Epidermolysis Bullosa, Challenges and Novel Therapies

Open Access Journal of Public Health

Open Access Full Text Article Research Article Epidermolysis Bullosa, Challenges and Novel Therapies This article was published in the following Scient Open Access Journal: Open Access Journal of Public Health Received July 05, 2019; Accepted July 22, 2019; Published July 29, 2019

3 Mohammad Hossein Abbasi and Maliheh Structured Abstract Nobakht1,2,3* 1Physiology Research Center, Iran University of Background: Epidermolysis bullosa (EB) is a congenital and life threatening disease Medical Sciences, Tehran, Iran and a genetic disorder of connective tissue with a prevalence of 3500 patients in the United 2Anti-microbial Resistance Research Center, Iran States of America until 2016. There are four major congenital types of disease including University of Medical Sciences, Tehran, Iran simplex, junctional, dystrophic and a newer type, kindler-be syndrome. 3Department of Anatomy and Cell Biology, school of medicine, Iran University of Medical Sciences, Method: In order to obtain data for this review article we have searched databases and Tehran, Iran resources of PubMed and Scopus. The search keywords included Epidermolysis bullosa, EB, treatment, Gene therapy, hemi desmosome and Stem cell. First, we studied the titles and abstracts of articles, then we reviewed the full texts of more relevant studies and data extracted from them. Results: EB patients are at increased risk of death from their disease consequences before the third decent of them life. Gene correction and stem cell transplantation or combination of tissue engineering and gene therapy are modern suggested treatments for EB. This review spends to etiologies and mutations resulting in different types of the disease and efforts conducted in order to modify mutations, especially those affecting hemi desmosome structures in epidermal keratinocytes in different types of EB. Conclusion: In vitro gene therapy of keratinocyte stem cells and transplant them back to the skin as a novel suggested treatment option is expected to improve clinical features in EB patients. Application of viral vectors for gene therapy is restricted due to ethical issues and usage of non-viral vectors is more applicable for gene therapy in these patients. Authors conclude from previous researches that there is a proportional relation between numbers of each different subunits of hemi desmosome in its structure (disturbed in EB), which have been neglected and should be considered in future gene therapy researches. Keywords: Epidermolysis bullosa, EB, Gene therapy, Hemi desmosome, Stem cell

Graphical Abstract: (Figure 1)

Figure 1: hemi desmosome structure subunits and other connective structures of human skin are involved in pathophysiology of epidermolysis bullosa disease by genetic mutations; (1) mutations in keratins types 5 and 14 genes ( in cytoskeleton formation) have been reported in patients with simplex EB. (2) Plectin (a hemi desmosome component) gene mutation is a causative factor for simplex EB with muscular dystrophy. (3) CD151 is a modulating factor in hemi desmosome structure and mutation in CD151 gene, results in simplex EB. (4) α6 β4 integral protein is the most important component of hemi desmosome structure which is involved in the formation of the central core. Mutations in the α6 β4 gene *Corresponding author: Maliheh Nobakht, results in junctional EB. (5) Mutation in laminin 5 gene also results in junctional type of EB. (6) BP180 Physiology Research Center, Iran University is another subunit of hemi desmosome which its mutations are present in simplex EB and generalized of Medical Sciences, Tehran, Anti-microbial benign atrophic type of junctional EB. (7) Collagen 7 is a connecting factor located in the basement Resistance Research Center, Iran University membrane and its mutations have been suggested as the etiology of dystrophic EB. of Medical Sciences, Tehran, Department of Main mutation targets in different types of EB: 1) Anatomy And Cell Biology, school of medicine, Simplex Epidermolysis bullosa (EB) 2) Simplex EB with muscular dystrophy Iran University of Medical Sciences, Tehran, Iran, 3) Simplex EB 4) Junctional EB 5) Junctional EB (at LAM B3 chain) Tel: +14085942935, Email: [email protected] 6) Simplex EB AND generalized benign atrophic type of junctional EB 7) Dystrophic EB

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Citation: Maliheh Nobakht, Mohammad Hossein Abbasi (2019). Epidermolysis Bullosa, Challenges and Novel Therapies Page 2 of 9

Text Organization of the disease including benign, non-lethal and lethal types. Lethal junctional EB type manifests by wounds around mouth, Introduction eyes and nose which subsequently accompany by granulation Epidermolysis bullosa is a congenital and life threatening tissue formation. Furthermore systemic involvements such as disease and a genetic disorder of the connective tissue with a lesions on cornea, conjunctiva, tracheobronchial airways, mouth, prevalence of 3500 patients in the United States of America until pharynx and esophagus, rectum and mucosa of genitourinary system and also cough and respiratory disorders are present in including simplex, junctional, dystrophic and a newer form, this type of disease. These patients are at high risk of sepsis and kindler-be2016 [1]. Theresyndrome. are four Epidermolysis major congenital bullosa types(EB) patients of the disease are at death [9]. increased risk of death from their disease consequences, before 2) Dystrophic epidermolysis bullosa The third main type of the disease manifests by blisters which fewthe ageclinical of 30 therapeutic [2]. In spite options of numerous including researches wound dressing, conducted daily in remains atrophic scars after resolving. Milias (white papules, inspectionorder to find of woundsthe certain and treatment, analgesic treatmentsuntil now there [3,4]. is just some 1-4 mm in diameter) are the other complication due to lesions to hair follicles. Involvement of nails are also expected. Lesions EB classification history: [5]. on mucosal surfaces will result in some events including atresia and stenosis of esophagus, anal atresia, urethral atresia, phimosis Now a day, there are four major types of EB according to and corneal scar. Malnutrition and growth retardation are the numerous clinical and basic science researches done during other complications [10]. These patients owe the higher risk decades. Those types including: of involvement by SCC later in them life [11]. Furthermore, the 1) Simplex epidermolysis bullosa (EBS)

EBS subtype accompanies with mechanical fragility and dermal3) fibrosisKindler–be is another syndr complicationome in these patients [12]. blisters occur on the epidermis. Previously, EBS was named as Kindler syndrome is an autosomal recessive disease “epidermolytic”.then EBS categorized into basal and suprabasal manifests by photosensitivity, blistering resulted from trauma, subgroups, according to the site of defect within the epidermis. skin atrophy and poikiloderma. Especially in early stages of this 2) junctional epidermolysis bullosa (JEB) syndrome, clinical manifestations overlap with dystrophic type of epidermolysis bullosa, however currently kindler-be syndrome In JEB, blisters occur at the junction, known as lamina Lucida, consider as a distinct type of epidermolysis bullosa [13]. of the skin basement membrane zone (BMZ). In kindler syndrome, defects and reduplication in basement ) 3) dystrophic epidermolysis bullosa (DEB membrane zone have been shown by immunohistochemical In the past DEB was known as “dermolytic” EB in which and ultrastructural studies, leading to reduced cell proliferation, blistering arises within the upper segment of dermis. adhesion, spreading and undirected migration (multiple polarities cells). FFH1 (the main disrupted agent in kindler- 4) Kindler–be syndrome be syndrome) establishes some interactions between ECM and membranous agents (beta 1 and beta 3 proteins) at focal Kindler syndrome manifests uniquely among other subtypes of adhesions [14]. There is also evidences show the increased risk EB byIn 2008,photosensitivity Kindler-be andsyndrome blistering added that to developsthe EB classification. in multiple of cutaneous and laryngeal squamous cell carcinoma in patients segments of skin within and/or under the basement membrane with kindler syndrome [15]. zone (BMZ). 3 Diagnostic approach Four main types of EB The diagnosis of different types of the disease performs 1) Epidermolysis bullosa simplex by evaluation of mutations by means of molecular genetic testing.by firstly, If evaluationthe diagnosis of clinicaldidn’t establish features by of patientsmolecular and genetic then period by diffuse blisters all over the body; especially in upper testing, histologic evaluation of skin biopsy by means of direct andThe lower first extremities main type [6].of EB This that type initially of the manifests disease isin theneonatal most prevalent subtype in western countries with milder skin lesions in comparison with junctional and dystrophic types [7]. components.immunofluorescence Molecular (IF) studies or immunohistochemistryare the only accurate (IHC)and will perform in order to determine defects in specific cellular Epidermolysis bullosa simplex with muscular dystro- accepted method in order to diagnose and determine the type of disease phy is a variant of simplex type of EB 4 Manifests by diffuse skin blisters and muscular dystrophy in Current[16-21]. treatments older ages. This type of disease usually accompanies by pyloric Unfortunately, until now the treatment options for patients atresia or hypoplasia of enamel with EB is limited to the wound care and symptom relieve Junctional epidermolysis bullosa [8]. treatments in order to compensate the complications [17]. The second main type of the disease which contains of blisters strategies and also some nonspecific immunosuppressive arise inside the lamina Lucida layer of basement membrane. of genes responsible for occurrence of the disease resulted in Junctional EB classify into three categories based on the severity Numerous previous studies have focused on finding mutations

comprehensive classification of different types of EB according to Volume 2 • Issue 4 • 025 www.scientonline.org Open Access J Public Health Citation: Maliheh Nobakht, Mohammad Hossein Abbasi (2019). Epidermolysis Bullosa, Challenges and Novel Therapies Page 3 of 9 their clinical manifestations and suggested involved genes. One In EB simplex with muscular dystrophy, mutations of the other therapies suggested is the implication of cultured in genes responsible for the expression of plectin, a hemi stem cells to compensate the defect of keratinocytes in the desmosome subunit, have been suggested in this type of disease skin wounds; as well as using skin grafts for long term closure resulted in manifestations of epidermolysis bullosa simplex with therapy for treatment of EB, implication of retroviral vectors have muscular[8, 29]. In dystrophy,a previous proofedstudy, mutations the responsibility applied on of plectin this gene genes in of chronic wounds. In major of researches in the field of gene pathophysiology of this type of disease [30]. blind spot of those researches and an obstacle in the way of their clinicalkept those application. studies on hold [22]. So the usage of viral vectors is the 2) Junctional epidermolysis bullosa The etiological factors proposed for junctional EB contains of Until now, despite conducted efforts for medication therapy in EB, no drugs or certain therapies approved. Phenytoin or tetracycline drugs which act as anti-collagenases weren’t mutations in the genes encoding LAM B3 chain of laminin-332 [9]. effective. Some researchers showed improving results by using studiesThe old namesthat, some of laminin-332 of subunits were of ‘laminincellular 5,hemi nicein desmosome (BM-600), complexKalinin and including, epiligrin laminin [31,32].It 5 (epiligrin has been / indicatedKalinin / innicein) previous and in affected skin [7]. Usage of colchicine in epidermolysis bullosa TGFβ1 suppressors such as losartan, in order to reduce fibrosis integrin beta 4 are disturbed in this type of EB leading to lack of formation of hemi desmosome structure [33-36]. adherentacquisita resultedcovering in material favorable and clinical also outcomesa padding [23]. for maintenance Skin blisters In generalized benign atrophic type of junctional epidermolysis firstly should be lanced, evacuated and then dressed by a non- bullosa, mutations in another hemi desmosome subunit, bullous inof stabilitythose patients and integrity. and requirement Growth retardation of nutritional in children support. with Blood EB as an etiological factor[37]. transfusionshould draw and attention iron supplementation to consider the fluid are and main electrolyte options balanceto cure pemphigoid antigen 2 (BPAG2, BP180 or collagen 17) is reported anemia in these patients. Other nutritional supplementations for In a previous research, mutation applied on the intracellular these patients consist of calcium, vitamin D, carnitine, selenium domain of integrin beta 4, resulted in disconnection between and zinc. Prevention from hand contracture could be acquired integrin beta 4 and intracellular keratin plexus, manifested the by occupational therapy. Surgical therapies including repeating clinical features of junctional epidermolysis bullosa. This result

for improving proof the role of integrin beta 4 as an etiological factor of JEB nutritional status and quality of life in patients with epidermolysis 3) Dystrophic epidermolysis bullosa: [38]. bullosa)release of fingers from each other, gastrostomy ( known to be affected by DEB in order to reduce trauma are the In this type of disease, mutation in exon number 64 of COL7A1 other treatment[24]. and options. cesarean Appropriate delivery forplays the with fetuses less who trauma are gene have been suggested among the Iranian population [10]. to the skin should be chosen for these patients to minimize Mutation in collagen VII gene results in renal disorders, mesangial blistering especially at bony prominences. Abnormal wounds with prolonged process of healing must undergo biopsy in order by dystrophic epidermolysis bullosa[39].(Figure 1) proliferative diseases, PSGN and renal amyloidosis accompanying to rolling out of squamous cell carcinoma. Yearly evaluations of 4) Kindler–be syndrome echocardiogram and bone mineral density (BMD) should be done to identify dilated cardiomyopathy and osteoporosis respectively The main gene which its mutations take the responsibility [16]. In patients with EB who suffer from esophageal stenosis of kindler-be syndrome is FERMT1 gene that encodes fermitin (manifests by dysphagia or odynophagia), when esophageal family homolog-1 (FFH1). This family play role as a focal adhesion dilation is demanded, endoscopic dilation by means of balloon molecule and an actin cytoskeleton component. 37 different loss catheter or bougie and in more severe cases, usage of gastrostomy tube are recommended as the main treatment options [7]. kindler-be syndrome [14]. of function mutations on FERMT1 gene have been identified in 5. Genetic mutations in different types of EB Molecular and cellular intermediates in EB 1) Simplex epidermolysis bullosa Defects in hemi desmosome structure and formation: Overall as mentioned previously, disturbances in hemi desmosome structure subunits are probable etiological factors of in this type of disease EB especially in junctional type. By electron microscopy studies, Genetic disturbances in keratins 5 & 14 genes are present it has been proofed that hemi desmosome structures appear in [25]. Furthermore mutations in genes lower numbers at basal surface of keratinocytes of patients who responsible for expression of intracellular domains of BPAG a stabilizer component of hemi desmosome structure which suffer from junctional type of EB [33]. 180supports protein constructional has been also placement reported of[26]. integrin Mutations alpha in6 CD151,beta 4, also have been suggested as the etiological genetic disturbance in Subunits of hemi desmosome contains of plectin, integrin to be associated with simplex type of epidermolysis bullosa; This this type of disease [27]. A new mutation also recently reported collagenalpha 6 betaprotein) 4, BPAG1e and CD or 151 BP230 [40]. (epithelial isoform of bullous and results in a degradation-resistant N-terminally truncated pemphigoid antigen 1), BPAG2 or BP180 (a transmembrane mutation occurs in the initiation codon of kelch-like 24 protein subunits establish the connection between ECM (extra cellular matrix)Integrin and Alphaintracellular 6 beta 4 keratin and BP180 plexus are (keratinstwo hemi 5desmosome & 14, the kelch-like 24 protein. Kelch- like 24 protein is suggested to play main keratins in epithelial keratinocytes) [41] role in the turnover of intermediate filaments especially keratin 14 in keratinocytes [28]. Volume 2 • Issue 4 • 025 www.scientonline.org Open Access J Public Health Citation: Maliheh Nobakht, Mohammad Hossein Abbasi (2019). Epidermolysis Bullosa, Challenges and Novel Therapies Page 4 of 9

The formation of hemi desmosome structures initiate by the intracellular connections of integrin beta 4 are vital in hemi desmosomeof connections structure with laminin formation. 332 Theseand alpha intracellular 1 subunit), domains however are theattachment role as ofthe integrin core of alpha hemi 6 desmosome beta 4 subunit structure to plectin formation. [42] by targets of mutations in epidermolysis bullosa disease [55]. Thismediation connection of fibronectin make some III subunit changes of in integrin the molecular beta 4 [43],playsstructure of both plectin and integrin beta 4, which consolidate the whole the formation of hemi desmosome while its intracellular domains structure [44].Subsequently, integrin beta 4 connects to other In a similar way, BP 180 extracellular terminal is not vital in are. Furthermore, integrin beta 4 regulates the spatial placement hemiIntegrin desmosome Alpha subunit 6 beta 4called has four BP 180 pair[42]. of connecting domains placementof BP180 atover the the basolateral cellular membrane surface ofsurface keratinocytes [56]. and the desmosome structure absence of beta 4, results in disarrangement of BP180 subunits to(fibronectin integrin alpha type 6 III) beta for 4 attachmentthrough the tosecond other pair subunits of connecting of hemi Other factors mediate EB [45].Related domains on BP180 connects Connections between epidermal keratinocytes establish necessary for the formation and strength of hemi desmosome by desmosome structures; when these keratinocytes domain fibronectin III on integrin beta 4, a connection which is corneodesmosomes. Defects in these connections result in complex [46-48]. epidermolysisbecome cornified, bullosa desmosomes and palmoplantar modify keratoderma and transform diseases to The other hemi desmosome subunit BP 230, attaches on [57]. one hand to BP180 and from the other hand to intracellular Defects in desmosome structures are also suggested in integrincytokeratin alpha filaments. 6 beta 4 BP in 230order also to tightenconnects the to hemi the forthdesmosome pair of epidermolysis bullosa disease. In lethal acantholytic epidermolysis structureconnecting more. domain fibronectin III of cytoplasmic terminal of

[47]. have been suggested as an etiology of the disease results in BP 180 furthermore connects to integrin beta 4, bullosa, homozygous deletion at exon 20 of desmoplakin gene, BP230The and mutant plectin type subunits of integrin beta 4 especially in junctional cardiomyopathy as a manifestation of LAEB [58]. formation.type of EB, However is inefficient there in is makingnot any connectiondisturbance with in connection plectin and of 9 differentTransglutaminases types of proteins (protein with different glutamine- roles in catalytic γ - integrinBP180 subunits, beta 4 with results its pair, in defects alpha 6in integrin hemi desmosome [45]. structure glutamyltransferase, TGase, TG) consist of a family containing The spatial placement of integrin beta 4 as a transmembrane protein in the basolateral surfaces of keratinocytes cellular and also cellular signaling processes. The principal TG proteins membrane, is regulated by a membrane surface protein called thetypes spinous in epidermal and granular layer layersconsist of of epidermis TG1, TG2, and and also TG3 in andthe basalTG5, CD 151, which is known as the sponsor framework that supports layerdistributed and hair diffusely follicles. in this layer of skin [59].TG5 is present at spatial placement of the other subunits during hemi desmosome formation [49].Furthermore, up regulation of integrin beta 4 suggested as the cause of acral peeling skin syndromes and the results in higher expression of CD 151[40]. absenceIn many of this previous protein studies, resulting mutations in a clinical in situationTG5 gene resembling have been Plectin as another subunit connects to intracellular keratins types 5 & 14 in keratinocytes through its connecting domains epidermolysisMutations bullosain collagen simplex VII [59-62]. gene and its absence in skin [50]. keratinocytes in dystrophic type of epidermolysis bullosa Integrin beta 4 also connects through its extracellular terminal results in changes in micro environment of skin tissue leading [40].Therefore the to prolonged wound healing process with subsequent increased connection between intracellular keratin plexus and extracellular basementto extra cellular membrane matrix establish protein, by laminin mediation 332 of integrin beta 4 – of squamous cell carcinoma in skin, as the main reason of death plectin complex. amonginflammation these patients in those [63].wounds and increased risk of development In previous studies it has been indicated that the absence Oxidative stress and mitochondrial dysfunction play main of intracellular keratins leading to absence of integrin beta 4 roles in the pathophysiology of kindler-be syndrome. Oxidative betathrough 4 and phosphorylation disjunction of of beta beta 4 4 from at ser plectin 1354 and[51].In ser other 1362 cysteinestress indexes ligase) such show as altered GSSG/GSH levels ratio in (oxidizedthis disease. and Electron reduced finally results in endocytosis and down regulation of integrin microscopyglutathione), studies MDA (malondialdehyde) on keratinocytes andin skin GCL (gamma-glutamylbiopsies of these been suggested as factors which phosphorylate integrin beta 4 patients showed mitochondrial morphological abnormalities and atstudies, ser 1356 EGF and and ser PMA 1364, (phorbol result 12-myristatein a same output; 13-acetate) disturbance have derangements [64] in hemi desmosome formation and increase in cellular migration Previous studies Hemi desmosome formation and Gene therapies of for hemi desmosome[52].Hemi desmosomeformation [53]and formation 1a isoform is not of dependent plectin is disturbed hemi desmosome subunits genes: Plectin isoform to laminin-332 existence however plectin is a key component [54].Over all, the formation of this structure isn’t dependent to extracellularmore specific domains for hemi and desmosome connections structures of integrin in beta keratinocytes 4 (consist university1a is the mostof Vienna, specific after isoform preparation presents of culture in hemi-desmosome of keratinocytes structures in human skin. In a research performed in 2003 at

Volume 2 • Issue 4 • 025 www.scientonline.org Open Access J Public Health Citation: Maliheh Nobakht, Mohammad Hossein Abbasi (2019). Epidermolysis Bullosa, Challenges and Novel Therapies Page 5 of 9 involved by epidermolysis bullosa simplex with muscular continuously. Stem cells divide into two types. First, embryonic dystrophy, accompanied by lack of plectin gene (PLECTIN -/-), stem cells which originate from inner cell mass of blastocysts during embryonal development and second type, adult stem cells, containing plectin 1a gene. Results showed the increase in number located at different organs and play role in tissue repair. ofresearchers hemi desmosome transfected structures those cells on by cell plasmids surface PBK23 to the & normalPGR99 Stem cells are also located at hair follicles and are multi values (even in some keratinocytes was higher than normal in potential and has the ability to give rise to many types of cells number) and cellular connections established. Transfection of containing epidermal cells (keratinocytes). Hair follicle stem cells by other isoforms of plectin gene, didn’t resulted the same; cells mostly reside at bulge region which is located between the opening of sebaceous gland and the attachment site of arrector Furthermore, the expression of only intracellular terminal of pili muscle. These stem cells are important in compensating plectinindicates 1a thewas specificity not enough of 1ato result isoform in inthe human same result keratinocytes. and the the cellular defects (due to lack of junctions and occurrence of expression of whole gene is recommended [54]. wounds) in diseases such as epidermolysis bullosa. In fact among stem cells of skin tissue, hair follicle stem cells are more potential on keratinocytes with junctional EB; done by means of antibodies for replacing epidermal cells in diseases and injuries resulting in Furthermore in electron and fluorescent microscopy studies skin defect [69-71]. the normal values of intracellular keratins in comparison to Hair follicle stem cells are suggested to be capable of repair normalagainst keratinocytes. intracellular In cytokeratin junctional type filaments, of EB, hemi results desmosome showed of skin defects due to previous injuries and isolated hair follicle structures were down regulated to periphery of nucleus instead stem cells in a small biopsy are applicable to repair extensive of basolateral membrane surface of keratinocytes [65]. full thickness skin defects. This autologous transplantation overcomes major challenges regarding the use of stem cells in transfected stem cells of keratinocytes of a patient was suffering clinical application, because it avoids immune reactions and graft fromIn dystrophicanother study epidermolysis in 2014, researchers bullosa by at means Stanford of Universitylenti viral rejection and ethical concerns vectors in order to conduct gene therapy for collagen 7, resulted In a previous study, patients with recessive dystrophic in normal keratinocytes with potentials for repair and regenerate [72]. epidermolysis bullosa (RDEB) have been injected subcutaneously the skin [66]. and intravenously by a combination of keratinocyte-derived Epidermolysis bullosa aquisita is another subtype of EB. pluripotent stem cells and stem cells from RDEB patients skin Immunologic factors have been indicated as etiological factors (KC-iPSCs-MSC) converted to mesenchymal stromal cells. in this type of the disease including Anti bodies against collagen Those stem cells have been cultured in a media containing 7. TNF alpha levels are also increased in the serum of these 6-bromoindirubin-3’-oxime, activin A and bone morphogenetic protein 4. Results showed improvements in healing process of pathophysiology of this disease. patients indicates the immunologic and inflammatory aspects in in type 7 collagen presentation at dermoepidermal junction surfaceskin in RDEB of new knocked-out proliferated (immune-deficient) keratinocytes. Those Mice pluripotent and increase stem cells can obtain from bone marrow and even lonely implanted suppressorIn an attempt drugs such to cure as etanercept. EB, in 2016 Results at University showed decrease of Lübeck, in in skin tissue results in improves in clinical outcomes of those amountGerman of researchers skin lesions used and blisters anti TNF [67]. monoclonal ABs and TNF patients [73,74]. In an effort in order to replace the gene of integrin beta 4, Human embryonic stem cells (hESCs) derived keratinocytes keratinocytes with junctional epidermolysis bullosa with pyloric are suitable alternatives for traditionally used immortalized atresia transfected by integrin beta 4 gene recombinant cDNA. cell lines (i.e. HaCaT cell line) for stem cell mediated treatment of skin wound. In a previous study regarding mechanical stress notThis oriented gene therapy like other resulted subunits in orientation and remained of plectin diffuse and in theBP180 cell results in increase in expression of some genes including membranetoward basolateral [45]. surface of keratinocytes; However BP230 did matrix-effects onmetallopeptidase hESCs it has been9, keratinocyte clarified thatgrowth-factor-receptor, mechanical stress In a previous research keratinocytes of benign atrophic junctional epidermolysis bullosa which have had normal bothconnexin43, cell line types catenin mentioned β1, endothelin1, above. hESCs integrin derived α6, keratinocytes desmoglein1, expressinterleukin matrix-metallopeptidase α1, E-cadherin, keratin1, gene 6, and earlier 10 and in laminin comparison α5 in ofintegrin viral vector beta 4(simian and plectin virus 40 genes (SV40)); but resulted mutant BPin expression 230 AND to HaCaT stem cells in response to mechanical stress. So hESCs BP180, transfected by recombinant cDNA of BP180 by means response characteristics are more resemble to that of normal at basolateral surface of the cell membrane in hemi desmosome human skin and so they are more suitable for stem cell assisted of BP180 and its orientation and placing beside integrin beta 4 treatment of skin diseases [75]. surfaces of keratinocytes, aggregated at hemi desmosome structures. Furthermore BP230 subunits oriented in basal investigated the intrahepatic injection of cord blood derived stem In 2015 an experimental study on mice models of RDEB structuresStem cell [68]. transplantation and tissue engineering cells; resulted in improvement of disease phenotypes [76] Stem cells give rise to any other types of cells in the body. Stem Placenta (Placenta derived stem cells (PDSCs)) and fetus cord cells play major roles in repair of different organs; as an example (cord blood derived stem cells) are sources for obtaining stem they take part in gastrointestinal tract lining epithelium renewal cells in cellular treatment of RDEB. Because of homogeneity of

Volume 2 • Issue 4 • 025 www.scientonline.org Open Access J Public Health Citation: Maliheh Nobakht, Mohammad Hossein Abbasi (2019). Epidermolysis Bullosa, Challenges and Novel Therapies Page 6 of 9 stem cells antigens and recipient antigens, immune reactions are this procedure, patients’ stem cells obtain by biopsy from skin not expected. Researchers used these stem cells for treatment or from peripheral blood. Transfection of stem cells by viral of RDEB in col7a1 gene knocked- out mice. Results showed vectors to replace defected col 7a1 gene is the next step in the increased junction between dermis and epidermis at dermoepidermal junction (DEJ) [77]. will transplant back to the skin in order to compensate absence treatment. Finally transfected and genetically modified stem cells Stem cell cultures containing normal keratinocytes are applicable to wounds of patients with junctional epidermolysis of collagenThe latest 7 in skin,treatment leading mentioned to improve inas clinicalthe combination features [87]. of tissue engineering and gene therapy is also effective in patients with simplex epidermolysis bullosa to restore skin integrity by bullosaTransplantation to compensate of bonethe skin marrow defects from [78]. human to mice through injection into venous blood (in a mice with epidermolysis bullosa and defect in collagen 17) resulted in compensation of collagen correction of genetic mutations in keratinocytes [88]. 17 defect in hemi-desmosome structures and improvement in of allogeneic cord blood derived platelet gel obtained from a + cells have term,In healthy a previous neonate study used in 2018to repair at university the mechanobullous of Milan, usage skin the potential to replace keratinocytes in the skin of patients ulcerations in patients with epidermolysis bullosa, resulted in clinicalsuffering outcomes. from epidermolysis It has been bullosa clarified [79]. also that CD34 promising clinical outcomes

Researchers also applied gene therapy over iPSCs to [89]. replace defect of collagen 7 gene in patients with RDEB. First, vivo, gene corrected, epidermal sheets obtained from a patient pluripotential stem cells obtained from patients with RDEB, withAn junctional Italian research epidermolysis group in bullosa 2006 successfullyand utilized generated it as a skin ex then those cells transfected by type 7 collagen gene (col 7a1) graft in vitro and then genetically manipulated ( corrected) stem Discussionsresulted in improvement of clinical features [23]. (HCL) results in replacement of defected cells with normal ones, As mentioned above, in epidermolysis bullosa, the targets of improvingcells expressed the patients’ col 7 [80].Hematopoieticclinical outcomes cell transplantation mutations are consisted of some of hemi desmosome structure Application of decidual stromal cells[81]. (DSC) as allogenic mesenchymal stromal cells (MSCs) are also effective in patients 5 & 14. Resulting from electron microscopy studies, the absence with generalized severe junctional epidermolysis bullosa (or ofsubunits hemi includingdesmosome integrin structures beta 4, plectin,at basolateral BP 180 andmembrane keratins previously called Herlitz JEB). Transient healing of wounds of keratinocytes is more prominent in junctional type of occur after treatment by these stem cells replacing defected skin. epidermolysis bullosa and is the main etiological factor in these Alloimmunization is a side effect of stem cell therapy which can patients [90]. result in clinical conditions like autoimmune cystitis or even graft From the previous studies we conclude that, hemi desmosome versus host disease subunits have reciprocal supportive effects on each other’s spatial placement and up regulation at keratinocytes membrane surfaces Transplantation[82]. of stem cells obtained from bone marrow or peripheral blood also can improve the clinical outcome in to maintain and support the hemi desmosome structure. These

keratins 5&14 on integrin beta 4 and also the reciprocal supportive patients with junctional epidermolysis bullosa [83]. effectinteractions between including integrin the beta moderator 4 and CD151. effect of These BP 180 supportive and intracellular effects of subunits on each other, indicate the mathematical and logical expressionExogenous and inductionso increase of mesenchymalin collagen 7 stemproduction cells byin TGF-βthose relationships in the form of certain ratios between the number cellsand TNF-α and also for increases 48 hours, the resulting tsg-6 expression in 8 – fold (resulting increase inin colwound 7a1 of each subunit at keratinocytes membrane surfaces and them healing acceleration and immunosuppression). Induction of concentrations in tissues resulting in arrangement of subunits and these cells by SDF-1alpha increases the expression of CXCR4, formation of hemi desmosome structures. stem cells in vivo in order to improve wound healing process in In many previous efforts in order to perform gene therapy destructivetsg-6 and col skin 7a1genes diseases [84].So such as when EB, the it molecularcomes to intermediatesapplication of for these mutant genes of hemi desmosome subunits in and induction factors should be considered in order to accelerate epidermolysis bullosa patients, researchers have not considered the process of cellular differentiation and wound healing. the previous mentioned point, and gene therapies have cared about just one of the subunits, however others are disturbed too and a single gene therapy, while the other genes are mutant stem cells of skin. This treatment in patients with dystrophic and them absence down regulates our target gene, would not be epidermolysisSubcutaneous bullosa daily results injection in decreaseof G-CSF stimulatesof lesion size and and recruits skin

sufficientAnother for criticism treatment. against those studies which spend to gene blisteringEpithelial [85]. stem cells (epiSCs) can also arrange in cultured therapy for treatment of EB is about the type of vectors we use. epithelial cell sheets (CES). CES has the potential to compensate Most of the researchers use viral vectors for gene therapy while skin defects by transplantation of cultured cell sheets over the they’re not appropriate for application in human species. One of lesion area in patients with epidermolysis bullosa the non-viral vectors suggested for gene therapy is HPAE (highly Combination of tissue engineering techniques[86]. and gene therapy by viral vectors have been also suggested as a treatment topical or subdermal usage on the skin of patients affected by branched poly (β-amino ester)) which is viable and suitable for option for dystrophic type of epidermolysis bullosa. During epidermolysis bullosa.

Tissue engineering techniques such as stem cell 10. Khaniani MS, Sohrabi N, Derakhshan N.M, Derakhshan S.M. One Novel transplantation are also among treatment options. Stem cells Frameshift Mutation on Exon 64 of COL7A1 Gene in an Iranian Individual Suffering Recessive Dystrophic Epidermolysis Bullosa. Ann Clin Lab Sci. can obtain from bone marrow, peripheral blood, umbilical cord, 2015;45(5):582-584. Placenta and etc. transplanted stem cells from a healthy individual 11. Weber F, Bauer J.W, Sepp N, et al. Squamous cell carcinoma in junctional regenerate skin tissue and accelerate healing of skin lesions. and dystrophic epidermolysis bullosa. Acta Derm Venereol. 2001;81(3):189- The combination of stem cell transplantation and gene therapy 192. consists of in vivo correction of the mutation and defected gene of 12. Nyström A, Bruckner-Tuderman L. Injury-and inflammation-driven skin EB patient stem cells. Then transfected stem cell transplants back fibrosis: The paradigm of epidermolysis bullosa.Matrix Biol. 2018;68-69:547- to the skin to regenerate skin tissue. 560. 13. Almeida J.r .H.L, Heckler G.T, Fong K, Lai-Cheong J, McGrath J. Sporadic Conclusion Kindler Syndrome with a novel mutation. An Bras Dermatol. 2013;88(6):212- Tissue engineering and gene therapy together are novel 215. suggested treatment options for EB patients, but there is some 14. Lai-Cheong J.E, Parsons M, Tanaka A, et al. Loss-of-function FERMT1 obstacles to obtain a certain treatment by gene therapy over mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation. Am J Pathol. 2009;175(4):1431-1441. stem cells in EB. Application of viral vectors in human species are among restrictions of gene therapy due to ethical issues in EB 15. Mizutani H, Masuda K, Nakamura N, Takenaka H, Tsuruta D, Katoh N. patients because of risk of spread of and infection by viruses and Cutaneous and laryngeal squamous cell carcinoma in mixed epidermolysis bullosa, kindler syndrome. Case Rep Dermatol. 2012;4(2):133-138. or unknown complications. Usage of non-viral vectors leading to higher applicability of gene therapy in EB patients. Author 16. Saunderson R.B, Vekic D.A, Mallitt K, Mahon C, Robertson S.J, Wargon O. A retrospective cohort study evaluating the accuracy of clinical diagnosis suggests from previous researches that there is a proportional compared with immunofluorescence and electron microscopy in children with and mathematical relation between number of each different inherited epidermolysis bullosa. Br J Dermatol. 2019;180(5):1258-1259. subunits of hemi desmosome in its structure, which has been 17. Koga H, Prost-Squarcioni C, Iwata H, Jonkman M.F, Ludwig R.J, Bieber K. neglected in previous gene therapy researches and those Epidermolysis Bullosa Acquisita: The 2019 Update. Front Med (Lausanne). proportions should be considered in gene therapy researches. In 2018;10(5):362. vitro gene therapy of stem cell keratinocytes and transplant them 18. Kirtschig G, Wojnarowska F. Autoimmune blistering diseases: an up‐date back to the skin is expected to improve the clinical features in EB of diagnostic methods and investigations. Clin Exp Dermatol. 1994;19(2):97- patients. 112. 19. Yenamandra V.K, Bhari N, Ray S.B, et al. Diagnosis of inherited epidermolysis Conflicts of Interest bullosa in resource-limited settings: immunohistochemistry revisited. Dermatology. 2017;233(4):326-332.

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