Intravenously Injected Recombinant Human Type VII Collagen Homes to Skin Wounds and Restores Skin Integrity of Dystrophic Epidermolysis Bullosa

Woodley, David T.; Wang, Xinyi; Amir, Mahsa; Hwang, Brian H.; Remington, Jennifer; Hou, Yingpin; Uitto, Jouni; Keene, Douglas R.; Chen, Mei

doi:10.1038/jid.2013.10

Cited by 95 publications

(81 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous work has shown that part of i.v. injected collagen VII can reach wounded skin and be deposited in the dermal-epidermal junction zone (39). We reasoned that i.p.…”

Section: The Lymphoid Collagen Vii-cochlin Axis Maintains Bacterial Cmentioning

confidence: 99%

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.collagen VII | innate immunity | bacteria | recessive dystrophic epidermolysis bullosa | cochlin

show abstract

“…Previous work has shown that part of i.v. injected collagen VII can reach wounded skin and be deposited in the dermal-epidermal junction zone (39). We reasoned that i.p.…”

Section: The Lymphoid Collagen Vii-cochlin Axis Maintains Bacterial Cmentioning

confidence: 99%

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Unfortunately, there are no cures or even effective treatments for RDEB. Various therapeutic strategies have been envisioned for RDEB, including recombinant type VII collagen-based protein therapy (6)(7)(8)(9)(10), bone marrow stem cells, or allogeneic dermal fibroblast-based cell therapy and transplantation of gene-corrected keratinocyte autografts (11)(12)(13)(14)(15)(16)(17). However, none of these therapies are consistently effective, and some have associated morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Woodley¹,

Cogan²,

Hou³

et al. 2017

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

BACKGROUND.Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients. METHODS.A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions. RESULTS.Both topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti-type VII collagen autoantibodies in patients' blood or skin.CONCLUSION. Topical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations. TRIAL REGISTRATION. ClinicalTrials.gov NCT02698735.

show abstract

“…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].…”

Section: лечениеunclassified

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

Agranovich

Евгеньевна²,

Buklaev

et al. 2015

Pediatr Traum Orthop Reconstr Surg

View full text Add to dashboard Cite

Буллезный эпидермолиз (БЭ)-это редкое наследственное заболевание, его главный признак -образование пузырей и мокнущих ран (эрозий) на коже и слизистых оболочках, возникающих при незначительном травмировании. Клинические проявления заболевания могут варьировать от локализованных пузырей на руках и стопах до генерализованных высыпаний по всему кожному покрову, а также с поражением слизистой оболочки внутренних органов. В настоящее время выделено четыре основные группы БЭ: простой, промежуточный, дистрофический и синдром Киндлера. Мутации вызывают изменения в структуре белков, ответственных за адгезию между слоями дермы, что и приводит к образованию везикул. Лечение БЭ представляет собой сложную задачу вследствие отсутствия возможности прямого воздействия на патогенез заболевания, и его основной целью является купирование существующих кожных проявлений и предотвращение появления новых элементов. В статье приводится описание основных типов БЭ, видов современной диагностики и лечения заболевания, а также представлен клинический случай редкого сочетания двух тяжелых патологий -дистрофического буллезного эпидермолиза и артрогрипоза с поражением верхних и нижних конечностей.Ключевые слова: буллезный эпидермолиз, артрогрипоз, сгибательные контрактуры конечностей.

show abstract

Intravenously Injected Recombinant Human Type VII Collagen Homes to Skin Wounds and Restores Skin Integrity of Dystrophic Epidermolysis Bullosa

Cited by 95 publications

References 15 publications

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

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

Contact Info

Product

Resources

About