Gene Therapy for Skin Diseases

Gorell, Emily S.; Ngôn, Nguyễn Chí; Lane, Alfred T.; Siprashvili, Zurab

doi:10.1101/cshperspect.a015149

Cited by 50 publications

(45 citation statements)

References 110 publications

(106 reference statements)

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“…Systemic retinoids have variable efficacy and multiple potential side effects (DiGiovanna and Robinson-Bostom, 2003). Experimental gene therapies are early in preclinical development (Gorell et al, 2014). Although cutaneous and systemic immune inflammation has been successfully targeted in atopic dermatitis (AD) and psoriasis (Czarnowicki et al, 2015c;Guttman-Yassky et al, 2017), little attention has been paid to targeting inflammation in ichthyosis.…”

Section: Introductionmentioning

confidence: 99%

The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood

Czarnowicki

Leonard

et al. 2018

Journal of Investigative Dermatology

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The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4/CD8 and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4/CD8 T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, transepidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P < 0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17- (P < 0.05) and IL-22-producing (P < 0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P < 0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P < 0.05) and similar IFN-γ frequencies (P > 0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-γ clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.

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Section: Introductionmentioning

confidence: 99%

The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood

Czarnowicki

Leonard

et al. 2018

Journal of Investigative Dermatology

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“…Die enormen Kosten, die mit einer Genersatztherapie einhergehen [8], bzw. die theoretischen Gefahren, die von den viralen Vektoren ausgehen, die für die Geneinbringung verwendet werden [9], begünstigen aber die Entwicklung kostengünstigerer bzw.…”

Section: Hindernisse Auf Dem Weg Zum Therapieerfolgunclassified

Ex-vivo-Stammzellgentherapie an der Haut

Koller¹

2020

Hautarzt

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Ex-vivo-Stammzellgentherapie an der Haut Reif für klinische Anwendungen? Die Haut stellt aufgrund ihrer Zugänglichkeit ein ideales Zielorgan für eine gentherapeutische Anwendung dar. Aktuelle klinische Studien bzw. präklinische Ansätze basieren auf einer Ex-vivo-Behandlung am Patienten. Bei einer Ex-vivo-Gentherapie werden Hautstammzellen aus dem Patienten gewonnen, mittels gentherapeutischer Verfahren unter Zellkulturbedingungen korrigiert und danach auf den Patienten zurücktransplantiert. Die Zellkorrektur kann durch eine im Zuge einer Genersatztherapie durchgeführten Geneinbringung oder durch eine gezielte Genmodifikation mittels Designer-Nukleasen erfolgen. Eine Gentherapie stellt die einzige Möglichkeit dar, die genetische Ursache einer Erkrankung zu beheben. Dabei kann die Genkorrektur in vivo oder ex vivo, also innerhalb oder außerhalb des Körpers erfolgen, wobei eine Ex-vivo-Behandlung mit weniger Risiken verbunden ist. Über eine einfache Hautbiopsie können Hautstammzellen vom Patienten entnommen, im Labor korrigiert und wieder im Gegensatz zu anderen Organen am Patienten zurücktransplantiert werden (. Abb. 1). Dies ermöglicht eine Sicherheitsanalyse der genetisch korrigierten Zellen, ehe diese am Patienten appliziert werden. Ihre ersten Anwendungen fand die Ex-vivo-Gentherapie in der blasenbildenden Hauterkrankung Epidermolysis bullosa (EB) [2, 11, 17].

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“…Owing to the great potential of gene delivery via skin, a broad range of approaches including biological, chemical, and physical approaches have been developed for different applications. In biological approaches, various viral vectors such as adenovirus serotype 5, and human immunodeficiency virus-1-based lentivirus were employed for gene therapy in skin [20][21][22].…”

Section: Approaches To Facilitate Gene Delivery Via Skin For a Range mentioning

confidence: 99%

Current and future technological advances in transdermal gene delivery

Chen

2018

Advanced Drug Delivery Reviews

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Transdermal gene delivery holds significant advantages as it is able to minimize the problems of systemic administration such as enzymatic degradation, systemic toxicity, and poor delivery to target tissues. This technology has the potential to transform the treatment and prevention of a range of diseases. However, the skin poses a great barrier for gene delivery because of the "bricks-and-mortar" structure of the stratum corneum and the tight junctions between keratinocytes in the epidermis. This review systematically summarizes the typical physical and chemical approaches to overcome these barriers and facilitate gene delivery via skin for applications in vaccination, wound healing, skin cancers and skin diseases. Next, the advantages and disadvantages of different approaches are discussed and the insights for future development are provided.

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Gene Therapy for Skin Diseases

Cited by 50 publications

References 110 publications

The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood

The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood

Ex-vivo-Stammzellgentherapie an der Haut

Current and future technological advances in transdermal gene delivery

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