Intravenously Administered Recombinant Human Type VII Collagen Derived from Chinese Hamster Ovary Cells Reverses the Disease Phenotype in Recessive Dystrophic Epidermolysis Bullosa Mice.

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disorder characterized by skin fragility, blistering, and multiple skin wounds with no currently approved or consistently effective treatment. It is due to mutations in the gene encoding type VII collagen (C7). Using recombinant human C7 (rhC7) purified from human dermal fibroblasts (FB-rhC7), we showed previously that intravenously injected rhC7 distributed to engrafted RDEB skin, incorporated into its dermal-epidermal junction (DEJ), and reversed the RDEB disease phenotype. Human dermal fibroblasts, however, are not used for commercial production of therapeutic proteins. Therefore, we generated rhC7 from Chinese hamster ovary (CHO) cells. The CHO-derived recombinant type VII collagen (CHO-rhC7), similar to FB-rhC7, was secreted as a correctly folded, disulfide-bonded, helical trimer resistant to protease degradation. CHO-rhC7 bound to fibronectin and promoted human keratinocyte migration in vitro. A single dose of CHO-rhC7, administered intravenously into new-born C7-null RDEB mice, incorporated into the DEJ of multiple skin sites, tongue and esophagus, restored anchoring fibrils, improved dermal-epidermal adherence, and increased the animals' life span. Furthermore, no circulating or tissue-bound anti-C7 antibodies were observed in the mice. These data demonstrate the efficacy of CHO-rhC7 in a preclinical murine model of RDEB.

• Authors: Yingping Hou, Lin T Guey, Timothy Wu, Robert Gao, Jon Cogan, Xinyi Wang, Elizabeth Hong, Weihuang Vivian Ning, Douglas Keene, Nan Liu, Yan Huang, Craig Kaftan, Bruce Tangarone, Igor Quinones-Garcia, Jouni Uitto, Omar L Francone, David T Woodley, Mei Chen
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 135 Issue 12 Pg. 3060-3067 (Dec 2015) ISSN: 1523-1747 [Electronic] United States
• PMID: 26203639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type VII
• Recombinant Proteins

Topics

• Animals
• Animals, Newborn
• CHO Cells
• Cell Movement (drug effects)
• Cells, Cultured
• Collagen Type VII (administration & dosage, chemistry, immunology, therapeutic use)
• Cricetulus
• Epidermolysis Bullosa Dystrophica (drug therapy)
• Humans
• Injections, Intravenous
• Phenotype
• Recombinant Proteins (therapeutic use)