Change the genes to fix the skin

Abstract

I t's not often that a figure in a scientific paper can make you wince with pain. But it's impossible to look at figure 1a in Michele De Luca's 2017 Nature paper and not feel a sympathetic twinge at the sight of a young boy, Hassan, covered from head to toe with red-raw wounds 1. The son of Syrian refugees who fled to Germany, Hassan was born with junctional epidermolysis bullosa (JEB)-a condition caused by a genetic fault in one of three genes (LAMA3, LAMB3 and LAMC2) encoding subunits of the laminin-332 protein, which binds the surface of the skin to the underlying layers. Affected children rapidly develop large, painful blisters over their skin and internal mucous membranes, which can easily become infected. By 2015, when Hassan was seven, his skin was almost entirely destroyed and he was suffering from severe bacterial infections. Doctors at Ruhr University in Bochum, Germany, could offer only palliative care to relieve his suffering. But Hassan's father enquired about experimental treatments, and the doctors got in touch with De Luca at the University of Modena and Reggio Emilia, Italy, who was working on a radical skin therapy. De Luca's research builds on the life-saving work of cell biologist Howard Green at the Massachusetts Institute of Technology in Cambridge. Green was the first to discover that sheets of skin cells could be grown in the laboratory, creating personalized skin grafts that avoid the problems of immune rejection. De Luca worked with Green at Harvard Medical School in Boston, Massachusetts, in the 1980s, and he later decided to develop Green's approach for treating genetic skin conditions by genetically modifying the skin cells to fix the disease-causing mutation. "We've been using epidermal skin-cell cultures for many years to treat hundreds of patients, carrying out a lot of work on basic stem-cell biology as well as gaining DERMATOLOGY Under the skin The largest organ in the body is a prime target for gene therapy.

Gene Delivery to the Skin – How Far Have We Come?

“…So far, genodermatoses cannot be cured, and current treatment options purely rely on the relief of symptoms. A potentially curative strategy is to repair the disease-causing mutations within the host genome using gene editing [ 1 , 8 ]. This, together with the high medical need, makes genodermatoses the prime candidate for cutaneous gene therapy.…”

“…Subsequently, large skin sheets were grown from the transfected keratinocytes, which were ultimately regrafted onto the boy. The transgenic skin grafts replaced 80% of the patient’s skin, and after 21 months, his skin had regained a normal appearance without any detachment from the dermis [ 8 ]. This long-term effect likely resulted from a co-incidental transfection of skin stem cells, which drive the skin regeneration.…”

“…detachment from the dermis [8]. This long-term effect likely resulted from a co-incidental transfection of skin stem cells, which drive the skin regeneration.…”

Engineering inkjet bioprinting processes toward translational therapies

“…Since then a second patient has successfully been operated with similar results (Menasché et al, ). The successful cases keep accumulating with each passing year and in different tissues, with preclinical and clinical studies to heal defects reported in cartilage (Cao, Vacanti, Paige, Upton, & Vacanti, ), tooth (Kawaguchi et al, ), bone (Gjerde et al, ), fat (Yoshimura, Eto, Kato, Doi, & Aoi, ), skin (Arney, ), and pulmonary artery (Shin'oka, Imai, & Ikada, ).…”