What is Epidermolysis Bullosa (EB)

Epidermolysis Bullosa (EB) is a rare genetic connective tissue disorder that causes painful blistering of the skin and the mucous membranes. It affects one in every 50,000 live births and can often times be fatal within the first year.

The human skin consists of two layers: an outermost layer called the epidermis and a layer underneath called the dermis. In individuals with healthy skin, there are protein anchors between these two layers that prevent them from moving independently from one another (shearing). In people born with EB, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin—even minor mechanical friction (like rubbing or pressure) or trauma will separate the layers of the skin and form blisters and painful sores. Sufferers of EB have compared the sores with third-degree burns.  Not all of these appear on the skin; the lining of the esophagus, stomach, throat and bladder can also form blisters, leading to further health risks. Furthermore, as a complication of the chronic skin damage, people suffering from EB have an increased risk of malignancies (cancers) of the skin.

There are three types of inherited epidermolysis bullosa, and a fourth extremely rare disorder that people may acquire later in life.

  1. Simplex– EB simplex is the most common form of the disorder. In this type, the genes that oversee the production of keratin — a protein that provides structure and toughness to skin — don’t signal enough to be produced. Keratin is also vital in the formation of other parts of the body, like fingernails and tooth enamel. As a result of low keratin production, people with EB simplex often have problems with their teeth and disfigured fingernails and toenails, as well as hair loss from fine and thinning hair.
  2. Junctional– In Junctional EB, the gene mutation leads to the underproduction of proteins that produce fibers called hemidesmosomes. Hemidesmosomes anchor the epidermis to the basement layer.
  3. Dystrophic– Recessive Dystrophic EB (RDEB) is one of the most severe forms of EB, which is characterized by the absence of Collagen VII, which is one of the proteins that keep the layers of skin together. Severe cases of this condition involve widespread blistering externally and internally, disfigurement (fusion of the fingers and toes from scarring; joint deformity) from repeated scarring and other serious medical problems (e.g., severe infections, skin cancer). RDEB affects less than 1 per million newborns.
  4. Acquisita– This form of EB usually appears after age 50 and is an autoimmune disorder, where the body’s immune system mistakes skin cells and structural fibers for foreign bodies and attacks them.
Traditional Treatment

By definition, inherited EB is a genetically transmitted disorder characterized by marked fragility of the skin. Any trauma, no matter how minimal it may seem, is likely to cause the skin of an EB child or adult to tear or blister. The following are recommended ways to avoid or minimize this problem:

  1. Reducing friction: Extreme care should be employed in handling the skin of any patient with EB.
  2. Non-adhesive bandages and dressings: Adhesive or semi-adhesive dressings, bandages, Band-aids, or tape should not be used on the surface of the skin. Instead, wounds should be covered with an appropriate non-adhesive dressing and then further wrapped loosely with rolled gauze. This can be secured by using a tubular dressing retainer.
  3. Keeping the skin cool: Nothing hot should ever be applied to the skin of a patient with EB. In particular, bath water should be no warmer than body temperature. Patients should avoid prolonged exposure to ambient heat and humidity. If possible, air conditioned environments should be sought whenever possible.
  4. Managing blisters: Because blisters in EB are not self-limiting, and can fill with fluid and grow quite large, they need to be drained.
  5. Clothing: In younger children, diapers may require additional padding at the legs and waist. Whenever possible, loose-fitting garments should be worn. If blisters develop from the seams of clothing, garments may be worn inside-out and tags, cuffs and necklines may be removed. Loosely-fitted, padded shoes are generally better tolerated.
  6. Nutritional deficiencies: Many children with EB become anemic due to a chronic loss of blood through wounds, poor nutritional intake, poor absorption of iron and bone marrow suppression from chronic inflammation. It is important to work with a nutritionist experienced in the care of special needs patients. Treatment for iron deficiency anemia is often necessary. Other patients have selenium and carnitine or vitamin D deficiencies which may predispose them to cardiomyopathy and osteoporosis. Many patients develop failure to thrive and require feeding gastrostomies.
  7. Monitoring for cancer: Squamous cell carcinoma is the leading cause of death in EB usually occurring after the 2nd decade of life. Patients with RDEB and JEB are at increased risk of developing skin cancers during their lifetimes. It is very important that all EB patients have at least yearly examination of all skin areas.
Experimental Treatments
There are several research teams around the globe working to come up with new solutions for individuals with EB.  Here are a few of the different ways they are looking to develop successful therapies that simultaneously alleviate the plethora of complications from this disorder while having a significant impact on survival and quality of life.
1.  Cellular Therapies:  Cell therapies involve injecting genetically correct cells from a donor, or the patients’ own stem cells after genetic correction, back into the body. Cell therapies can be delivered locally or systemically.
– Local Cell Therapies:  Cells are injected into a limited area to improve wound healing, reduce blistering, and strengthen the skin.
– Systemic Cell Therapies: Systemic therapies are designed to address complications throughout the body. This is important in disorders like EB where complications may be internal (e.g., esophagus or cornea) or external (e.g., skin)
– Bone Marrow Stem Cells: Bone marrow transplant therapy is a type of stem-cell therapy, in that it provides the treated patient with a new supply of genetically correct stem cells from the bone marrow of a healthy donor. The faulty cells in the bone marrow of the patient must first be destroyed by chemotherapy: cells from the donated bone marrow then replace the faulty cells in the bone marrow of the patient and eventually are able to produce healthy new cells of various body tissues.
– Mesenchymal Stem Cells: Bone marrow has long been known to produce stem cells, including MSC, that can help to repair body tissues, hence the use of bone-marrow transplants in medicine. MSC are already being used to supplement bone-marrow transplants for severe EB. MSC are a type of stem cell that can differentiate into cell types in a wide variety of tissues, including bone, fat and skin. When transplanted by injection into the bloodstream, MSC migrate to the site of injury. This has been shown in animal models for EB and underpins the hope that they will be useful to develop cures for EB. Anecdotal reports of MSC use to treat individual EB patients by injection of MSC, both local (into skin around wounds) and systemic (in the bloodstream to treat the whole body), report some benefits and limited side effects. An understanding of the natural biological role of MSC in body repair also indicates that they are good candidates for EB cell therapy.
– Induced Pluripotent Stem Cells: These are cells which resemble but are not the same as embryonic stem cells in that they are capable of developing into most types of body tissue.  iPSCs are produced in the laboratory from adult tissue cells (e.g. skin cells) by reversing the process by which they originally developed from embryonic stem cells. iPSCs can be produced using any of several different techniques which are still being refined to improve the safety and therapeutic usefulness of iPSCs. The advantage of iPSCs is that a new supply of stem cells for therapeutic purposes can be developed from a patient’s own tissue, so avoiding any of the problems of transplantation from a donor.
2. Gene Therapy: Gene therapy aims to correct the genetic defect by grafting sheets of cells containing the corrected gene. It is important to get the genes into skin stem cells, the cells with the ability to reproduce indefinitely. A major challenge in gene therapy is whole-body delivery of the therapeutic gene: large-scale grafting and internal sites are a problem
3. Protein Therapy: Protein therapies involve injecting whichever protein is deficient into the patient. The human protein is made in the laboratory, synthesized from the human gene which has been cloned. Early work injecting collagen protein directly into wounds shows good wound healing. Although protein therapies offer only temporary treatment, and patients will require repeat treatments for life, they offer the possibility of a likely relatively safe treatment that improves wound healing.
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