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New skin for Hassan

Born with a rare disease, a little boy is given new skin thanks to gene therapy...

A medical team at the Ruhr-University Bochum, Germany, burn unit and the Center for Regenerative Medicine at the University of Modena, Italy are the first ever to successfully treat a child suffering from extensive skin damage using transplant skin derived from his own genetically modified stem cells.

Hassan is a so-called butterfly child: he suffers from epidermolysis bullosa, a genetic skin disease that had destroyed approximately 80 percent of his epidermis. After all established therapies had failed, the medical team from Bochum decided to try an experimental approach: they transplanted skin derived from his genetically modified stem cells onto his wound surfaces. Thanks to this successful therapy, Hassan is now - two years after the treatment - able to participate in his family's life and his own social life.

The scientists published their report in Nature.

Epidermolysis bullosa is the scientific name of a congenital skin disease that is currently considered to be incurable. Its underlying mechanism is a defect in protein-forming genes that are essential for skin regeneration. Even minor stress can result in blisters, wounds, and skin loss with scarring. Depending on its severity, internal organs can be affected, leading to critical internaldysfunction as well.
The disease significantly reduces a patients' quality of life. Often it is life-threatening, as in Hassan's case. Seven years old, when admitted to the pediatric intensive care unit at Katholisches Klinikum Bochum, Germany in June 2015 — 60 percent of his skin was gone.

"He suffered from severe sepsis with high fever, and his body weight had dropped to a mere 17 kilograms (37.4786 lbs) - a life-threatening condition," explains Dr Tobias Rothoeft, Consultant at the University Children's Hospital at Katholisches Klinikum Bochum. All conservative and surgical therapy approaches had failed.

Due to his desperate prognosis, the Bochum-based team of pediatricians and plastic surgeons, in collaboration with Prof Dr Michele De Luca from the Center for Regenerative Medicine at the University of Modena, Italy, opted for experimental therapy: transplant skin derived from genetically modified epidermal stem cells.
Obtained from Hassan skin biopsy, stem cells were processed in Modena, Italy. Researchers transferred an intact (healthy) gene into them using retroviral vectors. These virus particles were modified and have no ability to harm a patient.

His genetically modified stem cells were cultivated in a clean room and subsequently turned into Hassan's transgenic skin transplants. After obtaining his parents' permission, authorities' approvals, certification of the operating rooms at the Bergmannsheil to be a genetic engineering facility, the transplantation team proceeded.
Eighty percent of Hassan's body surface was transplanted. At the Department of Plastic Surgery at the Bergmannsheil, transplants were applied to Hassan's arms, legs, entire back, flanks, and parts of his stomach, neck and face.

"Overall, 0.94 square meters (approximately 11 feet) of transgenic epidermis were transplanted onto our young patient in order to cover all his defects, accounting for 80 percent of his entire body surface."

Tobias Hirsch MD, Associate Professor, Head Consultant, Department of Plastic Surgery, Burn Centre, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany.

Following his first transplantation in October 2015, Hassan's condition began to improve. The new transgenic stem cells formed an epidermis with intact binding proteins in all of his transplant areas. Integration of the intact gene via retroviral gene transfer into Hassan's epidermal stem cells is successful and continues to be stable.

In February 2016, Hassan was discharged. Today, almost two years after his experimental therapy began, he has high-quality, stress-resistant skin with an intact hydrolipid film layer, the protective slightly acidic film that sits on the surface of our skin and protects us from the environment. He has early hair formation and, happily, no additional scarring has appeared in his transplanted areas. Hassan is attending school again and is actively taking part in his family's social life.

According to the international medical team, Hassan is the first patient worldwide who has been treated with skin transplants from transgenic epidermal stem cells over such a large surface. Because of the large scale of skin transplant, Hassan's case is considered unique worldwide.
"This approach has enormous potential for research into and development of new therapies for the treatment of epidermolysis bullosa as well as other diseases and trauma causing large skin defects."

Tobias Hirsch MD.

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.

Authors: Tobias Hirsch, Tobias Rothoeft, Norbert Teig, Johann W. Bauer, Graziella Pellegrini, Laura De Rosa, Davide Scaglione, Julia Reichelt, Alfred Klausegger, Daniela Kneisz, Oriana Romano, Alessia Secone Seconetti, Roberta Contin, Elena Enzo, Irena Jurman, Sonia Carulli, Frank Jacobsen, Thomas Luecke, Marcus Lehnhardt, Meike Fischer, Maximilian Kueckelhaus, Daniela Quaglino, Michele Morgante, Silvio Bicciato, Sergio Bondanza

The doctors from Bochum who were involved in Hassan's therapy are Associate Professor Dr Tobias Hirsch at the Ruhr-University Bochum, Head Consultant of the Department of Plastic Surgery and Burn Unit at the Bergmannsheil (director: Prof Dr Marcus Lehnhardt); as well as Dr Tobias Rothoeft and Dr Norbert Teig, Consultants at the University Children's Hospital at Katholisches Klinikum Bochum, Germany (director: Prof Dr Thomas Lücke).

This work was funded in part by a James S. McDonnell Scholar Award for Understanding Human Cognition to DA, and an NRSA fellowship (1-F32-MH108278-01) to KT from the National Institutes of Health. A James S. McDonnell Scholar Award and the National Institutes of Health (1-F32-MH108278-01) funded the research.]

The project was also funded by the Italian Ministry of Education, University and Research (MIUR), n. CTN01_00177_888744; Regione Emilia-Romagna, Asse 1 POR-FESR 2007-13; Fondazione Cassa di Risparmio di Modena, Italy; DEBRA Südtirol - Alto Adige; DEBRA Austria; European Research Council (ERC) as part of the Horizon 2020 programme (Grant Agreement no. 670126-DENOVOSTEM) and ERC as part of the seventh framework programme for research(Grant Agreement no. 294780-NOVABREED); Epigenetics Flagship project CNR-MIUR grants.

About the Burn Center at the Ruhr-University Bochum
Since the 1960s, the Department of Plastic Surgery with its burn unit and the University Children's Hospital are jointly treating burn victims of all ages and trauma severity. Therefore, the Burn Center at the Ruhr-University Bochum belongs to one of the oldest burn units in Germany.

A capacity of eight beds at the Bergmannsheil and three beds at the Children's Hospital are available for severely burned patients.

About Bergmannsheil
Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil is one of the largest urgent care clinics for maximum treatment in the Ruhr area. Founded in 1890 as the world's first Accident and Emergency clinic to provide treatment after mining accidents, Bergmannsheil today comprises 23 highly specialised clinics and specialist departments with 707 beds in total under one roof. More than 2,300 members of staff ensure professional care of approximately 89,000 patients per annum.

Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil is part of the BG Kliniken healthcare group. The group incorporates nine urgent care clinics under the German occupational insurance scheme, two clinics for occupational hazards, and two Accident and Emergency centres. With 12,500 members of staff and in excess 550,000 patients, the group is one of the largest clinic associations in Germany. Moreover, Bergmannsheil is part of the Ruhr-University Bochum's university clinic (UK RUB). http://www.bergmannsheil.de, http://www.bg-kliniken.de

About Katholisches Klinikum Bochum, Germany
With 1,400 beds and approximately 4,300 members of staff from 59 countries, Katholisches Klinikum Bochum, Germany (KKB) is one of the largest and most efficient hospital alliances in the Ruhr area. Treatment and care are provided to patients from all across Germany - with more than 50,000 patients per year receiving stationary and more than 166,000 ambulatory treatments. Approximately 400 young professionals are trained on average every year.

Katholisches Klinikum Bochum, Germany is part of the Ruhr-University Bochum's University Hospitals. From obstetrics through pediatrics to geriatrics - patients of all ages are treated at KKB. The largest hospital and headquarters of the corporation is St Josef-Hospital. http://www.klinikum-bochum.de

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Nov 13, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

Hassan had already seen more than his fair share of hardship. A week after he was born in Syria, a blister appeared on his back. His doctors diagnosed the genetic disorder epidermolysis bullosa, which leaves skin extremely fragile and prone to tearing. There was no cure. When Hassan’s family fled Syria and moved to Germany as refugees, the doctors there said the same thing. Meanwhile, the blisters were getting bigger. By the age of 7, Hassan was near death. Image credit: TheNewsFeed.org

Phospholid by Wikipedia