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Mesenchymal Stromal Cell Therapy for Recessive Dystrophic EB (RDEB)

Completed
Project lead Prof Leena Bruckner-Tuderman, Rupert Handgretinger
Organisation University of Freiburg Medical Center
Project budget EUR 205,000.00
Start date / Duration 01. Jan 2013 / 36 months
Funder(s) / Co-Funder(s) DEBRA Austria, MSAP/EBEP Recommended
Research area Cellular therapy

Project details

Short lay summary

Dystrophic epidermolysis bullosa (DEB) is caused by loss of function of collagen VII (C7), an adhesive protein which firmly attaches the outermost skin layer, the epidermis, with the underlying layer, the dermis. C7 is pivotal for the barrier function of the skin and its ability to resist mechanical stress. Currently, no cure exists for DEB, and the treatments are symptomatic.

This project deals with mesenchymal stromal cells (MSC) and their therapeutic potential to improve DEB and alleviate symptoms. MSC can be isolated from a number of sources such as bone marrow, umbilical cord blood, or adipose tissue, and they have been successfully used to treat other human diseases, which have certain biological similarities to C7 and DEB. MSC have stem cell-like properties, and the hypothesis is that they can develop into C7 producing cells when they come into contact with the dermis.

Scientific summary

The goal of this project is to test intradermally injected MSC as a form of cell therapy to improve DEB. For this, we combine expertise in pediatric hematology / MSC-isolation and in DEB research. In the first step, MSC were isolated from nine individual healthy donors and expanded under optimized culture conditions. Laboratory analyses showed two very positive things: 1) the MSC produce as much C7 as normal skin cells; 2) variation between individual healthy donors is low. The next step was to treat a DEB-mouse with the human MSC. This mouse has very little own C7 and shows all the signs and symptoms of DEB. Again here, significant results were obtained. Localized injection of human MSC into the skin of these mice led to: 1) clearly increased C7 content in the appropriate location along the dermal-epidermal junction; 2) increased C7 content at borders of healing wounds; 3) the collagen was derived from the injected therapeutic MSC, not other skin cells which may produce mutated, less functional C7; 4) importantly, the mice showed no adverse effects of the treatment. Taken together, our studies have so far indicated that locally injected stem cell-like MSC are safe and efficient in increasing C7 content in the skin. Based on this, improved skin integrity and enhanced wound healing can be expected. Thus, MSC, if present in sufficient numbers, may represent an efficacious cell-based therapy for DEB, especially for DEB-related wounds. Further studies must determine if systemic administration of MSC can provide sufficiently high cell numbers in the skin and thus render large body surfaces amenable to treatment.

What did this project achieve?

The goal of this project was to test intravenously and intradermally injected MSC as a form of cell therapy to improve RDEB. For this, we combined expertise in pediatric hematology / MSC-isolation and in RDEB research. In the first step, MSC were isolated from nine healthy donors and expanded under optimized culture conditions. Laboratory analyses showed two very positive things: 1) the MSC produce as much C7 as normal skin cells; 2) variation between individual healthy donors is low. The next step was to test treatment with human MSCs in a RDEB mouse model. This mouse has very little own C7 and shows all the signs and symptoms of RDEB. Again here, significant results were obtained. Intravenous injections of human MSC did not result in MSC migrating into the skin of increase of C7. Therefore, in the further investigation we concentrated on localized injections of human MSC into the skin of these mice. These showed efficacy and led to: 1) clearly increased C7 content in the appropriate location along the dermal-epidermal junction; 2) increased C7 at borders of healing wounds; 3) the collagen was derived from the injected therapeutic MSC, not other skin cells which may produce mutated, less functional C7; 4) improved skin integrity mediated through newly formed immature but functional anchoring fibrils; 5) no adverse effects of the treatment. Taken together, our studies indicate that locally injected MSC are safe and efficient in increasing C7 content in the skin, improved skin integrity and enhanced wound healing. Thus, MSC, if present in sufficient numbers, seem to represent an efficacious cell-based topical therapy option for RDEB, especially for RDEB-related wounds. Further studies must determine if intravenous administration of MSC can be developed further and modified to provide sufficiently high cell numbers in the skin and thus render large body surfaces amenable to systemic treatment.


Keywords

Bruckner-Tuderman
Freiburg
RDEB
Mesenchymal Stromal Cell
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