., Sárdy, M., Ruzicka, T., French, L. E., Bağcı, I. S. 2023

  Abstract

  Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two major autoimmune blistering skin diseases. Unlike PV, BP is accompanied by intense pruritus, suggesting possible involvement of the pruritogenic cytokine IL-31. However, the underlying mechanisms of the clinical difference between BP and PV in terms of pruritus are not fully understood. To compare the expression levels of IL-31 and its receptor IL-31RA in the lesional skin, including peripheral nerves in BP and PV patients, immunohistochemical staining for IL-31 and IL-31RA was performed in skin samples of BP and PV patients and healthy controls (HC). The IL-31RA-expressing area in epidermis and peripheral nerves was analysed using ImageJ and the percentage of positive cells for IL-31/IL-31RA in dermal infiltrating cells was manually quantified. Quantitative analyses revealed that IL-31/IL-31RA expressions in the epidermis and dermal infiltrate were significantly increased in BP compared to PV and HC. The difference between BP and PV became more obvious when advanced bullous lesions were compared. Peripheral nerves in BP lesions presented significantly higher IL-31RA expression compared to PV lesions. In conclusion, we found significantly augmented expressions of IL-31/IL-31RA in BP lesions, including peripheral nerves, in comparison to PV. These results suggest a possible contribution of IL-31/IL-31RA signalling to the difference between BP and PV in the facilitation of pruritus and local skin inflammation, raising the possibility of therapeutic targeting of the IL-31/IL-31RA pathway in BP patients.

  View details for DOI 10.1111/exd.14842

  View details for PubMedID 37260420

• Indirect immunofluorescence for bullous pemphigoid using ex vivo confocal laser scanning microscopy. The Journal of dermatology Bagci, I. S., Ergun, E. Z., Avci, P., Aoki, R., Krammer, S., Vladimirova, G., Sardy, M., Ruzicka, T., Hartmann, D. 2023

  View details for DOI 10.1111/1346-8138.16773

  View details for PubMedID 36914975

• In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nature medicine Gurevich, I., Agarwal, P., Zhang, P., Dolorito, J. A., Oliver, S., Liu, H., Reitze, N., Sarma, N., Bagci, I. S., Sridhar, K., Kakarla, V., Yenamandra, V. K., O'Malley, M., Prisco, M., Tufa, S. F., Keene, D. R., South, A. P., Krishnan, S. M., Marinkovich, M. P. 2022

  Abstract

  Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain-severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

  View details for DOI 10.1038/s41591-022-01737-y

  View details for PubMedID 35347281

• Simultaneous immunofluorescence and histology in pemphigus vulgaris using ex vivo confocal laser scanning microscopy. Journal of biophotonics Bagci, I. S., Aoki, R., Vladimirova, G., Sardy, M., Ruzicka, T., French, L. E., Hartmann, D. 2021

  Abstract

  BACKGROUND: Ex vivo confocal laser scanning microscopy (ex vivo CLSM) provides rapid, high-resolution imaging and immunofluorescence examinations of the excised tissues.OBJECTIVES: Evaluating the applicability of ex vivo CLSM in histomorphological and direct immunofluorescence (DIF) examination of pemphigus vulgaris (PV).METHODS: 20 PV sections were stained with fluorescent-labelled anti- IgG and anti-C3 using various dilutions and incubation periods. Subsequently, the determined ideal staining protocol was applied on 20 additional PV and 20 control sections.RESULTS: Ex vivo CLSM identified intraepidermal blisters and acantholytic cells in 80% and 60% of PV patients, respectively. The sensitivity of ex vivo CLSM in detecting intraepidermal fluorescence was 90% both with IgG and C3. The specificity of staining for IgG and C3 was 70% and 90%, respectively.CONCLUSION: Histomorphological and immunofluorescence features of PV could be detected within the same ex vivo CSLM session showing a comparable performance to conventional histopathology and DIF microscopy. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbio.202000509

  View details for PubMedID 33491324

• In vivo examination of healthy human skin after short-time treatment with moisturizers using confocal Raman spectroscopy and optical coherence tomography: Preliminary observations. Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI) Ruini, C., Kendziora, B., Ergun, E. Z., Sattler, E., Gust, C., French, L. E., Bağcı, I. S., Hartmann, D. 2021

  Abstract

  Skin is our barrier against environmental damage. Moisturizers are widely used to increase hydration and barrier integrity of the skin; however, there are contrasting observations on their in vivo effects in real-life settings. In cosmetic studies, corneometers and tewameters are traditionally used to assess skin hydration. In this study, two novel noninvasive diagnostic techniques, optical coherence tomography (OCT) and confocal Raman spectroscopy, were used to analyze stratum corneum and epidermal thickness (ET), water content, blood flow in function of depth, skin roughness, attenuation coefficient, natural moisturizing factor, ceramides and free fatty acids, cholesterol, urea, and lactates in 20 female subjects aged between 30 and 45 before and after 2 weeks application of a commercially available moisturizing lotion on one forearm. The untreated forearm served as control. A third measurement was conducted 1 week after cessation of moisturizing to verify whether the changes in the analyzed parameters persisted. We noticed a reduction in skin roughness, an increase in ceramides and free fatty acids and a not statistically significant increase in ET. As a conclusion, short time moisturizing appears insufficient to provide significant changes in skin morphology and composition, as assessed by OCT and RS. Novel noninvasive imaging methods are suitable for the evaluation of skin response to topical moisturizers. Further studies on larger sample size and longer treatment schedules are needed to analyze changes under treatment with moisturizers and to standardize the use of novel noninvasive diagnostic techniques.

  View details for DOI 10.1111/srt.13101

  View details for PubMedID 34555219

• New generation diagnostics in inflammatory skin diseases: immunofluorescence and histopathological assessment using ex vivo confocal laser scanning microscopy in cutaneous lupus erythematosuss. Experimental dermatology Bagci, I. S., Aoki, R., Vladimirova, G., Ergun, E., Ruzicka, T., Sardy, M., French, L. E., Hartmann, D. 2020

  Abstract

  BACKGROUND: Ex vivo confocal laser scanning microscopy (CLSM) offers real-time examination of excised tissue in reflectance, fluorescence and digital hematoxylin-eosin (H&E)-like staining modes enabling application of fluorescent-labelled antibodies.OBJECTIVES: To assess the diagnostic performance of ex vivo CLSM in identifying histopathological features and lupus band test in cutaneous lupus erythematosus (CLE) with comparison to conventional histopathology and direct immunofluorescence (DIF).MATERIAL AND METHODS: 72 sections of 18 CLE patients were stained with acridine orange (AO), anti-IgG, -IgM and -IgA; 21 control samples were stained with AO. Subsequently, ex vivo CLSM examination of all samples was performed in reflectance, fluorescence and digital H&E-like staining modes.RESULTS: Superficial and deep perivascular inflammatory infiltration (94.4%), interface dermatitis (88.9%), spongiosis (83.3%) and vacuolar degeneration (77.7%) were the most common features detected with ex vivo CLSM. Kappa test revealed a level of agreement ranging within "perfect" to "good" between ex vivo CLSM and conventional histopathology. ROC analysis showed that the combination of perivascular infiltration, interface dermatitis and spongiosis detected by ex vivo CLSM has the potential to distinguish between CLE and controls. Basement membrane immunoreactivity with IgG, IgM and IgA was identified in 88.8% (n=15), 55.5% (n=10) and 55.5% (n=10) of the CLE samples using ex vivo CLSM, respectively. Whereas, DIF showed IgG, IgM and IgA positivity in 94.4% (n=17), 100% (n=18) and 88.9% (n=16) of patients, respectively.CONCLUSION: Ex vivo CLSM enables simultaneous histopathological and immunofluorescence examination in CLE showing a high agreement with conventional histopathology, albeit with a lower performance than conventional DIF.

  View details for DOI 10.1111/exd.14265

  View details for PubMedID 33345402

• Immunofluorescence and histopathological assessment using ex-vivo confocal laser scanning microscopy in lichen planus. Journal of biophotonics Bağcı, I. S., Aoki, R. n., Krammer, S. n., Vladimirova, G. n., Ruzicka, T. n., Sárdy, M. n., French, L. E., Hartmann, D. n. 2020: e202000328

  Abstract

  Ex-vivo confocal laser scanning microscopy (CLSM) provides rapid, high-resolution imaging, fluorescence detection and digital hematoxylin-eosin (H&E)-like staining.Assessing the performance of ex-vivo CLSM in identifying histomorphology and immunoreactivity in lichen planus (LP) and comparing its accuracy with conventional histopathology and direct immunofluorescence (DIF).33 sections of 17 LP patients stained with acridine orange (AO) and FITC-labelled anti-fibrinogen antibody and 21 control samples stained with AO were examined using ex-vivo CLSM.Ex-vivo CLSM was in perfect agreement with conventional histopathology in identifying interface dermatitis, vacuolar degeneration and band-like infiltration. ROC analysis showed that the presence of vacuolar degeneration, interface dermatitis and band-like infiltration was useful to distinguish LP sections from controls (p<0.0001). The detection rates of fibrinogen deposition using DIF and ex-vivo CLSM were 93.8% and 62.5%, respectively.Ex-vivo CLSM enables histopathological and immunofluorescence examination in LP with the advantage of digital H&E-like staining. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbio.202000328

  View details for PubMedID 33025741