Can Type VII Collagen Injections Cure Dystrophic Epidermolysis Bullosa?

I ntensive international efforts are being made to devise new molecular therapies for genetic skin diseases. 1 There are three major reasons for these efforts. First, the skin is the largest organ in the human body, with an area of almost 2 m 2 and a weight of 2-3 kg. Therefore, diseases of the skin have a severe negative impact on the daily functions and quality of life of affected individuals. Second, a large number of individuals worldwide are affected by at least one of the nearly 400 known genodermatoses. Third, the skin is an ideal organ with which to study new therapeutic approaches, because it is easily accessible both for treatment and for macroscopic, microscopic, cell ular, and molecular analyses. Its advantages have already been proven in practice by the first pilot study on treatment of human junctional epidermolysis bullosa with keratinocyte gene therapy. 2 In this issue of Molecular Therapy, Remington et al. 3 report on an interesting approach to treating dystrophic epidermolysis bullosa (DEB) in a mouse model using protein therapy. DEB is a genetic skin disorder that manifests with mechanically induced skin blistering and scarring of varying clinical severity. All individuals with DEB are confronted with lifelong skin fragility and impaired resistance of the skin and mucous membranes to external shearing forces, a situation that can lead to secondary symptoms including joint contractures, mutilating deformities of hands and feet, malnutrition, anemia, and growth retardation. 6 Thus far, nearly 500 COL7A1 mutations have been reported, and homozygous, heterozygous, and compound heterozygous mutation constellations generate a broad spectrum of phenotypes. Remington et al. treated severely affected Col7a1 null mice with repeated intra dermal injections of recombinant full-length human type VII collagen (type VII procollagen). The authors report that the injected collagen was incorporated into the dermal-epidermal junction in the Col7a1 null mouse skin but also diffused into distant sites and persisted in the skin for about 2 months. Restoration of this collagen at the epidermal basement membrane significantly improved the phenotype of experimental DEB, as shown by decreased skin blistering and prolonged survival of the animals. Remarkably, the treatment of the DEB mice with heterologous type VII collagen induced development of antibodies to this antigen, but these neither bound to the dermal-epidermal basement membrane nor prevented the formation of anchoring fibrils. Moreover, this specific antibody response could be inhibited pharmacologically by treatment with a monoclonal antibody to CD40L. The findings of this study are intriguing in that they show that injections into the skin of a monomeric type VII collagen-a component of highly specific supramolecular polymers, the anchoring fibrils-can result in phenotypic improvement, and they suggest that intradermal injections of recombinant type VII collagen could represent a straightforward treatment rationale for human DEB. At the same time, the results raise several new interesting questions, a few of which are discussed below. The first is how the injected recombinant type VII procollagen matures to collagen and polymerizes into functional anchoring fibrils. Type VII collagen is the largest member of the collagen superfamily. 11 Under physiological conditions, it is synthesized by keratinocytes and fibroblasts as a procollagen polypeptide of about 300 kDa, which first forms a triple-helical trimer of 900 kDa and then undergoes a complex supramolecular aggregation process. During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner, the C-propeptides are removed by bone morphogenetic protein 1 (ref. 12), and the processed antiparallel dimers then laterally aggregate into anchoring fibrils 13 It will be interesting to learn whether the injected human type VII procollagen is processed in this manner in mouse skin or whether other, hitherto-unknown molecular and/or cellular mechanisms contribute to its effects as dermal-epidermal glue and to increased epidermal adherence in Col7a1 null mice receiving type VII collagen injections