Potential of Fibroblast Cell Therapy for Recessive Dystrophic Epidermolysis Bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin-blistering disorder caused by mutations in the COL7A1 gene that lead to reduced type-VII collagen and defective anchoring fibrils at the dermal-epidermal junction (DEJ). Presently there are no effective treatments for this disorder. Recent mouse studies have shown that intradermal injections of normal human fibroblasts can generate new human type-VII collagen and anchoring fibrils at the DEJ. To assess potential clinical benefits in humans, we gave single intradermal injections of allogeneic fibroblasts to five subjects with RDEB. We noted increased type-VII collagen at the DEJ at 2 weeks and at 3 months following injection and increased anchoring fibrils, although none of these had normal morphology. No adverse effects, clinical or immunopathologic, were noted. We believe the major effect of allogeneic fibroblasts is to increase the recipients' own COL7A1 mRNA levels with greater deposition of mutant type-VII collagen at the DEJ and formation of additional rudimentary anchoring fibrils. Nevertheless, this mutant protein may be partially functional and capable of increasing adhesion at the DEJ. This is the first study demonstrating that intradermal injections of allogeneic fibroblasts have therapeutic potential in human subjects with RDEB.

Long-Term Type VII Collagen Restoration to Human Epidermolysis Bullosa Skin Tissue

“…These studies have used direct gene (Woodley et al, 2004b) and protein (Woodley et al, 2004a;Remington et al, 2009) transfer as well as cell-based therapies using epidermal keratinocytes (Chen et al, 2002;Ortiz-Urda et al, 2002;Gache et al, 2004), dermal fibroblasts (Ortiz-Urda et al, 2003;Woodley et al, 2003;Kern et al, 2009), or even stem cells from bone marrow transplantation (Tolar et al, 2009). Although fibroblast-and protein-based therapies display attractive features, the short half-life of fibroblasts delivered to the dermis, as well as challenges in incorporating normal human type VII collagen into BMZ in clinical settings (Wong et al, 2008), supports the search for improved methods of administration in patients. At present, only ex vivo retroviral delivery to autologous keratinocytes followed by skin grafting has thus far led to successful correction of the JEB subtype in the clinical setting (Mavilio et al, 2006).…”

Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa

“…Recently, several molecular therapies are being investigated for the treatment of patients with different subtypes of EB, including ex vivo gene therapy, 1 protein replacement 2 and cellular therapy. [3][4][5][6][7] Herlitz junctional epidermolysis bullosa (HJEB) is one of the most severe variants of EB characterized by extensive mucocutaneous blistering and erosions at birth leading to early lethality. 8,9 HJEB, an autosomal recessive disease, is caused by mutations in any of the genes encoding the subunit polypeptides laminin-a3, laminin-b3 or laminin-w2 of the heterotrimeric laminin-332 protein.…”

Dystrophic epidermolysis bullosa associated with congenital contractures of the upper and lower limbs: literature review

“…Хирургическое лечение применяется для кор-рекции вторичных деформаций (псевдосиндакти-лий), контрактур верхних и нижних конечностей, для закрытия обширных кожных дефектов, в том числе с использованием «гибридных» кожных трансплантатов, содержащих кератиноциты паци-ента и донорские фибробласты [9,15]. В настоя-щее время активно развивается генная терапия БЭ, за которой будущее лечения этой сложной категории больных.…”

“…Согласно этим данным подкожное вве-дение фибробластов приводит к появлению новых отложений коллагена VII типа и полной регенера-ции слоев, ранее пострадавших [15][16][17].…”